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    Diabetes Mellitus Type 1 in Adults

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    Mar.19.2024

    Diabetes Mellitus Type 1 in Adults

    Synopsis

    Key Points

    • Diabetes mellitus type 1 is a chronic metabolic disease characterized by hyperglycemia secondary to destruction of pancreatic beta cells; absolute insulin deficiency and dependence on exogenous insulin to regulate blood glucose levels are hallmarks of the disease
    • Type 1 diabetes accounts for 5% to 10% of all cases of diabetes r1
    • Classic presentation includes signs and symptoms of hyperglycemia (eg, polyuria, polydipsia, polyphagia, unexplained weight loss, weakness, blurred vision), but these do not always occur in adults
    • History and findings on physical examination can suggest diabetes, but biochemical parameters are required for diabetes diagnosis; specific testing for pancreatic islet autoantibodies and C-peptide level can help differentiate diabetes type and confirm a diagnosis of type 1 disease
    • Differential diagnosis for type 1 diabetes most commonly includes type 2 diabetes, diabetes insipidus, monogenic diabetes, and drug-induced diabetes
    • Comprehensive care for patients with type 1 diabetes includes intensive insulin therapy, glucose monitoring, lifestyle management, ongoing diabetes self-management education and support, management of comorbidities and complications, and pancreatic transplant evaluation for selected patients
    • Most patients require intensive insulin therapy using multiple daily insulin injections or continuous subcutaneous insulin infusion via a device, coupled with frequent glucose assessment using multiple daily glucometer checks or continuous glucose monitoring via a device
    • Patients with type 1 diabetes should follow up with a health care professional at least annually; periodic monitoring parameters include assessment of glycemic control, laboratory assessment, and surveillance for complications and comorbidities
    • Complications may be glycemic (eg, hypoglycemia, DKA), microvascular (eg, retinopathy, nephropathy, neuropathy), and/or macrovascular (eg, cardiovascular disease, peripheral vascular disease, cerebrovascular disease)
    • Mortality rate is 2 times higher for patients with type 1 diabetes than for the general population, largely owing to cardiovascular complications r2

    Urgent Action

    • DKA and severe treatment-related hypoglycemia are life-threatening complications and must be treated emergently
      • Treatment of hypoglycemia
        • Alert and conscious patients should consume glucose (eg, juice, soft drink, milk, glucose tablet), then remeasure blood glucose level after 15 minutes; repeat glucose intake if blood glucose level remains low r3
        • Confused or unconscious patients should receive an injection of glucagon (1 mg) subcutaneously or intramuscularly from medical personnel or a trained family member and then be referred for emergency medical care
      • Initial treatment of DKA r4
        • IV rehydration with normal saline; add 5% to 10% dextrose when plasma glucose level is less than 200 mg/dL
        • IV insulin, delaying if serum potassium level is lower than 3.3 mEq/L; avoid rapid correction of hyperglycemia to prevent development of cerebral edema
        • Correction of hypokalemia with potassium supplementation
        • Monitoring serum potassium and plasma glucose levels

    Pitfalls

    • A discrepancy between preprandial self-monitored blood glucose levels and hemoglobin A1C can be due to high postprandial blood glucose
    • Acute onset of diabetes is often heralded by weight loss, but patients with overweight or obesity can also develop type 1 diabetes

    Terminology

    Clinical Clarification

    • Diabetes mellitus type 1 is a chronic metabolic disease characterized by hyperglycemia secondary to destruction of pancreatic beta cells
    • Usually leads to absolute insulin deficiency and complete dependence on exogenous insulin to regulate blood glucose levels

    Classification

    • Subclassification r5
      • Immune-mediated diabetes (type 1A)
        • Previously described as juvenile-onset diabetes or insulin-dependent diabetes
        • Caused by progressive cell-mediated autoimmune destruction of pancreatic beta cells
        • Defined by the presence of autoimmune markers, including autoantibodies to the following:
          • GAD65 (glutamate decarboxylase 2)
          • Insulin
          • Tyrosine phosphatases islet antigen-2 and islet antigen-2β
          • Zinc transporter protein ZnT8 (SLC30A8, a zinc transporter related to insulin secretion)
        • Accounts for most cases of type 1 diabetes mellitus, but only for 5% to 10% of all cases of diabetes
        • American Diabetes Association includes latent autoimmune diabetes in adults in this category
          • Latent autoimmune diabetes in adults is a slowly progressive form of autoimmune diabetes that develops in adults, defined by all of the following features: r6
            • Presence of glutamic acid decarboxylase antibodies
            • Age older than 30 years at onset
            • Insulin independence for at least 6 months after diagnosis
          • There is ongoing debate as to whether slowly progressive autoimmune diabetes with an adult onset should be termed latent autoimmune diabetes in adults or type 1 diabetes
      • Idiopathic diabetes (type 1B)
        • Type 1 diabetes mellitus with nonimmune basis for pancreatic β-cell destruction
        • Characterized by varying degrees of insulinopenia and episodic ketoacidosis
        • Strongly inherited and lacks evidence of autoimmunity
        • Mainly occurs in patients of African or Asian ancestry and accounts for a minority of patients with type 1 diabetes mellitus
    • Stages of type 1 diabetes r5
      • Stage 1: presymptomatic; euglycemic in the presence of β-cell autoimmunity as evidenced by development of 2 or more type 1 diabetes–associated islet autoantibodies
      • Stage 2: presymptomatic; progresses to glucose intolerance or dysglycemia, also in the presence of β-cell autoimmunity
      • Stage 3: onset of symptomatic disease, as defined by standard criteria; autoantibodies may no longer be present

    Diagnosis

    Clinical Presentation

    History

    • Initial presentation varies depending on severity of manifestations and rate of β-cell destruction r3
      • Asymptomatic in some adults who may also present with modest fasting hyperglycemia c1
    • Symptoms develop as hyperglycemia worsens, including: r3
      • Polyuria c2
      • Polydipsia c3
      • Polyphagia c4
      • Unexplained weight loss c5c6
        • Acute onset of diabetes is often heralded by weight loss, but patients with overweight or obesity can also develop type 1 diabetes
      • Weakness c7
      • Fatigue c8
      • Blurred vision c9
    • DKA is an uncommon initial presentation in adults; adults frequently retain sufficient pancreatic β-cell function in the early stage of disease to prevent ketoacidosis c10

    Physical examination

    • Often, there are no signs with mild to moderate hyperglycemia c11
    • Patients with symptomatic moderate to severe hyperglycemia at presentation show signs of volume depletion c12
      • Dry mucous membranes c13
      • Hypotension c14
      • Poor skin turgor c15
    • Signs of complications
      • Increased blood pressure c16
      • Heart rate variability during deep inspiration, position change, or Valsalva maneuver c17
      • Microaneurysms, exudates, and/or macular edema on funduscopic examination c18c19c20
      • Decreased lower extremity sensation c21c22c23c24
      • Weak pedal pulses c25
      • Foot ulcers, deformities, or wounds c26c27c28c29

    Causes and Risk Factors

    Causes

    • Autoimmune (type 1A) c30
      • T cell–mediated autoimmune disease characterized by selective destruction of pancreatic beta cells c31
      • Disease emerges through a complex interrelation of genetic and environmental factors, most of which have yet to be identified
    • Idiopathic (type 1B) c32
      • Pancreatic β-cell failure occurring without autoimmune destruction

    Risk factors and/or associations

    Age
    • Incidence rates stabilize in adolescence and young adulthood (ages 15-29 years) after a peak incidence at puberty r7c33c34
    • Approximately one-quarter of type 1 diabetes cases are diagnosed in adulthood r7c35
    Sex
    • Approximately equal distribution between male and female individuals overall r7
      • In areas of relatively high incidence (populations of European descent), males are at higher risk c36c37
      • In areas of relatively low incidence (populations of non-European descent), females are at higher risk c38c39
    Genetics
    • Risk of type 1 diabetes is conferred by 2 susceptible haplotypes in the class II region of the HLA complex r8
      • Specific HLA DR/DQ alleles associated with type 1 diabetes include DRB1*03:01-DQB1*02:01 (DR3/DQ2) or DRB1*04:01-DQB1*03:02 (DR4/DQ8) r9c40c41
      • While a large proportion of people with type 1 diabetes carry a susceptible haplotype, only a small proportion of people in the general population with this susceptible haplotype actually develop the disease
        • 40% to 50% of familial clustering in type 1 diabetes is due to the susceptible haplotype in the HLA complex r10
        • Remaining proportion of familial clustering caused by genetic susceptibility is associated with variations on numerous (more than 50) other loci, each of which accounts for a modest impact on risk r11
    • Familial clustering r7
      • Having a first-degree relative with type 1 diabetes carries a 5% lifetime risk of developing the disease compared with a 0.3% risk in the general population r3c42
        • Monozygotic twins have a cumulative concordance rate of 65%,r12 whereas dizygotic twins have a concordance rate of 6% to 10%r7c43
        • Offspring of affected mothers have a 2% to 3% risk, whereas offspring of affected fathers have a 7% risk r7
    Ethnicity/race
    • Incidence and prevalence are highest in non-Hispanic White people r3c44
    • Most patients with idiopathic (type 1B) diabetes are of Asian or African descent r5c45c46
    Other risk factors/associations
    • Clustering with other autoimmune disorders associated with genetic susceptibility r7
      • Autoimmune thyroid disease c47
        • Presence of thyroid autoantibodies (eg, peroxidase and thyroglobulin antibodies) at diagnosis is predictive of thyroid disease r3
      • Celiac disease c48
        • Occurs more frequently in patients with type 1A diabetes (1%-16%) compared with the general population (0.3%-1%) r3
        • Autoantibodies indicative of celiac disease include IgA antitissue transglutaminase and antiendomysial antibodies
      • Autoimmune polyendocrine syndrome type 1r13(OMIM #240300)r14c49
        • Rare autosomal dominant or autosomal recessive disorder caused by mutations in the AIRE gene (autoimmune regulator)
        • Up to 18% of patients with this syndrome develop type 1 diabetes r15
        • Syndrome includes at least 2 of the 3 major features: mucocutaneous candidiasis, hypoparathyroidism, or Addison disease
      • Autoimmune polyendocrine syndrome type 2r13(OMIM %269200)r16c50
        • Rare disorder of unknown molecular basis; susceptibility linked to class II alleles within the major histocompatibility complex
        • Approximately 50% of patients with this syndrome develop type 1 diabetes
        • Syndrome is recognized by the slow onset and variable penetrance of several autoimmune disorders, including Addison disease, Graves disease, primary hypothyroidism, and primary hypogonadism
    • Season of birth r7c51
      • Higher prevalence among those born in April through July
      • Lower prevalence among those born in November through February
    • Season of onset r7
      • Higher incidence of onset from late autumn through early spring compared with the rest of the year c52c53
    • Vitamin D level r7
      • Vitamin D deficiency is associated with an increased risk of developing type 1 diabetes c54
    • COVID-19 infection r5
      • May trigger onset or unmask type 1 diabetes
    • Immune checkpoint inhibitor therapy r5
      • Majority of cases precipitated by immune checkpoint inhibitors occur in people with high-risk HLA-DR4 allele

    Diagnostic Procedures

    Primary diagnostic tools

    • History and physical examination can suggest diabetes, but biochemical parameters are required for diabetes diagnosis c55
      • Testing for pancreatic islet autoantibodies and C-peptide level can help differentiate diabetes type and confirm a diagnosis of type 1 disease
    • Laboratory confirmation of diabetes can be achieved with either of the following: r5r17
      • 2 diagnostic test results from among the following 3 tests, using the same or 2 different types of tests and the same or 2 different test samples:
        • Hemoglobin A1C measurement of at least 6.5% c56
          • Measurement of hemoglobin A1C can give an indication of duration of disease
        • Fasting plasma glucose measurement of at least 126 mg/dL (7 mmol/L) c57
        • 2-hour glucose measurement of at least 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test c58
          • More useful in asymptomatic patients, primarily when type 2 diabetes is suspected r18
      • 1 random plasma glucose measurement of 200 mg/dL or higher when classic symptoms of hyperglycemia or hyperglycemic crisis are present c59
        • Measuring the specific blood glucose level not only confirms the diagnosis but also directs further management of severe hyperglycemia
    • After a diagnosis of diabetes is made and if clinical presentation suggests type 1, specific laboratory testing with assessment of pancreatic islet autoantibodies can confirm type 1 disease and allow for further classification r5r17c60
      • Consider alternative diagnosis of type 2 diabetes in patients aged older than 35 years with negative islet autoantibodies
    • Measurement of C-peptide level can help differentiate diabetes type when pancreatic autoantibodies are negative, especially when measured beyond 3 years after initial diabetes diagnosis r1r17
    • Evaluate comorbidities at time of diagnosis r3
      • Measure blood pressure, obtain fasting lipid panel, and measure urinary albumin excretion (urine albumin-creatinine ratio) c61c62c63
      • Obtain resting ECG for patients with hypertension or suspected cardiovascular disease r19c64
      • Refer to ophthalmologist for baseline dilated eye examination, starting 5 years after diagnosis c65

    Laboratory

    • Fasting glucose measurement c66c67c68
      • Diagnostic thresholds are as follows: r5
        • Fasting glucose reference range: less than 100 mg/dL (5.6 mmol/L)
        • Impaired fasting glucose: 100 to 125 mg/dL (5.6-6.9 mmol/L)
        • Diabetes mellitus: 126 mg/dL (7 mmol/L) or higher
      • Fasting requires no caloric intake for at least 8 hours
      • In absence of unequivocal symptomatic hyperglycemia, diabetes diagnosis must be confirmed by another abnormal test result; can be the same or different type of test and can be from the same or different test samples
    • Random glucose measurement c69
      • A single measurement of 200 mg/dL (11.1 mmol/L) or greater when signs or symptoms of hyperglycemia are present confirms diagnosis of diabetes r5
    • Hemoglobin A1C c70
      • Diagnostic threshold is 6.5% or greater r5
      • In absence of unequivocal symptomatic hyperglycemia, diabetes diagnosis must be confirmed by another abnormal test result; can be the same or different type of test and can be from the same or different test samples
      • Results may be altered in presence of some clinical conditions, causing problematic interpretation r5
        • Hemoglobinopathy
        • Iron deficiency
        • Hemolytic anemia
        • Thalassemia
        • Spherocytosis
        • Severe hepatic disease
        • Severe renal disease
        • Recent blood loss or transfusion
        • HIV treated with certain medications
        • Pregnancy and postpartum period
        • Erythropoietin therapy
    • Oral glucose tolerance test c71
      • Performed 2 hours after oral ingestion of 75 g anhydrous glucose dissolved in water
      • Diagnostic thresholds are as follows: r5
        • Glucose tolerance reference range: less than 140 mg/dL (7.8 mmol/L)
        • Impaired glucose tolerance: 140 to 199 mg/dL (7.8-11.1 mmol/L)
        • Diabetes mellitus: 200 mg/dL (11.1 mmol/L) or greater
      • In absence of unequivocal symptomatic hyperglycemia, diabetes diagnosis must be confirmed by another abnormal test result; can be the same or different type of test and can be from the same or different test samples
      • Adequate carbohydrate intake of at least 150 g/day for 3 days before testing is necessary
    • Pancreatic islet autoantibodies r3c72
      • Autoimmune markers indicative of type 1 diabetes include several different pancreatic islet autoantibodies (commercial laboratory assays measure all 4 types) r20r21c73c74c75c76
        • Autoantibodies against a glutamic acid decarboxylase isoform (GAD2, also known as GAD65): this is the most widely available and best characterized test c77c78
          • Such antibodies are detected in approximately 50% to 80% of patients at time of diagnosis with type 1 diabetes r20r21
          • Seroconversion usually precedes onset of clinical manifestations of disease, and result remains positive thereafter
        • Autoantibodies against certain protein tyrosine phosphatases that are cell membrane autoantigens, including those on islet cells (ie, PTPRN and PTPRN2, also known as islet antigen-2 and islet antigen-2β, respectively): detected in 30% to 70% of patients with newly diagnosed disease r20c79c80
        • Autoantibodies against a zinc transporter protein (SLC30A8, also known as ZnT8) (solute carrier family 30 member 8): test is largely available in research settings; antibodies are detected in 50% to 70% of patients with newly diagnosed disease r20r22
        • Autoantibodies to insulin r20c81
          • Detected in approximately 50% to 90% of patients with newly diagnosed disease r20
          • Must be measured before or within 2 weeks of commencing insulin therapy
      • Patients with clinical features compatible with type 1 diabetes and 1 or more positive islet autoantibodies are considered to have type 1 diabetes, regardless of insulin requirement at initial diagnosis r1
      • Absence of pancreatic autoantibodies does not rule out type 1 diabetes r1
        • Up to 5% to 10% of patients with new-onset type 1 diabetes in White European study populations have been found to lack islet antibodies r1
        • Pancreatic autoantibody titers diminish over time, which can produce false-negative results r23
    • C-peptide r1c82
      • Surrogate marker for insulin secretion
      • Can be obtained if islet autoantibodies are absent and diabetes type remains unclear
      • Recommended test when diabetes type remains uncertain more than 3 years after initial diabetes diagnosis
      • Interpretation: r1
        • Less than 200 pmol/L or absent: indicative of type 1 diabetes c83
        • 200 to 600 pmol/L: indeterminate; consider repeat C-peptide measurement in 5 years and genetic testing for monogenetic diabetes in patients aged younger than 35 years with compatible features
        • Greater than 600 pmol/L: strongly suggestive of type 2 diabetes, especially in patients aged older than 35 years; consider genetic testing for monogenetic diabetes in patients aged younger than 35 years with suggestive features
    • Additional laboratory tests recommended at diagnosis to screen for associated diseases and complications include: r3
      • Fasting lipid panel c84
      • Renal function tests for nephropathy c85
        • Estimated GFR c86
        • Urine albumin-creatinine ratio c87
      • Thyroid disease
        • TSH c88
        • Thyroid autoantibodies c89
          • Thyroid peroxidase c90
      • Celiac disease
        • IgA antitissue transglutaminase c91
        • Antiendomysial antibodies c92
      • Liver function tests c93

    Differential Diagnosis

    Most common

    • Type 2 diabetes mellitus c94d1
      • Shares biochemical parameter of hyperglycemia with type 1 diabetes
      • Patients with type 2 diabetes may be asymptomatic, with hyperglycemia detected through screening or as an incidental finding
        • In symptomatic patients, hyperglycemia symptoms predominate (eg, polyuria, polydipsia)
      • Typically occurs in older adult patients and patients with overweight or obesity who often have a family history of type 2 diabetes
      • Differentiated from type 1 diabetes on the basis of clinical course over time, absence of pancreatic autoantibodies, and detectable or elevated C-peptide level
        • Clinical course of type 1 diabetes is characterized by ongoing, absolute insulin requirement that is lifelong, whereas insulin dependency is usually absent in early phase of type 2 diabetes
        • Younger age (less than 35 years) at initial diagnosis strongly favors type 1 diabetes; after age 35 years, type 2 diabetes is increasingly likely with absent pancreatic autoantibodies and older age r1
        • Lower BMI, unintentional weight loss, ketoacidosis, and severe hyperglycemia at presentation also favor type 1 diabetes r1
        • Type 2 diabetes most often responds to noninsulin antihyperglycemic agents (eg, metformin, glyburide) early in the course of disease
      • Genetic risk scores determined from common genetic variants can accurately discriminate between type 1 and type 2 diabetes in adults, but this testing is not commercially available yet r24
    • Diabetes insipidus c95d2
      • Spectrum of diseases that display hypotonic polyuria and inability to concentrate urine owing to inadequate secretion of or impaired renal responsiveness to arginine vasopressin
      • Presenting symptoms of polyuria, polydipsia, and nocturia overlap with those of diabetes mellitus when the latter is associated with symptomatic hyperglycemia
      • Diagnosis of diabetes insipidus is suggested by a 24-hour urine volume greater than 3 L and low urinary osmolality; definitive diagnosis requires a water deprivation test
      • Most easily differentiated from diabetes mellitus on the basis of laboratory test results (eg, from plasma glucose level, oral glucose tolerance test, hemoglobin A1C)
    • Monogenic diabetes/maturity-onset diabetes of youth r25c96c97c98c99
      • Autosomal dominant disorders causing β-cell dysfunction and impaired insulin secretion, with onset of hyperglycemia at young age (younger than 25 years)
      • Features include young age at presentation and strong family history of diabetes, but without typical features of type 2 diabetes (ie, absence of obesity, low-risk ethnic group)
      • Differentiated from type 1 diabetes by genetic testing, most commonly with identification of mutations in HNF1A (HNF1 homeobox A) or GCK (glucokinase), as well as by C-peptide level higher than 200 pmol/L r1
    • Drug-induced diabetes c100
      • Drugs can have a toxic, irreversible effect on pancreatic beta cells (eg, pentamidine), typically inducing type 1 diabetes
      • Drugs promoting hyperglycemia (eg, glucocorticoids, thiazide diuretics, somatostatin analogues) may also induce diabetes (typically type 2) in a genetically susceptible person r26
      • Checkpoint inhibitors for cancer treatment have recently been associated with development of autoimmune disease, including fulminant type 1 diabetes; specific pathophysiology is unclear, and typical type 1 diabetes autoantibodies are frequently absent r5
      • Drug-induced diabetes is identified when hyperglycemia or ketoacidosis develops after an inciting drug is used r27

    Treatment

    Goals

    • Glycemic goals
      • Glycemic targets differ slightly among professional organizations; however, all organizations agree that target goals should be individualized
      • Take into account the following factors: age and life expectancy, disease duration, presence or absence of micro- and macrovascular complications, cardiovascular risk factors, comorbid conditions, and risk for hypoglycemia r28
      • For recent-onset type 1 diabetes mellitus in nonpregnant adults without cardiovascular disease, normal (or near normal) glycemia is the goal to prevent or delay the progression of micro- and macrovascular complications
      • Hemoglobin A1C targets
        • Guideline recommendations vary slightly by professional society
        • American Diabetes Association recommends a target hemoglobin A1C of less than 7% as appropriate for most nonpregnant adults; a lower level may be acceptable if it can be achieved safely without significant hypoglycemia r28
        • American Association of Clinical Endocrinologists recommends a target hemoglobin A1C level of 6.5% for most nonpregnant adults if it can be achieved safely r29
        • National Institute for Health and Care Excellence suggests adults aim for a target hemoglobin A1C of 6.5% or lower; however, target should be individualized based on likelihood of complications, comorbidities, occupation, and history of hypoglycemia
        • Less stringent target of 7% to 8% is acceptable for select patients with any of the following: r28r29
          • Limited life expectancy
          • Severe comorbidities
          • Extensive micro- or macrovascular complications
          • History of severe hypoglycemia
          • Long-standing diabetes in which glycemic goal is difficult to attain despite diabetes self-management education, appropriate glucose monitoring, and effective doses of insulin
      • Self-monitoring of blood glucose targets
        • Fasting plasma glucose target of less than 80 to 130 mg/dL (American Diabetes Association)r28 or less than 110 mg/dL (American Association of Clinical Endocrinologists)r29
        • 2-hour postprandial glucose target of less than 180 mg/dL (American Diabetes Association)r28 or less than 140 mg/dL (American Association of Clinical Endocrinologists)r29
      • Ambulatory glucose profile targets (continuous glucose monitoring)
        • More than 70% of time in range 70 to 180 mg/dL with less than 4% of time below range (less than 1% of time below 54 mg/dL) r28r30r31
        • More than 50% of time in range and less than 1% of time below range is recommended for patients who are frail or at high risk for hypoglycemia r28
    • Inpatient glucose targets vary by setting and circumstance r32
      • Glucose target between 140 and 180 mg/dL is recommended for most critically and noncritically ill patients
      • Glucose target between 110 and 140 mg/dL may be appropriate for selected patients (eg, those who have undergone cardiac surgery, who have history of stroke, or who have acute ischemic cardiac events), provided that the target can be achieved without significant hypoglycemia
    • Cardiovascular goals
      • Blood pressure
        • American Diabetes Association, American Association of Clinical Endocrinologists, and American College of Cardiology/American Heart Association guidelines recommend blood pressure target of lower than 130/80 mm Hg for most patients r29r33r34
        • Individualization of blood pressure targets is emphasized in all guidelines, with consideration of other factors such as age and presence of kidney disease and/or coronary artery disease
        • Blood pressure threshold of lower than 140/80 mm Hg is recommended for initiating or titrating treatment of hypertension during pregnancy; systolic blood pressures of 110 to 135/85 mm Hg reduce the risk of uncontrolled maternal hypertension and minimize impaired fetal growth r35
        • There is a lack of trial data to guide blood pressure targets for patients with type 1 diabetes; targets are based largely on patients with type 2 diabetes r1
      • Lipid goals
        • American Heart Association does not specify a numeric LDL-C goal but does comment that epidemiologic evidence suggests that an LDL-C level higher than 100 mg/dL is associated with increased cardiovascular disease risk r36
        • American Diabetes Association recommends reducing LDL-C by 50% or more from baseline or to a goal of less than 70 mg/dL in patients with 1 or more atherosclerotic cardiovascular disease risk factors and less than 55 mg/dL in patients with established atherosclerotic cardiovascular disease r33
        • American Association of Clinical Endocrinologists specifies numeric LDL-C goals according to degree of atherosclerotic cardiovascular disease risk r37
          • High risk: for patients with diabetes and no atherosclerotic cardiovascular disease or major cardiovascular risk factors, LDL-C goal is less than 100 mg/dL and non–HDL-C goal is less than 130 mg/dL
          • Very high risk: for patients with diabetes and at least 1 additional major atherosclerotic cardiovascular disease risk factor (eg, hypertension, family history, low HDL-C level, smoking), LDL-C goal is less than 70 mg/dL and non–HDL-C goal is less than 100 mg/dL
          • Extreme risk: patients with diabetes and history of a previous atherosclerotic cardiovascular disease event: LDL-C goal is less than 55 mg/dL and non–HDL-C goal is less than 80 mg/dL
        • There is a lack of trial data to guide lipid targets for patients with type 1 diabetes; targets are based largely on patients with type 2 diabetes r1

    Disposition

    Admission criteria

    DKA r38

    • Plasma glucose level higher than 250 mg/dL with any of the following:
      • Arterial pH less than 7.3
      • Serum bicarbonate level lower than 15 mEq/L
      • Moderate ketonuria (more than 2+ on test strip) or ketonemia (3 mmol/L or greater)
    • Volume depletion
    • Acute kidney injury

    Hypoglycemia with neuroglycopenia r38

    • Any of the following:
      • Blood glucose level less than 50 mg/dL refractory to treatment (no prompt recovery of sensorium)
      • Coma, seizures, or altered behavior due to hypoglycemia

    Uncontrolled diabetes r38

    • At least 1 of the following:
      • Hyperglycemia with volume depletion
      • Hyperglycemia associated with metabolic deterioration
      • Recurrent fasting plasma glucose level higher than 300 mg/dL and refractory to outpatient treatment
      • Hemoglobin A1C 100% or more above the upper limit of reference range
      • Frequent episodes of severe hypoglycemia with blood glucose level lower than 50 mg/dL and refractory to outpatient treatment
      • Metabolic instability as evidenced by frequent swings between fasting hyperglycemia and hypoglycemia
      • Recurrent DKA not precipitated by infection or injury
      • Severe psychosocial issues that cause uncontrolled metabolic function and cannot be managed in an outpatient setting
    Criteria for ICU admission
    • Critically ill and mentally obtunded patients with DKA where continuous IV insulin is the standard of care r39
    • Need for IV insulin infusion that can only be administered in ICU setting

    Recommendations for specialist referral

    • Certified diabetes educator for diabetes self-management education and ongoing support
    • Registered dietitian for medical nutrition therapy
    • Endocrinologist for uncertain diagnosis or treatment of labile glycemia (eg, recurrent hypoglycemia, persistent hyperglycemia, ketoacidosis)
    • Nephrologist for persistent proteinuria, decreased GFR, labile blood pressure, or hyperkalemia
    • Cardiologist for associated cardiovascular disease management
    • Ophthalmologist to screen for or treat diabetic retinopathy
    • Podiatrist for orthotic footwear and prevention or treatment of diabetic foot ulcers
    • Mental health specialist for depression, self-harm, blatant disregard for self-care, severe anxiety, diabetes-related distress, suspicion for a serious mental illness, fear of hypoglycemia, repeated hospitalizations for DKA, intentional omission of insulin, or eating disorders r40
    • Neuropsychologist or other specialist trained in assessing cognitive capacity if capacity changes significantly or is inadequate for decision-making and/or self-care
    • Dentist for comprehensive dental and periodontal examination

    Treatment Options

    Comprehensive management includes the following components:

    • Intensive insulin therapy
    • Glucose monitoring
    • Lifestyle management including medical nutrition therapy
    • Ongoing diabetes self-management education and support
    • Management of comorbidities and complications
    • Pancreatic transplant evaluation in selected patients

    Intensive insulin therapy using physiologic replacement regimens, consisting of both basal and prandial insulin r3

    • Delivered through 1 of 2 methods, both of which involve matching prandial insulin to carbohydrate intake, preprandial blood glucose, and anticipated physical activity
      • Multiple daily insulin injections (3-4 per day)
        • Consists of once (or twice) daily injection of a long-acting or intermediate-acting basal insulin combined with several injections of short-acting or rapid-acting insulin analogues throughout the day with meals
      • Continuous subcutaneous insulin infusion (insulin pump)
        • Uses very rapid insulin analogues to continuously provide basal insulin; additional operator-delivered mealtime bolus doses must account for carbohydrate intake and blood glucose levels
        • 1 advantage of this delivery system is the ability to alter basal rates in accordance with variable needs throughout the day
        • Automated insulin delivery systems (also called closed-loop or artificial pancreas systems) are available; they combine an insulin pump, a continuous glucose sensor, and an algorithm controller that adjusts insulin delivery; advanced forms also deliver correction boluses as needed r41r42
        • American Diabetes Association recommends that a version of continuous subcutaneous insulin infusion with continuous glucose monitoring or an automated insulin delivery system be offered to all patients with type 1 diabetes who are capable of using the device safely, either by themselves or with caregiver assistance r43
    • Insulin management via continuous subcutaneous insulin infusion is associated with slightly lower hemoglobin A1C and fewer severe hypoglycemic events compared with use of multiple daily insulin injections r44
      • Patients using completely automated insulin delivery systems had greater reduction in hemoglobin A1C and spent a higher percentage of time in the target glucose range without an increase in frequency of hypoglycemia compared with those using other modes of insulin delivery along with continuous glucose monitoring (semi-automated) r45
      • Use of continuous subcutaneous insulin infusion by patients with type 1 diabetes is also associated with lower cardiovascular mortality versus insulin therapy delivered by multiple daily injections r46

    Noninsulin pharmacologic treatments are not generally recommended r43r47r48

    • Pramlintide is approved for treatment of type 1 diabetes in adults and is associated with modest reduction in hemoglobin A1C levels and modest weight loss
      • May be considered as an adjunct to insulin for selected patients
    • Agents such as metformin, glucagon-like peptide 1 receptor agonists, and sodium–glucose cotransporter 2 (SGLT2) inhibitors have demonstrated reductions in body weight, insulin dose, and hemoglobin A1C levels in studies in patients with type 1 diabetes
      • Currently these are approved only for treatment of type 2 diabetes and potential for use in type 1 diabetes continues to be evaluated

    Glucose monitoring is an essential element of effective management and is necessary for preventing hypoglycemia, adjusting the dosing and timing of basal and prandial insulin, and determining individual response to therapy r49

    • Self-monitoring of blood glucose provides a profile of daily glycemic fluctuations that reflects meals, physical activity, and actions of specific components of insulin
    • Self-monitoring of blood glucose is performed via glucometer testing of fingerstick blood or continuous glucose monitoring; use of continuous glucose monitoring devices is now the standard of care for most patients and should be considered from the outset r42

    Lifestyle issues of nutrition, physical activity, and psychosocial factors require attention throughout the life span r40

    • Periodically evaluate patient's general and diabetes-related quality of life, as well as emotional well-being (eg, watch for signs of distress or depression)

    Provide ongoing diabetes self-management education and support

    • Should be individualized, culturally sensitive, and developmentally appropriate

    Management of comorbidities (eg, hypertension, dyslipidemia) is important to reduce the risk of complications

    • Few trials have been specifically designed to assess the impact of cardiovascular risk reduction strategies on patients with type 1 diabetes r33

    β-Cell replacement with simultaneous transplant is an option for patients with poor glycemic control, using either whole pancreas transplant or islet transplant r3r50

    Drug therapy

    • Insulin r51c101c102c103c104
      • Overall, insulin regimen and dosing are highly individualized and based on age, duration of diabetes, comorbidities, history of diabetic complications, and risk of hypoglycemia
      • Preferred insulin regimen in American Diabetes Association/European Association for the Study of Diabetes consensus guidelines is a long-acting basal analogue (eg, detemir, glargine, degludec) combined with a rapid-acting or ultra-rapid-acting prandial analogue r1
      • Other less-preferred alternative insulin regimens include use of short-acting (regular), intermediate-acting NPH (neutral protamine Hagedorn [isophane insulin suspension]), and premixed insulin preparations; these regimens may be less labor intensive and/or have lower cost but generally lead to suboptimal glycemic control and higher risk of hypoglycemia
        • A recent systematic review and network meta-analysis concluded that long-acting insulin analogues were superior to intermediate-acting insulin in reducing hemoglobin A1C; fasting glucose; weight gain; and the incidence of major, serious, or nocturnal hypoglycemia in patients with type 1 diabetes r52
        • In contrast, a recent Cochrane review, using different inclusion, exclusion, and analytic criteria, found that there was lower risk of severe hypoglycemia with insulin detemir compared with NPH insulin, but otherwise no significant differences in clinical outcomes between detemir, glargine, degludec, and NPH insulin preparations r53
      • Suggested insulin initiation strategy at time of new diagnosis in insulin-naive patients is as follows: r43
        • Start with multiple daily injections consisting of a long-acting basal analogue dose combined with several prandial insulin doses before meals (basal-bolus strategy)
        • Step 1: determine total daily insulin dose
          • If initiating insulin therapy: typical total daily dose ranges from 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is commonly used
          • If intensifying insulin regimen: total daily dose equals sum of all current doses in a day
        • Step 2: determine daily basal insulin requirement (50% of total daily insulin dose from step 1)
        • Step 3: give basal insulin as a single subcutaneous dose once daily
        • Step 4: determine daily prandial insulin requirement (50% of total daily insulin dose from step 1)
        • Step 5: divide total daily prandial insulin requirement by 3 and administer as a subcutaneous dose of immediate analogue insulin before each meal
      • Insulin titration c105
        • Titrate insulin therapy to achieve individualized glycemic targets by changing doses and timing of administration in accordance with blood glucose measurements and patterns or by transitioning to continuous subcutaneous insulin infusion therapy
          • If fasting blood glucose target is not achieved, increase basal insulin dose by increments of approximately 10% to 20% every 2 to 3 days r29c106c107c108
          • If a 2-hour postprandial glucose measurement or a preprandial glucose measurement is higher than 180 mg/dL, increase the prandial dose for the next meal by 10% to 20%
          • If hypoglycemia occurs between meals after use of prandial insulin, reduce the next prandial insulin dose; if nighttime hypoglycemia occurs, reduce basal insulin or reduce prandial insulin taken before dinner
          • If fasting blood glucose level is lower than 70 mg/dL, reduce basal insulin by 10% to 20%
        • FDA-approved insulin dose calculators and decision support systems are available to assist with titration
      • Continuous subcutaneous insulin infusion via insulin pump with continuous glucose monitoring is preferred over multiple daily injections for most patients r42r43
        • Associated with modest improvements in hemoglobin A1C reduction and avoidance of nocturnal hypoglycemia
      • Use of insulin pens is generally preferred over syringe administration due to simplicity and ease of dosing if multiple daily injections are given
    • Basal insulins r54c109c110
      • Basal insulin is designed to provide a constant low level of insulin to maintain euglycemia between meals and overnight r18
      • Necessary to suppress hepatic glucose production r55
      • Basal insulin is available in intermediate-acting and long-acting formulations; long-acting insulin analogues better mimic endogenous basal insulin secretion compared with intermediate-acting insulins (eg, isophane insulin) and may also reduce the risk of hypoglycemia, especially nocturnal hypoglycemia r55
      • Insulin degludec c111c112
        • Insulin Degludec Solution for injection; Adults: 33% to 50% of the total daily insulin dose subcutaneously once daily, initially. Adjust dose every 3 to 4 days based on metabolic needs, blood glucose, and glycemic control goal. Use short-acting, prandial insulin to satisfy the remainder of the daily insulin requirements. The typical total daily insulin dose is 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is a typical starting total daily dose.
      • Insulin detemir c113c114c115c116c117c118
        • Insulin Detemir (Recombinant) Solution for injection; Adults: 33% to 50% of the total daily insulin dose subcutaneously once daily, initially. Adjust dose based on metabolic needs, blood glucose, and glycemic control goal. Use short-acting, prandial insulin to satisfy the remainder of the daily insulin requirements. The typical total daily insulin dose is 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is a typical starting total daily dose.
      • Insulin glargine c119c120c121c122c123c124c125c126
        • Insulin Glargine Solution for injection; Adults: 33% to 50% of the total daily insulin dose subcutaneously once daily, initially. Adjust dose based on metabolic needs, blood glucose, and glycemic control goal. Use short-acting, prandial insulin to satisfy the remainder of the daily insulin requirements. The typical total daily insulin dose is 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is a typical starting total daily dose.
      • NPH (neutral protamine Hagedorn) c127c128c129c130c131c132c133c134c135
        • Insulin Suspension Isophane (NPH) (Recombinant) Suspension for injection; Adults: 50% of the total daily insulin dose subcutaneously once daily or divided twice daily, initially. Adjust dose based on metabolic needs, blood glucose, and glycemic control goal. Use short-acting, prandial insulin to satisfy the remainder of the daily insulin requirements. The typical total daily insulin dose is 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is a typical starting total daily dose.
    • Prandial insulins r18c136c137
      • Rapid-acting and ultra-rapid-acting insulins more closely mimic physiologic insulin secretion after a meal owing to rapid onset and short duration of action; dosing to match meal intake results in less of a postprandial spike in blood glucose and reduced risk of late hypoglycemia r55
      • When used in a multiple daily insulin injection regimen, prandial doses (rapid-acting or ultra-rapid-acting analogues) are used to limit glucose excursions that occur after meals or snacks
      • Short-acting insulin
        • Regular insulin c138c139c140c141c142c143c144c145c146c147c148c149c150
          • Insulin Regular (Recombinant) Solution for injection; Adults: 50% of the total daily insulin dose subcutaneously divided 2 to 3 times daily approximately 30 minutes before meals, initially. Adjust dose based on metabolic needs, blood glucose, and glycemic control goal. Use intermediate or long-acting basal insulin to satisfy the remainder of the daily insulin requirements. The typical total daily insulin dose is 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is a typical starting total daily dose.
      • Rapid-acting insulin
        • Insulin aspart (Novolog insulin aspart products only) c151c152c153c154c155c156c157
          • Insulin Aspart (Recombinant) Solution for injection; Adults: 50% of the total daily insulin dose subcutaneously divided 5 to 10 minutes before meals, initially. Adjust dose based on metabolic needs, blood glucose, and glycemic control goal. Use intermediate or long-acting basal insulin to satisfy the remainder of the daily insulin requirements. The typical total daily insulin dose is 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is a typical starting total daily dose.
          • Novolog insulin aspart is not interchangeable with Fiasp insulin aspart.
        • Insulin glulisine c158c159c160c161
          • Insulin Glulisine Solution for injection; Adults: 50% of the total daily insulin dose subcutaneously divided 15 minutes before or within 20 minutes after start of meals, initially. Adjust dose based on metabolic needs, blood glucose, and glycemic control goal. Use intermediate or long-acting basal insulin to satisfy the remainder of the daily insulin requirements. The typical total daily insulin dose is 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is a typical starting total daily dose.
        • Insulin lispro c162c163c164c165c166c167c168c169c170c171c172c173
          • Insulin Lispro Solution for injection; Adults: 50% of the total daily insulin dose subcutaneously divided 15 minutes before or immediately after meals, initially. Adjust dose based on metabolic needs, blood glucose, and glycemic control goal. Use intermediate or long-acting basal insulin to satisfy the remainder of the daily insulin requirements. The typical total daily insulin dose is 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is a typical starting total daily dose.
      • Ultra-rapid-acting insulin
        • Insulin aspart (Fiasp insulin aspart products only) c174
          • Insulin Aspart (Recombinant) Solution for injection; Adults: 50% of the total daily insulin dose subcutaneously divided at the start of or within 20 minutes after starting meals, initially. Adjust dose based on metabolic needs, blood glucose, and glycemic control goal. Use intermediate or long-acting basal insulin to satisfy the remainder of the daily insulin requirements. The typical total daily insulin dose is 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is a typical starting total daily dose.
          • Fiasp insulin aspart is not interchangeable with Novolog insulin aspart.
        • Inhaled human insulin (Afrezza) c175
          • For insulin-naïve persons
            • Insulin (Human Recombinant) Inhalation powder; Adults: 4 units inhaled by mouth at each meal, initially. Use in combination with basal insulin. Adjust dose based on metabolic needs, blood glucose, and glycemic control goal.
          • For conversion from subcutaneous prandial insulin
            • Insulin (Human Recombinant) Inhalation powder; Adults: 4 units inhaled by mouth at each meal for up to 4 units/dose prandial subcutaneous insulin; 8 units inhaled by mouth at each meal for 5 to 8 units/dose prandial subcutaneous insulin; 12 units inhaled by mouth at each meal for 9 to 12 units/dose prandial subcutaneous insulin; 16 units inhaled by mouth at each meal for 13 to 16 units/dose prandial subcutaneous insulin; 20 units inhaled by mouth at each meal for 17 to 20 units/dose prandial subcutaneous insulin; and 24 units inhaled by mouth at each meal for 21 to 24 units/dose prandial subcutaneous insulin. Use in combination with basal insulin. Increase the frequency of blood glucose monitoring when switching a patient's insulin regimen. Adjust dose based on metabolic needs, blood glucose, and glycemic control goal.
    • Rapid insulin analogues for continuous subcutaneous insulin infusion devices r51c176
      • When used in these devices, rapid-acting or ultra-rapid-acting insulin analogues serve as the equivalent of basal insulins
        • Insulin aspart (Novolog insulin aspart products only) c177c178
          • Insulin Aspart (Recombinant) Solution for injection; Adults: 40% to 60% of the total daily insulin dose by continuous subcutaneous infusion by insulin pump. Bolus mealtime and correction insulin dose by pump based on insulin-to-carbohydrate ratio and/or insulin sensitivity factor and target glucose 5 to 10 minutes before meals. Adjust basal dose based on overnight, fasting, or daytime glucose outside of activity of bolus doses. The typical total daily insulin dose is 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is a typical starting total daily dose.
        • Insulin aspart (Fiasp insulin aspart products only)
          • Insulin Aspart (Recombinant) Solution for injection; Adults: 40% to 60% of the total daily insulin dose by continuous subcutaneous infusion by insulin pump. Bolus mealtime and correction insulin dose by pump based on insulin-to-carbohydrate ratio and/or insulin sensitivity factor and target glucose at the start of or within 20 minutes after starting meals. Adjust basal dose based on overnight, fasting, or daytime glucose outside of activity of bolus doses. The typical total daily insulin dose is 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is a typical starting total daily dose.
        • Insulin glulisine c179
          • Insulin Glulisine Solution for injection; Adults: 40% to 60% of the total daily insulin dose by continuous subcutaneous infusion by insulin pump. Bolus mealtime and correction insulin dose by pump based on insulin-to-carbohydrate ratio and/or insulin sensitivity factor and target glucose 15 minutes before or within 20 minutes after starting meals. Adjust basal dose based on overnight, fasting, or daytime glucose outside of activity of bolus doses. The typical total daily insulin dose is 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is a typical starting total daily dose.
        • Insulin lispro c180
          • Insulin Lispro Solution for injection; Adults: 40% to 60% of the total daily insulin dose by continuous subcutaneous infusion by insulin pump. Bolus mealtime and correction insulin dose by pump based on insulin-to-carbohydrate ratio and/or insulin sensitivity factor and target glucose 15 minutes before or immediately after meals. Adjust basal dose based on overnight, fasting, or daytime glucose outside of activity of bolus doses. The typical total daily insulin dose is 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is a typical starting total daily dose.
    • Amylin mimetic r56c181
      • Pramlintide is the only noninsulin medication currently FDA approved to treat type 1 diabetes c182c183
        • Pramlintide Acetate Solution for injection; Adults: 15 mcg subcutaneously immediately before each major meal. May increase dose by 15 mcg/dose when no clinically significant nausea has occurred for at least 3 days. Max: 60 mcg/dose. If significant nausea persists at 45 or 60 mcg/dose, decrease dose to 30 mcg/dose; if 30 mcg/dose is not tolerated, consider discontinuation. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Can be used as an adjunct to insulin (multiple daily injections or insulin pump) to reduce wide glycemic excursions and mitigate weight gain r57
      • Coformulations of pramlintide with insulin as well as possibility of use in insulin pump systems are currently under investigation r1
    • Glucagon r3c184c185c186
      • Indicated for hypoglycemia; administered (subcutaneously, intramuscularly, or intranasally) by medical personnel or trained family member if patient is confused or comatose
      • Parenteral
        • Glucagon Hydrochloride Solution for injection; Adults: 1 mg IM, IV, or subcutaneously. May repeat dose if there has been no response after 15 minutes.
      • Intranasal
        • Glucagon Intranasal powder; Adults: 3 mg (1 actuation) into 1 nostril. May repeat dose if there has been no response after 15 minutes.

    Nondrug and supportive care

    Glucose monitoring

    • Blood glucose meter monitoring is indicated for all patients with type 1 diabetes; introduced at diagnosis r42c187c188
      • Point-of-care testing in which a small volume of capillary blood is placed on a test strip and inserted into a glucometer, providing a real-time digital display of blood glucose level
      • Glucose data are used by the patient to make immediate decisions about food, physical activity, and insulin dosing, and data are analyzed by the health care professional to tailor the treatment plan
      • Frequency of blood glucose monitoring is inversely correlated with hemoglobin A1C levels in patients with type 1 diabetes
      • Frequency is variable, depending on individualized patient needs and goals, but usually is 6 to 10 times per day r42
        • Before meals and snacks
        • At bedtime
        • Before and after exercise
        • At onset of hypoglycemia and after treatment of hypoglycemia until euglycemia is achieved
        • Before potentially hazardous tasks (eg, driving)
      • Additional testing may be needed owing to clinical condition (eg, illness, pregnancy)
    • Continuous glucose monitoring c189
      • Testing technology in which a catheter with a glucose oxidase sensor is placed subcutaneously to measure and record interstitial glucose concentrations and provide a real-time display of glucose levels
      • Allows for close monitoring of blood glucose levels with insulin and lifestyle changes and eliminates burdens of frequent glucometer testing
      • Recommended as standard of care for all patients with type 1 diabetes treated with multiple daily injections of insulin or an insulin pump who are capable of using the device safely, either by themselves or with caregiver assistance r31r42
      • Most patients use personal continuous glucose monitoring devices, which provide real-time immediate feedback
        • Retrospective continuous glucose monitoring devices are also available for patients to wear for 72 hours as a short-term method to obtain information about glucose trends
      • Combined continuous subcutaneous insulin infusion and glucose monitoring systems deliver insulin and sample/measure interstitial fluid glucose levels and alter basal insulin dose on the basis of this; some automatically provide correction bolus doses
      • Combined continuous subcutaneous insulin infusion and glucose monitoring systems with threshold suspension functionality halt insulin delivery when the sensor glucose value reaches a predetermined lower threshold as a safety measure against an impending hypoglycemic event r42
      • Glucometric data analysis by the patient or health care professional is used to modify insulin doses
      • Glycemic outcomes associated with continuous glucose monitoring r58
        • Modest improvement in glycemic control (reduces hemoglobin A1C approximately 0.5%) r44r59
        • Reduced hypoglycemia, potentially facilitating safer intensification of glucose control r44r60
      • Patients using continuous glucose monitoring must still have access to glucometer monitoring in case of technical issues or in circumstances where blood glucose may change rapidly, leading to discrepancies r42
      • Inform patients that contact dermatitis can develop with continuous glucose monitoring devices that attach to the skin r1

    Medical nutrition therapy c190

    • Individualized nutrition counseling, preferably provided by a registered dietitian, is recommended for all patients
    • Patients using multiple daily injections or continuous subcutaneous insulin infusion need instruction on how to adjust insulin doses based on planned carbohydrate, fat, and protein intake r40
      • Participation in an intensive flexible insulin therapy education program using the carbohydrate-counting meal-planning approach can result in improved glycemic control capable of reducing hemoglobin A1C levels by 0.3% to 1% r61
    • Patients using fixed insulin regimens need guidance on consistent carbohydrate intake with respect to timing and amount c191
    • Regardless of insulin regimen, nutrition therapy assists with devising a meal plan based on metabolic needs, preferences, physical activity, and schedule
    • Patients with overweight and obesity should aim to achieve and maintain minimum weight loss of 5% r40
    • Guidance is available to assist with management of diabetes during fasting for Ramadan and during intercurrent illness r62r63c192
    • Macronutrient consideration r40
      • Ideal distribution of calories among carbohydrates, fats, and proteins for patients with type 1 diabetes to optimize glycemic control is unknown, but there is no universal ideal macronutrient distribution
      • Individualize macronutrient distribution based on the dietary reference intake recommendations for healthy eating, metabolic goals, and total caloric needs
        • Emphasize nonstarchy vegetables, minimize added sugars and refined grains, and avoid highly processed foods r64
      • Carbohydrates
        • Monitoring carbohydrate intake, by carbohydrate counting or experience-based estimation, is recommended for patients using intensive insulin regimens to adjust insulin doses c193
        • Evidence is insufficient to advise a specific amount of carbohydrate intake; however, reducing overall carbohydrate intake may improve glycemic control r64
        • Carbohydrate intake should emphasize high-fiber (at least 14 g per 1000 kcal), nutrient-dense, minimally processed carbohydrate sources
        • Carbohydrates from vegetables, fruits, whole grains, legumes, and dairy products are preferred over other sources that contain added fats, sugars, or sodium
        • Reduce consumption of sugar-sweetened and non-nutritive sweetened beverages and encourage water as an alternative
      • Fats
        • Recommended total fat intake is 20% to 35% of total calories (same as for general population)
        • Emphasis is on consumption of monounsaturated healthy fats and avoidance of saturated and trans fats r65c194c195c196
      • Proteins
        • Emphasize protein in conjunction with low saturated fat intake (eg, fish, egg whites, beans) c197
        • Ideal protein intake
          • For patients without diabetic nephropathy, the evidence is inconclusive regarding the ideal protein intake for optimizing glycemic control or improving cardiovascular risk; therefore, protein intake should approximate the recommended daily allowance for the general population (0.8 g/kg of body weight) r66
          • For people with diabetic nephropathy (either micro- or macroalbuminuria), dietary protein restriction is not recommended because it does not alter glycemic measures, cardiovascular risk measures, or the course of GFR decline r67r68
            • For patients with non–dialysis-dependent diabetic kidney disease, the recommended daily dietary protein intake is the same as that for the general population (0.8 g/kg of body weight)
            • For patients receiving dialysis, consider higher levels of dietary protein intake
    • Micronutrients r65
      • Routine supplementation is not recommended because there is no clear evidence of benefit for patients with diabetes who do not have underlying deficiencies
      • A healthful diet can usually provide sufficient micronutrients
    • Alcohol r40c198
      • Alcohol should be consumed in moderation, if at all (ie, 1 or fewer drinks per day for females, 2 or fewer drinks per day for males)
      • Ingestion of alcohol can increase the risk of delayed hypoglycemia, especially in conjunction with insulin therapy
    • Sodium r40
      • Recommended total sodium intake is less than 2300 mg/day (same as for general population) c199
      • Further sodium reduction is recommended for concurrent hypertension

    Physical activity counseling c200

    • Benefits of physical activity for adults with type 1 diabetes include improvements in physical fitness and muscle strength,r69 and protection against cardiovascular diseaser70
    • Pre-exercise medical clearance is unnecessary for patients before beginning low- or moderate-intensity physical activity not exceeding the demands of brisk walking or everyday living, unless symptoms of cardiovascular disease are present r71r72
      • Pre-exercise medical clearance is recommended for patients attempting to begin a vigorous exercise program or increasing from a relatively sedentary level of activity to a more vigorous level of exercise and for patients with symptoms of cardiovascular disease regardless of exercise intensity level r71r73
    • Provide individualized exercise prescription with the following general guidance: r74
      • Goal for optimal health benefit for most patients is 150 minutes of moderate intensity (50%-70% of maximum heart rate) aerobic exercise per week, spread out over at least 3 days per week; more than 2 consecutive days without exercise should be avoided r67r68
      • Patients should engage in resistance exercise 2 to 3 sessions per week on nonconsecutive days
      • Older adults also benefit from flexibility and balance training 2 to 3 times per week
      • Interrupt prolonged sitting every 30 minutes with short bouts of physical activity r72
    • Strategies to prevent exercise-induced hypoglycemia include: r74
      • Aiming for blood glucose level of 100 mg/dL or higher at start of exercise c201
      • Adjusting insulin or carbohydrate intake in 1 of the following ways:
        • Reducing the prandial insulin dose for the meal or snack preceding exercise
        • Reducing basal insulin rates (in continuous subcutaneous insulin infusion device)
        • Consuming additional carbohydrates during prolonged physical activity
      • Increasing frequency of self-monitoring of blood glucose to detect hypoglycemia during and after activity

    Smoking cessation c202d3

    • Patients with diabetes who also smoke or have been exposed to secondhand tobacco smoke are at greater risk for microvascular complications of diabetes, cardiovascular disease, and sudden death
    • Patients should avoid cigarettes and other tobacco products, including e-cigarettes
    • Offer patients counseling, pharmacologic measures, or both to assist with cessation

    Diabetes self-management education and support c203c204c205

    • Ongoing processes of facilitating the knowledge, skill, and ability necessary for the patient to participate in diabetes self-care
    • Particularly critical at diagnosis when not meeting targets, when therapeutic or life changes occur, or when complications develop r1
    • Education and support can be provided through 1-to-1 counseling and education, informal ongoing learning resources, and structured education programs r1
    • Mandatory educational topics consist of instruction on how to recognize and treat hypoglycemia, sick day management, blood glucose testing, and carbohydrate counting
    • Referral to digital coaching and digital self-management interventions can be effective
    • For intensive insulin therapy, instruct patients on how to match prandial insulin dose to carbohydrate intake, preprandial blood glucose level, and anticipated activity
    • Participation in an intensive insulin therapy education program can result in improved glycemic control when the carbohydrate-counting meal-planning approach is used

    Immunizations

    • Provide routinely recommended vaccinations as indicated by age r75
    • American Diabetes Association supports following the recommendations of CDC and Advisory Committee on Immunization Practices r75
      • The following immunizations are highly recommended for adult patients with diabetes:
        • COVID-19 vaccine series according to CDC recommendations r76
        • Annual influenza vaccination with inactive or recombinant vaccine; live attenuated influenza vaccine should not be given c206
        • Pneumococcal vaccine
          • PPSV23 (pneumococcal vaccine polyvalent) is recommended with 1 dose at ages 19 to 64 years and an additional dose at 65 years or older c207c208
          • PCV13 (pneumococcal conjugate vaccine) is no longer routinely recommended at age 65 years and older because of declining incidence of pneumonia due to those strains
        • Hepatitis B vaccine (2- or 3-dose series) for patients aged younger than 60 years; consider for those aged 60 years and older based on individual patient risk c209c210
        • HPV vaccine for adults aged 26 years and younger; consider for adults aged 27 through 45 years c211
        • Zoster vaccine for adults aged 50 years and older (2-dose Shingrix, even if previously vaccinated) c212
        • Tetanus, diphtheria, pertussis booster every 10 years c213
        • Respiratory syncytial virus vaccine in adults aged 60 years and older
    Procedures
    Continuous subcutaneous insulin infusion (insulin pump) therapy r31r77r78c214c215
    General explanation
    • Mechanically driven insulin delivery technology in which a catheter is placed subcutaneously to provide a continuous infusion of rapid-acting insulin
    • Provided as a preset basal rate with operator-driven periodic boluses; basal delivery rate can be programmed to vary throughout the day
    • A sensor-augmented pump is a continuous subcutaneous insulin infusion device combined with a continuous glucose monitoring feature
      • A pump with threshold suspension functionality temporarily halts delivery of insulin when interstitial glucose levels fall below a set threshold
        • Use of sensor-augmented pump therapy with threshold suspension functionality reduces rate of severe hypoglycemia r79
      • Sensor-augmented pumps are superior to multiple daily insulin injections for improving glycemic control without increasing the risk for hypoglycemia r80
    • Comparison of outcomes using multiple daily insulin injections versus continuous subcutaneous insulin infusion shows that the latter is associated with slightly lower hemoglobin A1C levelsr44, lower risk of DKAr81, and improved quality of lifer78
    • Use of continuous subcutaneous insulin infusion is associated with reduction in all-cause and cardiovascular mortality when compared with multiple daily insulin injections r46
    • Automated insulin delivery systems that combine an insulin pump, a continuous glucose sensor, and an algorithm controller that adjusts insulin delivery are available; these form an artificial or "bionic pancreas" r42r43r82r83
      • Patients still must enter carbohydrate intake and periodically calibrate the sensor
      • The simplest form is a sensor-augmented pump that suspends insulin delivery when glucose reaches low threshold; these pumps are ideal for patients with frequent nocturnal hypoglycemia, recurrent severe hypoglycemia, or hypoglycemia unawareness r84
      • In hybrid closed-loop systems, pump automatically adjusts delivery of basal insulin based on glucose values as determined by the continuous glucose monitor, without requiring intervention from the user; the pump automatically increases, decreases, and suspends basal insulin delivery in response to continuous glucose monitoring; user initiates delivery of mealtime boluses r84
        • More advanced systems also deliver automated correction boluses (advanced hybid closed-loop systems) r85
      • Patients using completely automated insulin delivery systems had greater reduction in hemoglobin A1C and spent a greater percentage of time in the target glucose range without an increase in frequency of hypoglycemia compared with those using other modes of insulin delivery along with continuous glucose monitoring r45
      • Several commercially available hybrid closed-loop systems have been approved by FDA r41r85
        • Patients may also develop "do-it-yourself" closed-loop systems using open-source algorithms designed to automate insulin delivery that link to existing continuous glucose monitors and insulin pumps; these have glycemic efficacy similar to that of commercially available systems r86
      • Guidelines for implementing commercial and open-source automatic insulin delivery systems in diabetes management have been developed r86r87
    • American Diabetes Association has developed a resource to help clinicians and patients in choosing the initial device to be used r88
    Indication
    • Any motivated patient who is intensively managed and has received comprehensive diabetes education
    • Ideal candidates are those who currently perform at least 3 insulin injections and self-monitored blood glucose measurements daily and who are: r31
      • Motivated to achieve optimal blood glucose control
      • Willing and able to carry out the tasks required to use this complex and time-consuming therapy safely and effectively (eg, carbohydrate counting, frequent blood glucose monitoring, maintenance of infusion sets)
      • Willing to maintain frequent contact with the health care team
    • American Diabetes Association recommends offering insulin pump therapy or automatic insulin delivery systems to all patients with type 1 diabetes who are capable of using the devices safely, either by themselves or with caregiver assistance r42
    Contraindications
    • Physical or cognitive impairment precluding insulin pump therapy
    • Do not offer a hybrid closed-loop system to: r82
      • Patients aged younger than 7 years
      • Patients who require total daily insulin dose of less than 8 units/day; system requires a minimum of 8 units/day to operate safely
    Pancreatic transplant c216
    General explanation
    • Most often performed in combination with kidney transplant, either as simultaneous pancreas-kidney transplant or as pancreas-after-kidney transplantation c217c218
      • Simultaneous pancreas-kidney transplant for patients with type 1 diabetes improves quality of life and long-term survival compared with medical management alone and compared with other transplant modalities r89
      • Pancreas-after-kidney transplant for patients with type 1 diabetes improves quality of life compared with medical treatment alone; data on whether it prolongs life expectancy are inconclusive r89
    • Pancreatic transplant alone (in the absence of an indication for kidney transplant) is controversial owing to perceived risks of mortality and immunosuppression r3
      • Cautiously recommended as a consideration for patients without kidney failure who have marked glucose lability and hypoglycemia unawareness
    • All transplant procedures require lifelong immunosuppression to prevent graft rejection and recurrence of autoimmune islet destruction
    • Simultaneous pancreas-kidney transplants function for an average of 9 years, compared with 6 years for pancreas-after-kidney transplants r90
    • 5-year pancreas allograft survival rate after pancreatic transplant alone and after pancreas-after-kidney transplant is between 55% and 70%; for simultaneous pancreas-kidney transplant recipients, 5-year graft survival rate is higher than 85% r91
    Indication
    • Consider for patients with type 1 diabetes undergoing kidney transplant in either simultaneous or sequential form r92r93
    • Simultaneous pancreas-kidney transplant is considered gold-standard therapy for patients with type 1 diabetes in addition to advanced or end-stage kidney disease without contraindications r1
    • Consider for those with preserved kidney function who have recurrent ketoacidosis or severe hypoglycemia despite aggressive glycemic management, for those with severe clinical and emotional problems with exogenous insulin therapy, and for those with consistent failure of insulin-based management r92
    • Patient selection criteria vary by center, but most pancreatic transplants are undertaken for patients aged younger than 50 years who do not have obesity or coronary artery disease r94
    Contraindications
    • Active malignancy or infection
    • Psychiatric disease so severe or unstable that the stress of a major operation would likely result in marked decompensation
    • Inability or unwillingness to take immunosuppressant medications regularly such that graft failure would be certain
    Pancreatic islet transplant r95c219
    General explanation
    • Islet allografting involves harvesting islets from pancreases of deceased organ donors
      • After pancreas selection from deceased donor, islets are extracted, isolated, and purified
      • Islets are infused via a percutaneous transhepatic catheter that has been guided into the hepatic portal vein
      • Requires long-term immunosuppression to prevent graft rejection and recurrence of autoimmune islet destruction
    • Ultimate goal of islet transplant is to achieve insulin independence
    • Euglycemia without insulin was maintained in approximately 44% of patients for an average of 3 years r96
    • FDA has approved an allogeneic pancreatic islet cellular therapy (Lantidra) for the treatment of adults with type 1 diabetes who are unable to approach glycemic targets because of current repeated episodes of severe hypoglycemia despite intensive diabetes management and education r97r98
    Indication
    • There are no standard criteria, but most centers require patients to meet all of the following criteria: r95
      • At least 5 years after type 1 diabetes diagnosis
      • Aged older than 18 years
      • Negative stimulated C-peptide test result (less than 0.3 ng/mL)
      • Hypoglycemic unawareness and glycemic lability (eg, brittle diabetes, high variability in glucose levels) despite optimal insulin therapy
    • Other criteria that may be required include:
      • Absence of malignancy or untreated infection
      • Ability to comply with immunosuppression and close follow-up
    • American Diabetes Association recommends referring patients with type 1 diabetes and debilitating complications of the disease to research centers for protocolized islet cell transplant, if patients are interested in study participation r3
    • Can be offered to older adult patients and those with medical comorbidities who are not eligible for whole-pancreas transplant r1
    • Diabetes Canada recommends considering pancreatic islet transplant (as an alternative to whole pancreas transplant) for patients with preserved kidney function or patients who have undergone successful kidney transplant who have persistent metabolic instability (severe glycemic lability or severe hypoglycemia) despite best efforts to optimize glycemic control r93
    Contraindications
    • For islet-alone transplant: r99
      • Uncontrolled hypertension
      • Severe cardiac disease
      • Macroalbuminuria
      • GFR less than 80 mL/minute/1.73 m²
      • Inability or unwillingness to take immunosuppressant medications regularly

    Complications

    • Portal vein thrombosis
    • Bleeding
    • Portal hypertension

    Comorbidities

    • Hypertension c220c221c222d4
      • Treatment of hypertension reduces cardiovascular events and microvascular complications; however, a specific blood pressure goal for patients with diabetes has been uncertain; suggested targets vary by professional society r29r34
      • American Diabetes Association, American College of Cardiology/American Heart Association, and others generally recommend a target blood pressure lower than 130/80 mm Hg for patients with diabetes
        • Individualize treatment but do not target to less than 120/80 mm Hg, as this is associated with adverse events r33
      • Association of British Clinical Diabetologists and Renal Association UK recommend blood pressure target of lower than 140/90 mm Hg for patients without microalbuminuria and lower than 130/80 mm Hg for those with microalbuminuria (urine albumin to creatinine ratio greater than 3 mg/mmol) r100
        • Target blood pressure of 120/80 mm Hg is recommended for adults younger than 30 years, and 140/90 mm Hg, for those older than 65 years
        • It may be appropriate to target a diastolic blood pressure of lower than 80 mm Hg in selected patients aged 30 to 65 years with higher lifetime risk due to earlier age at onset of type 1 diabetes
        • A higher target of 150/90 mm Hg may be appropriate for frail adults aged older than 75 years
      • Treatment
        • Advise all patients with blood pressure higher than 120/80 mm Hg to undertake lifestyle changes for reducing blood pressure, such as: r33
          • Weight loss for those with overweight or obesity c223c224c225c226
          • DASH diet (Dietary Approaches to Stop Hypertension) or variations thereof; such diets include reducing sodium intake and increasing potassium intake c227
          • Moderation of alcohol intake c228c229c230c231
          • Increased physical activity
        • Start pharmacotherapy in addition to lifestyle changes for patients with blood pressure higher than 130/80 mm Hg r33
          • For patients with diabetes and hypertension but without albuminuria for whom cardiovascular disease prevention is the primary goal, any of the following drug classes may be considered: ACE inhibitor, angiotensin receptor blocker, thiazide diuretic, or dihydropyridine calcium channel blocker
          • For patients with hypertension, diabetes, and early-stage heart failure, treatment with a thiazide-type diuretic or an ACE inhibitor is more effective than treatment with a calcium channel blocker in preventing progression to symptomatic heart failure r101
          • For patients with diabetes, albuminuria, and hypertension, start either an ACE inhibitor or an angiotensin receptor blocker, but not both; titrate to maximum tolerated dose r100
          • Multidrug therapy (ie, thiazide diuretic and ACE inhibitor/angiotensin receptor blocker at maximal doses) is often required to achieve blood pressure target r33
            • If blood pressure is 150/90 mm Hg or higher, start pharmacotherapy with 2 agents in addition to lifestyle modifications
    • Dyslipidemia c232d5
      • There is a lack of consensus among medical professional organizations regarding the use of numeric lipid goals
        • American Diabetes Associationr33 and American Heart Associationr102 do not specify a numeric LDL-C goal
        • American Association of Clinical Endocrinologists recommends an LDL-C goal less than 100 mg/dL for patients with diabetes and no other atherosclerotic cardiovascular disease or major risk factors (high risk), less than 70 mg/dL for patients with 2 or more major risk factors for atherosclerotic cardiovascular disease (very high risk), and less than 55 mg/dL for patients with established cardiovascular disease (extreme risk) r29r37
      • Treatment
        • Lifestyle modifications for dyslipidemia are recommended for all patients with diabetes, regardless of whether pharmacotherapy is used, including:
          • Medical nutrition therapy (low saturated fat, low trans fat, low cholesterol, increased omega-3 fatty acids, increased fiber)
          • Weight loss, if necessary
          • Increased physical activity
          • Smoking cessation
        • Intensify lifestyle modifications and optimize glycemic control for patients with triglyceride levels 150 mg/dL or higher and/or HDL-C levels lower than 40 mg/dL (males) or 50 mg/dL (females) r33
        • Pharmacotherapy
          • Statin therapy is first line drug therapy for patients with dyslipidemia; because adults with type 1 diabetes are at substantial risk for coronary artery disease, moderate- or high-intensity statin therapy is indicated r102
            • Primary prevention r33
              • Moderate-intensity statin therapy is indicated for adults aged 40 to 75 years with diabetes mellitus without known atherosclerotic cardiovascular disease r103
              • High-intensity statin therapy to reduce the LDL-C by 50% of baseline or greater and to target an LDL-C goal of less than 70 mg/dL is indicated for adults aged 40 to 75 years who are at higher risk (1 or more atherosclerotic cardiovascular disease risk factors)
              • Addition of ezetimibe or a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor to maximum tolerated statin therapy is reasonable for these patients, especially those with multiple atherosclerotic cardiovascular disease risk factors and an LDL-C of 70 mg/dL or greater
              • Initiation of statin therapy may be reasonable for adults aged 20 to 39 years with diabetes and additional atherosclerotic cardiovascular disease risk factors or long-standing diabetes (ie, 20 or more years)r103r33
              • Initiation of moderate-intensity statin therapy is reasonable for adults older than 75 years with diabetes based on individual risks and benefits; it is reasonable for those who are already on statin therapy to continue beyond age 75 years r36r104
            • Secondary prevention
              • High-intensity statin therapy to target an LDL-C reduction of 50% or more from baseline with a goal of less than 55 mg/dL is recommended for patients with diabetes and atherosclerotic cardiovascular disease
              • Addition of ezetimibe or a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor is recommended if goals are not achieved on maximum tolerated statin therapy
          • Patients who are intolerant of statin therapy who require cholesterol-lowering therapy can be treated with bempedoic acid or PCSK9 inhibitor therapy with monoclonal antibody treatment or inclisiran siRNA r33
    • Chronic kidney disease c233d6
      • Chronic kidney disease in patients with diabetes may occur as a complication of diabetes itself or have other causes
      • Patients with diabetes and kidney disease have substantially elevated mortality rates, which are primarily caused by cardiovascular disease r105
      • Treatment with an ACE inhibitor or an angiotensin receptor blocker is recommended for patients with albuminuria (urine albumin–creatinine ratio 30 mg/g creatinine or higher) and/or eGFR less than 60 mL/minute/1.73 m² to prevent the progression of kidney disease and reduce cardiovascular events r106
      • As GFR declines, insulin dose adjustments are required because of reduced renal insulin clearance
      • Risks of hypoglycemia and hypoglycemia unawareness are greater for patients with chronic kidney disease; hemoglobin A1C targets may need to be relaxed for those with diabetes and kidney disease
    • Coronary artery disease r33c234
      • Use American College of Cardiology/American Heart Association atherosclerotic cardiovascular disease risk calculator to assess 10-year atherosclerotic cardiovascular disease risk and to guide therapy r33r102
      • Promote lifestyle modifications to reduce cardiovascular risk, including: r107r108
        • Smoking cessation
        • Maintaining body weight within reference range
        • Regular physical activity
        • Consumption of a balanced diet replete with fruits and vegetables, low in saturated fat and sodium, and enriched with whole grains
      • Maintaining optimal glycemic control may prevent cardiovascular events and reduces risk of recurrent events
      • Treat risk factors such as hypertension and dyslipidemia
      • Antiplatelet therapy with low-dose aspirin is recommended for secondary prevention in patients with a history of cardiovascular disease and may be considered for primary prevention for patients at increased risk for cardiovascular events; use clopidogrel in event of aspirin allergy r33
        • Also consider ACE inhibitor or angiotensin receptor blocker for patients with known cardiovascular disease
      • Routine screening for coronary artery disease is not recommended for asymptomatic patients
      • Obtain resting ECG for patients with hypertension or suspected cardiovascular disease; exercise ECG can also be used as an initial screening test
      • Exercise ECG may be considered for cardiovascular risk assessment for patients with cardiac symptoms or an abnormal resting ECG
      • Coronary artery calcium measurement may be considered for patients aged 40 years or older
    • Psychosocial disorders
      • Diabetes distress (also called diabetes-related distress) is the experience of being overly burdened by the ongoing behavioral demands of managing the disease (eg, medication dosing, frequency, and titration; monitoring blood glucose level, food intake, and eating patterns; physical activity) r109
        • Refer such patients to diabetes education or to a mental health specialist if areas of diabetes care are adversely impacted
      • Depression c235
        • Highly prevalent in patients with diabetes (approximately 21% of patients diagnosed with type 1 diabetes are affected by depression) r110
        • Associated with increased risk of myocardial infarction and mortality
        • Depression and diabetes distress are associated with poor self-care, nonadherence to treatment plan, and poor glycemic control
        • Screen patients annually and refer to a mental health specialist for assessment and treatment
      • Anxiety r110c236
        • Anxieties unique to diabetes include fear of complications and hypoglycemia
        • Screen for anxiety about insulin injections or infusion, complications, and hypoglycemia when it appears to interfere with self-management behaviors r40
        • Refer to a mental health specialist patients who report fear, dread, or irrational thoughts or show anxiety symptoms such as avoidance behaviors, excessive repetitive behaviors, or social withdrawal
      • Disordered eating r40c237
        • Omitting insulin to promote glycosuria to lose weight is the most commonly reported disordered eating behavior
        • Screen for disordered eating when hyperglycemia and weight loss are unexplained
          • One validated screening tool is the Diabetes Eating Problems Survey,r111 which includes questions regarding insulin adjustment specifically for the purposes of weight reduction

    Special populations

    • Older adults
      • Standard glycemic targets are appropriate for healthy older adults who are functionally and cognitively intact with a significant life expectancy r112
        • Hemoglobin A1C: below 7.0% to 7.5%
        • Bedtime blood glucose level: 80 to 180 mg/dL
        • Fasting blood glucose level: 80 to 130 mg/dL
      • Less stringent glycemic targets are appropriate for older adults in intermediate health with multiple medical comorbidities or mild to moderate functional or cognitive impairments r113
        • Hemoglobin A1C: below 8.0%
        • Bedtime blood glucose level: 100 to 180 mg/dL
        • Fasting blood glucose level: 90 to 150 mg/dL
      • For older adults with very complex/poor health (end-stage chronic conditions or severe functional or cognitive impairments), in long-term care, or at the end of life, focus should be avoiding hypoglycemia and symptomatic hyperglycemia rather than specific A1C targets r114
      • Avoid hypoglycemic events in older adults with diabetes, as these increase risk of cognitive decline r113
        • Routinely ask patients and caregivers about hypoglycemia and hypoglycemia unawareness
        • Simplifying insulin regimens (ie, with use of premixed insulins) may be appropriate to avoid errors and hypoglycemic events
        • Consider continuous glucose monitoring to minimize hypoglycemia
      • Older adults continue to require some form of basal insulin even if they are not eating meals r113
      • Older adults commonly need extra assistance with monitoring and insulin injections because deficits in self-care capacity, mobility, and autonomy can adversely impact glycemic control r113
      • Encourage adequate nutrition, protein intake, and exercise, including aerobic activity, weight-bearing exercise, and/or resistance training
      • Individualize screening and treatment of other comorbidities and complications for older patients
    • Pregnant patients
      • Pregestational type 1 diabetes affects 0.1% to 0.2% of all pregnancies r3
      • Manage patients with preexisting diabetes who are planning a pregnancy or who become pregnant in a multidisciplinary care setting, if available
      • Offer preconception counseling to all patients with diabetes and reproductive potential as part of routine care r35
        • Include:
          • Comprehensive nutrition assessment and counseling
          • Lifestyle recommendations
          • Comprehensive diabetes self-management education, including glycemic targets
          • Counseling on diabetes in pregnancy
          • Supplementation with prenatal vitamins with folic acid
          • Comprehensive medical evaluation
          • Appropriate screening for diabetes and pregnancy-related complications and comorbidities, genetic diseases, and infectious diseases
            • Refer for baseline ophthalmologic examination in first trimester and monitor every trimester and for 1 year post partum as indicated by degree of retinopathy
          • Immunizations
          • Contraceptive planning
      • Some medications commonly used for both diabetes and its complications are teratogenic and should be discontinued before conception or during pregnancy, including: r35
        • Statins
        • ACE inhibitors
        • Angiotensin receptor blockers
      • Diabetes is associated with increased risk of preeclampsia; prescribe low-dose aspirin during second and third trimesters to reduce risk r35
        • Doses of 100 to 150 mg/day are recommended; however, a dose of 162 mg/day may be acceptable (ie, 2 of the 81-mg tablets, which is the low-dose aspirin available in the United States)
        • Aspirin doses of less than 100 mg are not effective in reducing risk of preeclampsia
      • Glycemic targets for pregnant patients with type 1 diabetes
        • American Association of Clinical Endocrinologists targets r29
          • Hemoglobin A1C: lower than 6% if it can be accomplished without significant hypoglycemia
          • Preprandial, bedtime, and overnight glucose levels: 60 to 95 mg/dL
          • 1-hour postprandial glucose: 110 and 140 mg/dL
          • 2-hour postprandial blood glucose level: 100 to 120 mg/dL
        • American Diabetes Association targets r35
          • Hemoglobin A1C: 6% or lower
          • Fasting blood glucose level: lower than 95 mg/dL
          • 1-hour postprandial blood glucose level lower than 140 mg/dL
          • 2-hour postprandial blood glucose level lower than 120 mg/dL
      • Pregnancy changes maternal insulin sensitivity, which results in altered insulin requirements r35
        • First-trimester insulin requirements are typically lower, whereas second- and third-trimester requirements are typically higher, owing to increasing insulin resistance
        • Risk of hypoglycemia is increased in the first trimester, and hypoglycemia awareness may be reduced
        • Pregnancy is a ketogenic state, and DKA can occur at lower blood glucose levels than in nonpregnant patients
        • Either multiple daily injections or insulin pump technology can be used
        • Preprandial and postprandial self-monitoring of blood glucose is recommended
        • When used as an adjunct to preprandial and postprandial blood glucose monitoring, continuous glucose monitoring can help achieve glycemic targets and reduce macrosomia and neonatal hypoglycemia
    • Hospitalized patients r32
      • Obtain hemoglobin A1C for all admitted patients if no previous readings in the past 3 months
      • Exogenous insulin is required regardless of nutritional intake and should be administered using validated protocols that allow for adjustments based on glycemic fluctuations
        • Consult with specialized diabetes or glucose management team whenever available
      • Maintain a glucose level between 140 and 180 mg/dL in most critically and noncritically ill patients
        • More stringent glucose targets between 110 and 140 mg/dL may be appropriate for select patients (eg, those with previous cardiac surgery, stroke, or acute ischemic cardiac events), provided that the target can be achieved without significant hypoglycemia
        • A target range of 100 to 180 mg/dL may be acceptable in noncritically ill patients
        • Glucose levels higher than 250 mg/dL may be acceptable in terminally ill patients with a short life expectancy
      • Avoid iatrogenic hypoglycemia (less than 70 mg/dL) r32
        • Inpatient hypoglycemia is associated with higher complication rates and greater mortality
        • Identify potential triggers of hypoglycemia and manage preemptively when possible
          • Triggers include emesis, reduced oral intake, new NPO status, reduction in glucocorticoid doses, interruption or change in enteral/parenteral feedings, change in infusion rate of IV solutions that contain dextrose, or inappropriate timing of short-acting insulin in relation to meals
        • Hemoglobin A1C level at admission can predict risk for in-hospital hypoglycemia for older patients; levels lower than 7% are associated with highest rate of hypoglycemic episodes r115
        • Continuous glucose monitoring is recommended for inpatients at high risk for hypoglycemia r116r117
          • Use in combination with periodic point-of-care blood glucose testing to validate the accuracy of continuous glucose monitoring
      • Patients in non-ICU settings r32
        • Clinically stable patients with good nutritional intake are preferably given scheduled multiple daily subcutaneous injections of insulin with basal, prandial, and correctional components
        • A basal plus bolus correction insulin regimen is the preferred treatment for noncritically ill patients with poor oral intake or those who have NPO status
        • Home insulin regimen can be continued, but most often, the usual insulin schedule must be modified because of altered insulin needs due to the effects of illness, any alterations in renal function, and change in nutritional intake
        • Self-management of insulin dosing is appropriate for clinically stable, alert patients who successfully use continuous subcutaneous insulin infusion devices at home r118
        • Prolonged use of sliding scale insulin regimens is inadvisable
        • Daily adjustments in insulin dosing are made based on blood glucose patterns, as needed
          • Adjust basal insulin dose according to fasting glucose levels (titrate up if fasting level is higher than 140 mg/dL)
          • Adjust nutritional (prandial) insulin based on the glucose level before each meal
      • Patients in ICU setting r32
        • Administer IV insulin infusions using validated written or computerized protocols (where available) that allow for predefined adjustments in the insulin infusion rate based on glycemic fluctuations and insulin dose
      • Perioperative patients
        • Target glucose range for the perioperative period is 100 to 180 mg/dLr32; attempts to achieve tighter perioperative glucose control lead to unacceptable rates of hypoglycemiar119
        • Measure blood glucose level every 4 to 6 hours while NPO and provide additional doses of short- or rapid-acting insulin as needed to limit hyperglycemia
      • Patients receiving enteral/parenteral feedings r32
        • Provide basal, prandial, and correctional insulin; basal insulin must continue even if feedings are held or discontinued
        • Dosing can be determined based on preadmission basal insulin dose
        • NPH (neutral protamine Hagedorn)–based or basal bolus regimens are recommended for patients receiving enteral nutrition r120
        • Tube feedings: use 1 unit of insulin for 10 to 15 g of carbohydrate
        • Enteral bolus feeding: give 1 unit of regular or immediate-acting insulin per 10 to 15 g of carbohydrate before each feeding
        • Continuous peripheral or central parenteral delivery: add 1 unit of regular insulin per 10 g of dextrose; insulin may be added to the solution and administered parenterally
        • Administer correctional doses, based on point-of-care blood glucose measurements, every 6 hours in all cases using regular insulin or an immediate-acting insulin
        • Continuous enteral or parenteral feeding results in a constant postprandial state and attempting to reduce blood glucose levels to lower than 140 mg/dL will greatly increase the risk of hypoglycemia

    Monitoring

    • Follow-up r1
      • Visits with a provider should occur at least annually
      • More frequent visits are beneficial for:
        • Newly diagnosed patients
        • Patients not meeting therapeutic goals
        • Patients needing closer management of complications or comorbidities
        • Therapeutic regimen changes
        • Patients needing more intensive psychosocial support and patient education
      • Preliminary data suggest that telemedicine and telemedical interventions, in lieu of or in addition to in-person visits, can improve clinical outcomes, quality of life, access to care, costs, and patient satisfaction r1r121
    • Glycemic control c238
      • Real time measurements are obtained via self-monitoring of blood glucose using a glucometer or continuous glucose monitoring
        • Frequency of self-monitoring varies among patients, but for those on intensive insulin regimens, self-testing typically occurs 6 to 10 times per day
        • Most patients on intensive insulin regimens (multidose insulin or insulin pump therapy) should perform self-monitoring of blood glucose at a minimum before meals and snacks
        • Additional testing times include after meals or snacks, at bedtime, before exercise, when low blood glucose level is suspected, after treating low level until euglycemic, and before critical tasks (eg, driving)
      • Long-term control r28
        • Measure hemoglobin A1C at least twice a year (or periodically use other assessment of glycemia such as time in range or glucose management indicator) in patients who are meeting treatment goals and every 3 months in those whose treatment has changed or who are not meeting goals c239
          • Hemoglobin A1C provides a 2- to 3-month estimation of glycemia, although it does not provide a measure of glycemic variability or hypoglycemia
        • Review patient records of self-monitored blood glucose and continuous subcutaneous insulin infusion data (if applicable) every 3 months
      • A discrepancy between preprandial self-monitored blood glucose results and hemoglobin A1C can be due to high postprandial blood glucose or other factors
        • Measure serum fructosamine level as a substitute for hemoglobin A1C in patients with hemoglobinopathies or other conditions that shorten RBC life span
        • When discrepancies do arise, use other glucose measurement methods such as fructosamine, glycated albumin, and, in particular, data from continuous glucose monitor to assess glycemic control, analyze glucose trends, and adjust insulin therapy r122
    • Other laboratory evaluation
      • Measure fasting lipid profile, liver enzyme levels, spot urinary albumin to creatinine ratio, serum creatinine with estimated GFR, and TSH level annually c240c241c242c243c244
      • Check serum potassium levels in patients on ACE inhibitors, angiotensin receptor blockers, and/or diuretics at least annually; more frequent monitoring may be necessary for patients with known chronic kidney disease or changes in medication regimen
    • Surveillance for complications
      • Nephropathy r106
        • Measure urine albumin to creatinine ratio and estimated GFR at least annually; if urinary albumin is more than 300 mg/g of creatinine and/or estimated GFR is less than 60 mL/minute/1.73 m², measure every 6 months c245
      • Retinopathy r123
        • Refer to retinal specialist for initial dilated and comprehensive eye examination within 5 years of initial diabetes diagnosis
        • Once initial examination is complete, annual dilated eye examinations are recommended; these may be done every 2 years for some patients who have 1 or more consecutive eye examinations with normal findings
      • Neuropathy r123
        • Assess all patients for peripheral neuropathy within 5 years of initial diabetes diagnosis and at least annually thereafter
          • Assessment includes temperature, pinprick or vibration, and 10-g monofilament examination
        • Also assess presence of autonomic neuropathy in patients with microvascular complications
      • Foot care r123
        • Perform comprehensive foot examination annually, which includes: c246
          • Visual inspection
          • Assessment of foot deformities
          • Neurologic and vascular assessment
      • Cognitive impairment r40r113
        • Screen annually for early detection of cognitive impairment in adults aged 65 years or older and monitor cognitive capacity longitudinally
      • Heart failure
        • Measure natriuretic peptide or high-sensitivity cardiac troponin at least annually to identify early-stage heart failure and determine risk for progression to symptomatic heart failure r101
          • Most data regarding biomarker testing to predict onset of heart failure in patients with diabetes has been focused on patients with type 2 diabetes; however, available data suggest similar associations exist in patients with type 1 diabetes
      • Osteoporosis and fractures r75
        • Monitor bone mineral density using dual-energy X-ray absorptiometry in high-risk patients aged older than 65 years and in younger patients with multiple risk factors every 2 to 3 years
      • Peripheral arterial disease r33
        • Screen with ankle-brachial index testing in asymptomatic patients aged 50 years and older and patients of any age with microvascular disease in any location, foot complications, or end-organ damage due to diabetes
        • Also consider screening for individuals who have had diabetes for 10 or more years
    • Surveillance for coexistent autoimmune diseases
      • Celiac disease
        • Measure serum levels of tissue transglutaminase or antiendomysial antibodies if the following symptoms develop: r3c247c248
          • Diarrhea
          • Weight loss or poor weight gain
          • Abdominal pain
          • Bloating
          • Chronic fatigue
          • Malnutrition due to malabsorption
          • Unexplained hypoglycemia
          • Erratic blood glucose levels
        • Refer patients who test positive for either of these antibodies to a gastroenterologist for possible small bowel biopsy r3
      • Autoimmune thyroid disease
        • Measure serum TSH level annuallyr75 or more frequently if the following events occur: unusual glycemic variation, thyromegaly on examination, or symptoms of thyroid diseaser3c249
    • Monitoring of comorbidities r33r108r124
      • Hypertension c250
        • Measure blood pressure at every routine visit, at least annually
        • Advise patients with hypertension and diabetes to monitor blood pressure at home
        • Check serum potassium levels in patients on ACE inhibitors, angiotensin receptor blockers, and/or diuretics at least annually; more frequent monitoring may be necessary for patients with known chronic kidney disease or changes in medication regimen r75
      • Dyslipidemia r75
        • Measure lipid profile at time of diabetes diagnosis and annually thereafter; consider less frequent measurement for patients without dyslipidemia and not on cholesterol-lowering agents c251
        • If pharmacologic (statin) therapy is initiated, measure lipid profile before initiation of therapy, 4 to 12 weeks after initiation and dose changes, and at least annually otherwise
      • Cardiovascular disease r33c252
        • Annually assess cardiovascular risk factors (eg, dyslipidemia, hypertension, family history of early cardiovascular disease, smoking, presence of albuminuria [strongly linked to cardiovascular disease]); manage as appropriate
        • In addition to screening for hypertension and dyslipidemia, measure urinary albumin to creatinine ratio yearly to screen for kidney disease, beginning 5 years after diagnosis; obtain creatinine level to estimate GFR
          • If kidney disease develops, treatment with ACE inhibitors is recommended to reduce disease progression and mortality
    • Treatment intensification
      • When intermediate outcomes are not met (eg, failure to meet hemoglobin A1C, blood pressure, and lipid goals), the following strategies are advisable:
        • Assess adherence to lifestyle recommendations and pharmacotherapy
          • Explore barriers to adherence with the patient/caregiver and find a mutually agreeable approach to overcoming the barriers
          • If adherence is high, implement the following changes: r40
            • Increase the frequency of self-monitoring of blood glucose
            • Change doses and timing of insulin administration
            • Transition to continuous subcutaneous insulin infusion therapy
        • Establish a follow-up plan that confirms the planned treatment change and assesses progress in reaching the target

    Complications and Prognosis

    Complications

    • Acute
      • Hypoglycemia (treatment related) c253
        • Results from the interplay of relative or absolute therapeutic insulin excess and compromised counterregulatory defenses against falling glucose levels
        • Glucose thresholds r117r125
          • Hypoglycemia below 70 mg/dL (but at least 54 mg/dL) is low enough to alert patient to ingest fast-acting carbohydrate to prevent progressive hypoglycemia
          • Hypoglycemia below 54 mg/dL indicates serious, clinically important hypoglycemia; associated with increased risk for cognitive dysfunction and mortality
          • Any hypoglycemia (no specific threshold) characterized by altered mental and/or physical state requiring assistance is considered severe; this is life-threatening and requires emergent treatment
        • Hypoglycemia unawareness refers to impairment or loss of the sympathoadrenal and neurogenic responses to hypoglycemia; it occurs in the setting of recurrent hypoglycemia or autonomic failure and can be reversed by scrupulous avoidance of hypoglycemia
          • Hypoglycemia unawareness should prompt reevaluation and adjustment of treatment regimen r28
          • Patients with an episode of hypoglycemia unawareness should raise their glycemic targets to strictly avoid hypoglycemia for at least several weeks to reduce recurrent episodes
        • Continuous glucose monitoring is preferred over self- monitoring of blood glucose by fingerstick for patients with type 1 diabetes receiving multiple daily insulin injections r117
        • Treatment
          • Alert and conscious patients should consume glucose (eg, juice, soft drink, milk, glucose tablet), then remeasure blood glucose after 15 minutes; repeat glucose intake if blood glucose remains low r3
          • Confused or unconscious patients should receive an injection of glucagon subcutaneously or intramuscularly from medical personnel or a trained family member and then be referred for emergency medical care
        • If untreated, treatment-related hypoglycemia can lead to unconsciousness, seizure, coma, and death
        • Severe or frequent hypoglycemia is associated with cognitive decline in older adults, increased risk for cardiovascular events, and increased mortality
        • Prescribe glucagon for all patients with type 1 diabetes; caregivers and family members should know where it is and when and how to administer it r28
      • DKA r4c254d7
        • Presents with the biochemical triad of marked hyperglycemia (higher than 250 mg/dL), ketonemia, and metabolic acidosis
        • Signs and symptoms include polyuria, polydipsia, polyphagia, weight loss, weakness, abdominal pain, nausea, vomiting, Kussmaul respirations, and acetone breath
        • Treat with fluid resuscitation, insulin infusion, electrolyte replacement, and correction of the precipitating factors r126
        • Suggested initial treatment: r4
          • IV rehydration with normal saline at rate of 500 to 1000 mL/hour during the first 2 to 4 hours; add 5% to 10% dextrose when plasma glucose level reaches 200 mg/dL
          • Initiate continuous IV insulin infusion provided that serum potassium level is higher than 3.3 mEq/L; avoid rapid correction of hyperglycemia to prevent development of cerebral edema
            • Delay insulin therapy for patients with serum potassium levels lower than 3.3 mEq/L at admission because it may cause severe hypokalemia and cardiac arrhythmias; administer potassium replacement at a rate of 10 to 20 mEq/hour until level increases to greater than 3.3 mEq/L
          • Monitor serum potassium and plasma glucose levels
          • Begin potassium replacement when serum level is lower than 5.2 mEq/L; aim to maintain a level of 4 to 5 mEq/L
        • Diabetic self-management education, home ketone testing, and telemedicine are examples of interventions that can reduce DKA risk and prevent admissions r1
    • Chronic
      • Cardiovascular disease r33c255
        • Patients with diabetes are at 2 to 3 times higher risk for cardiovascular disease and associated increased mortality rate compared with patients with euglycemia r127
          • Poor glycemic control is associated with an increased risk of cardiovascular disease; cardiac autoimmunity may be a mechanism by which hyperglycemia contributes to cardiovascular complications r128
        • Coronary artery disease is the leading cause of mortality, and cumulative incidence of coronary artery disease in those with type 1 diabetes is approximately 15% over 15 years of follow-up r108d8
        • Heart failure is another major source of morbidity and mortality in patients with diabetes; rates of heart failure–related hospitalization and mortality are 2- to 5-fold higher for patients with type 1 diabetes compared with those without r101
        • Intensive metabolic control, aimed at achieving near euglycemia, reduces the risk of cardiovascular events, including myocardial infarction, stroke, and death from cardiovascular disease r129r130
        • Antiplatelet therapy with low-dose aspirin, statin therapy, and aggressive blood pressure and glycemic control is recommended; consider the addition of an ACE inhibitor or angiotensin receptor blocker
      • Peripheral vascular disease r33c256d9
        • Especially atherosclerotic occlusive disease of the medium and small vessels of the lower extremities, initially characterized by intermittent claudication
        • Presence of peripheral vascular disease is indicative of systemic vascular disease (ie, coronary, renal, cerebral) and associated risk for myocardial infarction, cerebral vascular events, and death
        • Treatment focuses on smoking cessation, exercise therapy, foot care, glycemic control, control of dyslipidemia and hypertension, antiplatelet therapy, and symptom control with pentoxifylline or cilostazol
        • In 1 study, the cumulative probability of lower-extremity amputation among patients with type 1 diabetes was 11% for female patients and 20% for male patients r131
      • Retinopathy r123c257d10
        • Diabetic retinopathy includes macular edema, nonproliferative diabetic retinopathy, and proliferative diabetic retinopathy
        • Present in 79% of patients with type 1 diabetes in the United States r132
        • Begin annual assessment for diabetic retinopathy within 5 years of type 1 diabetes diagnosis r123
        • Intensive treatment of diabetes reduces the rate of incident retinopathy, slows progression of retinopathy, and preserves visual acuity r133
        • Progression of diabetic retinopathy may be slowed by optimizing control of blood pressure, lipids, and glycemia
        • Treatment may include laser photocoagulation therapy, intravitreal injections of anti–vascular endothelial growth factor, and intravitreal injections of corticosteroid r134
      • Nephropathy c258d6
        • Diabetic nephropathy develops in 20% to 40% of people with diabetes, typically around 5 to 15 years after diagnosis of type 1 diabetes r106
        • Elevated urinary albumin excretion is usually the first indicator
        • Begin annual assessment for diabetic nephropathy 5 years after diagnosis, including assessment of urinary albumin to creatinine ratio and serum creatinine level for estimated GFR r106r135
          • Albumin to creatinine ratio greater than 30 mg/g (from 2 or more specimens) is considered pathologic r135
            • Albumin to creatinine ratio of 30 to 299 mg/g is referred to as moderately increased albumin excretion
            • Albumin to creatinine ratio of 300 mg/g or higher is referred to as severely increased albumin excretion
        • Onset and progression of diabetic nephropathy may be slowed with aggressive control of blood pressure, lipids, and glycemia r136r137
        • Treatment with an ACE inhibitor or an angiotensin receptor blocker is recommended for a urinary albumin to creatinine ratio greater than 30 mg/g creatinine r106r137
          • Both drug classes have the dual effects of controlling blood pressure and slowing the progression of kidney damage
          • Avoid combined use of an ACE inhibitor and an angiotensin receptor blocker, owing to higher risks of hyperkalemia and acute kidney injury
        • Supportive care measures are also important components of management (eg, maintaining a low-protein/low-fat diet, engaging in physical exercise, reducing alcohol consumption, and smoking cessation)
      • Neuropathy c259
        • Diabetic neuropathy affects approximately 28% of patients with type 1 diabetes r138
        • Begin annual neurologic assessment 5 years after type 1 diabetes diagnosis r123
        • Optimizing glycemic control, blood pressure, and lipid levels can prevent or delay the development of neuropathy in people with type 1 diabetes, particularly when near normal glucose control is achieved early in the course of diabetes r123
        • Encompasses an array of heterogeneous conditions, most commonly classified as diabetic peripheral neuropathy and diabetic autonomic neuropathy
          • Diabetic peripheral neuropathy c260
            • Signs and symptoms include decreased sensation, pain, paresthesia, decreased reflexes, decreased pulses, abnormalities in foot structure, impaired skin integrity, and decreased skin temperature; occurs primarily in the feet, legs, and ankles
              • Main morbidity is foot ulceration, which may lead to gangrene and amputation r139d11
            • Painful neuropathy may be treated with tricyclic antidepressants, selective serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, and/or anticonvulsants
            • Large fiber neuropathies cause ataxia and increase the risk of falls; management consists of physical therapy, orthotics, tendon lengthening, casting, and/or surgery
            • Small fiber neuropathies may be diagnosed with a skin punch biopsy; management consists of measures to protect the feet (eg, prevention of heat injury, padded socks, daily inspection, skin emollients)
            • Painful neuropathy may be treated with tricyclic antidepressants, selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, gabapentinoids, and sodium channel blockers r123
          • Diabetic autonomic neuropathy c261d12
            • Signs and symptoms vary based on the system affected
              • Cardiovascular autonomic neuropathy: orthostatic hypotension; exercise intolerance; resting tachycardia; heart rate variability on Valsalva maneuver, deep inspiration, or position change
              • Gastrointestinal autonomic neuropathy: gastroparesis (delayed gastric emptying with bloating, heartburn, early satiety, and epigastric pain), constipation, fecal incontinence, nausea, vomiting, erratic glucose control
              • Genitourinary autonomic neuropathy: erectile dysfunction, vaginal dryness, urinary frequency, urinary urgency, urinary retention, nocturia, urinary incontinence
              • Vasomotor autonomic neuropathy: anhidrosis, hyperhidrosis, heat intolerance, impaired visceral sensation, hypoglycemic unawareness
            • Cardiovascular autonomic neuropathy is significant as a risk factor for cardiovascular mortality
            • Treatment is dependent on the system affected and is aimed at symptom management
      • Other complications r75
        • Osteoporosis and fractures
        • Cognitive impairment and dementia
        • Low testosterone

    Prognosis

    • Type 1 diabetes is associated with increased risk of mortality
      • All-cause and cardiovascular-related mortality rates are at least twice as high as in matched controls r2
      • Excess risk of death from any cause and death from cardiovascular causes appears to vary according to glycemic control, with the risk for death rising as hemoglobin A1C levels increase r140
    • Life expectancy for females and males with type 1 diabetes is reduced by approximately 13 and 11 years, respectively, compared with the general population r141
    • Over the long term, an initial period of intensive diabetes therapy (duration of 6.5 years) is associated with a modestly lower all-cause mortality rate compared with conventional therapy r140

    Screening and Prevention

    Screening

    At-risk populations

    • First-degree relatives of patients with type 1 diabetes have 5- to 10-fold elevated risk of developing diabetes when compared with the general population (approximately 5% cumulatively) r12c262

    Screening tests

    • Immune-mediated diabetes accounts for most cases of type 1 diabetes and is characterized by detectable autoimmune markers including islet cell autoantibodies and autoantibodies to glutamic acid decarboxylase, insulin, islet antigen-2 and islet antigen-2β, and zinc transporter 8
      • Stage 1 of type 1 diabetes is defined by the presence of 2 or more of these autoimmune markers and is presymptomatic
    • Screening can be considered for first-degree relatives of patients with type 1 diabetes and may identify those who are at risk for developing the disease r142c263
      • Screening, coupled with education about disease symptoms and close observation, may enable earlier identification of type 1 diabetes onset r142
        • In addition, clinical studies are evaluating various methods of preventing type 1 diabetes in patients with islet autoantibodies
      • Widespread screening of low-risk asymptomatic individuals is not recommended but may be available in the context of clinical research trials or specific screening programs that are available in Europe and the United States r5
    • Presymptomatic type 1 diabetes can be identified by testing for autoantibodies to insulin, glutamic acid decarboxylase, islet antigen 2, or zinc transporter 8
      • Presence of multiple islet autoantibodies indicates risk for subsequently developing clinical diabetes; testing for dysglycemia may aid in evaluating near-term risk r5
    • In patients in whom multiple islet autoantibodies are identified: r143
      • Monitor for disease progression with hemoglobin A1C approximately every 6 months and 75-g oral glucose tolerance test annually; can individualize frequency of monitoring
      • Consider referral to a specialized center for evaluation and/or consideration of a clinical trial or therapy aimed at delaying development of clinical diabetes

    Prevention

    • Various methods of preventing and treating stage 2 type 1 diabetes in patients with evidence of autoimmunity are being studied with promising results
    • The anti-CD3 antibody, teplizumab, may delay development of overt diabetes (stage 3) in patients with stage 2 type 1 diabetes; this has received FDA approval and can be considered in selected patients aged 8 years or older with stage 2 type 1 diabetes r143r144r145
      • A single 14-day course of daily IV teplizumab infusions delays diagnosis of type 1 diabetes by a median of approximately 2 years in individuals at high risk for developing the disease (ie, relatives of people with type 1 diabetes who themselves have stage 2 type 1 diabetes characterized by abnormal glucose tolerance and presence of at least 2 diabetes autoantibodies) r146
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