Condition

Type 1 Diabetes Mellitus in Adults

Editors: Jennifer Raymond MD, MCR; Mala S. Sivanandy MD; Samir Malkani MBBS, MD, MRCP; Zbigniew Fedorowicz PhD, MSc, DPH, BDS, LDSRCS

American College of PhysiciansProduced in collaboration with American College of Physicians
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Background Information

Description

  • Diabetes mellitus type 1 is an endocrine disorder characterized by hyperglycemia due to beta-cell destruction, usually leading to absolute insulin deficiency.
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  • Chronic hyperglycemia of diabetes can lead to multiorgan damage, resulting in renal, neurologic, cardiovascular, and other serious complications.
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Also Called

  • Type 1 diabetes
  • Juvenile onset diabetes mellitus
  • Insulin-dependent diabetes mellitus (no longer a preferred term)

Types

  • American Diabetes Association (ADA) classifies type 1 diabetes as either immune-mediated or idiopathic.
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    • Immune-mediated type 1 diabetes is reported to account for 5%-10% of diabetes. It results from cellular-mediated autoimmune destruction of beta cells of the pancreas.
    • Idiopathic type 1 diabetes is uncommon and occurs in persons with no evidence of autoimmunity.
      • It is strongly inherited, mostly in persons of Black or Asian ancestry, and not associated with human leukocyte antigens.
      • Patients with idiopathic type 1 diabetes may have permanent insulinopenia and are likely to have diabetic ketoacidosis (DKA).
  • Latent autoimmune diabetes of the adult (LADA) is a slowly progressive subtype of immune-mediated diabetes mellitus type 1 that occurs in adults.
    • Commonly used diagnostic criteria for LADA includes all of:
      • Onset of diabetes at > 30 years old
      • Presence of circulating islet autoantibodies
      • Insulin independence for ≥ 6 months after diagnosis
    • Reference - Front Med 2012 Sep;6(3):243
    • Review of management of LADA can be found in Curr Diabetes Rev 2019;15(3):188.
  • Brittle diabetes is a historic term used to refer to patients with insulin-dependent diabetes (usually type 1) who experience significant glucose variability resulting in disruption in activities of everyday life and recurrent and/or prolonged hospitalizations.
    • Brittle diabetes is reported in 3 per 1,000 patients with insulin-dependent diabetes, particularly in young female adults.
    • It can present with ≥ 1 of the following:
      • Frequent, severe, unpredictable episodes of hypoglycemia
      • Recurrent DKA
    • Brittle diabetes may be caused by delayed gastric emptying as a result of autonomic neuropathy, malabsorption, certain drugs (such as alcohol or antipsychotics), defective insulin absorption or degradation, or a defect of hyperglycemic hormones (especially glucocorticoid and glucagon).
    • The term brittle diabetes is not commonly used in current literature, and most clinicians instead refer to the clinical presentation itself (severe hypoglycemia and/or recurrent DKA).
    • Reference - Ann Endocrinol (Paris) 2006 Sep;67(4):287
  • Other types of diabetes:

Epidemiology

Incidence/Prevalence

  • In 2021, 5.7% of adults ≥ 20 years old with diabetes were reported to have type 1 diabetes treated with insulin (Centers for Disease Control and Prevention [CDC] 2024 National Diabetes Statistics Report CDC 2024 May 15).
  • STUDY SUMMARY
    0.5% prevalence of diabetes mellitus type 1 in adults in the United States in 2016-2017
    CROSS-SECTIONAL STUDY: BMJ 2018 Sep 4;362:k1497

  • STUDY SUMMARY
    incidence of type 1 diabetes 1.01 per 100,000 person-years in China from 2010 to 2013
    COHORT STUDY: BMJ 2018 Jan 3;360:j5295

Risk Factors

Family History
  • Compared to the overall risk of type 1 diabetes in the general population (0.4%), higher risk is reported in first-degree relatives.
    • Siblings of patients with type 1 diabetes are reported to have 6%-7% risk of the disease.
    • Children of female patients with type 1 diabetes are reported to have 1.3%-4% risk of the disease.
    • Children of male patients with type 1 diabetes are reported to have 6%-9% risk of the disease.
    • Monozygotic twins are reported to have > 70% long-term risk of concordant disease compared to 6% with dizygotic twins.
    • Reference - Curr Diab Rep 2017 Oct 28;17(12):129
  • Genetic predisposition is necessary, but not sufficient for developing type 1 diabetes (Nat Rev Dis Primers 2017 Mar 30;3:17016).
    • Several genetic loci have been accepted as susceptibility regions based on linkage and association studies. The HLA class II region on chromosome 6 (containing genes involved in innate and adaptive immune functions) being notable.
      • About 50% of heritability of type 1 diabetes is reported to be accounted for by this HLA region.
      • Highest risk HLA class II haplotypes are reported to include DR4-DQ8 and DR3-DQ2.
      • Some haplotypes are reported to confer disease resistance. Examples include DRB1*1501 and DQA1*0102-DQB1*0602.
      • References - Lancet 2014 Jan 4;383(9911):69, Curr Diab Rep 2017 Oct 28;17(12):129
    • ≥ 60 non-HLA loci associated with type 1 diabetes have been reported to be identified in genome wide association studies (Lancet 2018 Jun 16;391(10138):2449).
  • STUDY SUMMARY
    onset of type 1 diabetes by age 60 years reported in 65% of monozygotic twins of persons with type 1 diabetes
    COHORT STUDY: N Engl J Med 2008 Dec 25;359(26):2849

Islet Cell Autoantibodies
  • Islet cell autoantibodies is a term used to describe any groups of antibodies directed against Langerhans islets (of the pancreas) or, in some circumstances, against insulin-producing beta-cell autoantigens (Biomed Res Int 2016;2016:6219730).
  • Islet cell autoantibodies are considered biomarkers of type 1 diabetes associated autoimmunity and can be used to identify individuals at risk of developing type 1 diabetes (Nat Rev Dis Primers 2017 Mar 30;3:17016).
  • The main islet cell autoantibodies detected in type 1 diabetes include:
    • Anti-insulin autoantibodies (IAA)
    • Anti-glutamic acid decarboxylase autoantibodies (GADA)
    • Anti-islet cell (ICA)
    • Insulinoma-associated-2 autoantibodies (IA-2A), also called anti-tyrosine phosphatase autoantibodies
    • Anti-zinc transporter 8 autoantibodies (ZnT8A)
    • Reference - Biomed Res Int 2016;2016:6219730
  • Islet cell autoantibodies usually develop months to years before the symptomatic onset of diabetes.
    • IAA or GADA are typically the initial autoantibodies detected.
      • IAA usually develop first in children with the HLA-DR4-DQ8 haplotype, with a peak onset at ages 1-2 years.
      • GADA usually develop first in children with the HLA-DR3-DQ2 haplotype and who are > 1 year old.
    • IA-2A and ZnT8A can develop after IAA or GADA.
    • Development of IA-2A as either the second or third autoantibody is reported to increase risk of symptomatic type 1 diabetes.
    • Reference - Nat Rev Dis Primers 2017 Mar 30;3:17016
Increased Weight
  • STUDY SUMMARY
    high birth weight associated with increased risk of developing type 1 diabetes
    SYSTEMATIC REVIEW: Am J Epidemiol 2009 Jun 15;169(12):1428SYSTEMATIC REVIEW: Diabetologia 2010 Apr;53(4):641

Additional Risk Factors
  • STUDY SUMMARY
    increased risk of type 1 diabetes observed among first-degree family members of persons with systemic lupus erythematosus
    COHORT STUDY: JAMA Intern Med 2015 Sep 1;175(9):1518

  • STUDY SUMMARY
    stress-related disorder associated with increased risk of diabetes mellitus type 1
    COHORT STUDY: JAMA 2018 Jun 19;319(23):2388

  • STUDY SUMMARY
    presence of insulin resistance in persons with family history of diabetes mellitus type 1 may be associated with increased risk for type 1 diabetes
    COHORT STUDY: Diabetes Care 2007 Sep;30(9):2314COHORT STUDY: Diabetes Care 2008 Jan;31(1):146

Associated Conditions

Other Autoimmune Disease
Overview of Associated Autoimmunities in Type 1 Diabetes
  • The most common autoimmune conditions in patients with type 1 diabetes include:
  • Specific autoantibodies associated with these autoimmune conditions can be detected in blood serum prior to the development of clinically overt disease (Biomed Res Int 2016;2016:6219730).
  • STUDY SUMMARY
    childhood-onset type 1 diabetes associated with increased development of several comorbid autoimmune diseases in persons in the United Kingdom
    COHORT STUDY: Lancet 2023 Jun 3;401(10391):1878

  • STUDY SUMMARY
    additional autoimmune disease appears common among adults with long-term type 1 diabetes; factors associated with increased prevalence of autoimmune disease include longer diabetes duration (≥ 21 years), female gender, and later age at diabetes onset (≥ 21 years old)
    COHORT STUDY: Diabetes Care 2019 Jan;42(1):32

Autoimmune Thyroid Diseases
  • Autoimmune thyroid diseases are common in patients with type 1 diabetes.
    • Their prevalence is reported to be 2-4-times higher in patients with type 1 diabetes than in the general population.
    • Overt hypothyroidism is reported in 4%-18% of patients with type 1 diabetes, while subclinical hypothyroidism is reported in 40%–55% of patients.
    • Autoimmune thyroid disorders are characterized by lymphocytic infiltration due to a loss of immunologic tolerance to thyroid autoantigens, which is manifested in the production of autoantibodies. As a result, functional impairment of the thyroid can range in severity.
      • Autoantibodies against thyroid proteins include:
        • Thyroglobulin (ATG)
        • Thyroxin peroxidase (ATPO)
        • Thyroid-stimulating hormone receptor (A-TSHR)
      • Genetic associations have been reported.
        • Haplotypes HLA-DQA1*0301, DQB*0301, and DQB1*0201 are associated with the development of hyperthyroidism.
        • Haplotype DQA1*0501 is associated with the development of hypothyroidism.
        • Haplotype HLADQB1*05 may have a protective role against the development of autoimmune thyroid disease.
    • Autoantibodies can be developed and may be detected in patients with type 1 diabetes at different times.
      • 17%-25% of patients are reported to have autoantibodies at the time of diagnosis.
      • In most patients, autoantibodies appear within 3 years of disease progression.
      • Rarely, autoantibodies may develop prior to a type 1 diabetes diagnosis.
      • The presence of autoantibodies is reported to increase with:
        • Age
        • Duration of disease
        • Long-term persistence of anti-glutamic acid decarboxylase (GAD) autoantibodies:
          • Anti-GAD autoantibodies are produced against glutamic acid dehydrogenase.
          • Glutamic acid dehydrogenase induces conversion of glutamic acid to gamma-aminobutyric acid (GABA).
          • In the thyroid, GABA is located in follicular cells and is involved in regulation of thyroid hormone secretion.
    • Many patients do not present with symptoms of thyroid dysfunction, even in the presence of antithyroid autoantibodies.
    • When signs are present, patients more often present with hypothyroidism than with hyperthyroidism.
    • Serologic screening for thyroid disease:
      • Serologic screening and evaluation of thyroid function should be performed:
        • Every 12 months if no autoantibodies are present
        • Every 6 months if anti-thyroid autoantibodies develop
      • To screen for Hashimoto thyroiditis hypothyroidism, perform annual laboratory testing of:
        • Free thyroxine (FT4) levels
        • Thyrotropin (also called thyroid-stimulating hormone [TSH]) levels
        • Thyroid peroxidase (TPO) antibodies
        • Thyroglobulin antibodies
      • To screen for Graves disease hyperthyroidism (based on signs and symptoms thyrotoxicosis or by unexplained hypoglycemias), perform laboratory testing of
        • TSH
        • Free thyroxine (T4) and triiodothyronine (T3)
        • Thyroid-stimulating immunoglobulin (TSI)
    • Thyroid ultrasound should be performed at least once/year if autoantibodies are detected or if a goiter is found with physical exam.
    • Physiologic effects of thyroid hormones on glycemic control:
      • Even small changes in thyroid hormone levels may affect glycemic control.
      • Thyroid diseases may influence glucose metabolism and glycemic control.
        • Patients have an increased tendency toward hypoglycemia in cases of hypothyroidism, owing to:
          • Reduced intestinal glucose absorption
          • Reduced glycogenolysis
          • Reduced insulin catabolism
          • Increased insulin sensitivity
        • Patients have an increased tendency toward hypoglycemia and diabetic ketoacidosis in cases of hyperthyroidism, owing to:
          • Reduced intestinal glucose absorption
          • Increased insulin sensitivity and insulin metabolism in target tissue
          • Lipolysis
    • Reference - Biomed Res Int 2016;2016:6219730
Celiac Disease
  • Celiac disease can occur in patients with type 1 diabetes.
    • Celiac disease is a chronic autoimmune enteropathy occurring in genetically predisposed persons.
      • Celiac disease is caused by intolerance to gluten, a plant protein that is a component of certain grains including wheat, rye, and barley.
      • Types of celiac disease include silent, potential, latent, and classical.
      • Gluten induces a specific immune reaction, resulting in:
        • Production of autoantibodies (antireticulin [ARA], anti-endomysial [EMA], antigliadin [AGA], and anti-tissue transglutaminase [ATG])
        • Atrophy of intestinal villi
    • Prevalence, disease onset, and risk factors for celiac disease in patients with type 1 diabetes:
      • 90% of cases of celiac disease are reported to develop during the course of type 1 diabetes.
      • Celiac disease rarely occurs before the diagnosis of diabetes.
      • Female gender and diabetes diagnosis at an earlier age may each be associated with higher risk of celiac disease.
      • Genotypes HLA-DQ8 (DQB1*0302- DQA1*0301) and DQ2 (DQB1*0201-DQA1*0501) may be associated with higher risk of both celiac disease and type 1 diabetes.
      • Wheat gluten is also thought to be an environmental factor that is associated with the development of type 1 diabetes.
    • Evaluation of celiac disease in patients with type 1 diabetes:
      • Detection of autoantibodies present in celiac disease is important since most cases are asymptomatic.
      • Diagnosis of celiac disease is based on both of:
        • Detection of specific antibodies (most importantly EMA and ATG)
        • Confirmation of disease through biopsy of small intestine
      • In patients with celiac disease, incidence of IgA deficiency is higher than in the general population. If the total IgA is low, IgG antibodies should be assessed.
      • For screening of celiac disease in patients with type 1 diabetes, consensus is reported to be lacking among guidelines from various diabetic societies.
    • Clinical impact of celiac disease in patients with type 1 diabetes:
      • Intestinal villus atrophy results in malabsorption of nutrients, fat soluble vitamins, B vitamins, folic acid, iron, and/or calcium. Consequently, celiac disease in patients with type 1 diabetes may be associated with:
        • Hypoglycemia episodes
        • Growth impairment
        • Loss of body weight
        • Bone impairment (bone demineralization, osteoporosis, osteopenia, and rickets)
      • Delayed bone maturation and growth disorders typically coexist with disturbances in sexual maturation.
      • Female persons can also be affected by reproductive disorders, such as infertility or recurrent miscarriages.
    • In patients with classical or subclinical disease symptoms, a strict, lifelong gluten-free diet should be introduced under supervision of an experienced specialist.
    • Reference - Biomed Res Int 2016;2016:6219730
Autoimmune Gastritis
  • Autoimmune gastritis can occur in patients with type 1 diabetes.
    • Autoimmune gastritis is an asymptomatic and common disease.
      • The presence of specific genotype HLA-DQA1*0501- DQB1*0301 in patients with type 1 diabetes may be associated with increased risk of developing autoimmune gastritis.
      • A laboratory diagnosis is based on determination of serum biomarkers, such as anti-parietal cell autoantibodies (APCA) and antibodies directed against an inner factor.
      • Patients with type 1 diabetes and serum APCA are at increased risk of gastric autoimmunity, anemia with iron deficiency, and/or pernicious anemia.
      • In patients with type 1 diabetes and serum glutamic acid decarboxylase (GAD) and/or anti-thyroid antibodies, periodic exams to assess for autoimmune gastritis are especially critical as they help prevent and introduce early treatment of:
        • Iron and vitamin B12 deficiencies
        • Precancerous and cancerous lesions
    • Clinical symptoms appear with disease progression and development of atrophic gastritis with iron and vitamin B12 deficiency (pernicious anemia).
      • Atrophic gastritis may be associated with the development of carcinoid tumors and gastric cancer.
      • Laboratory diagnosis of atrophic gastritis is based on alterations in concentration of pepsinogen and gastrin.
    • Suggested testing:
      • In patients with APCA, annual investigations generally include blood morphology and levels of ferritin, vitamin B12, and gastrin.
      • In patients with high APCA titer and hypergastrinemia, gastroscopy with multiple biopsy is typically performed.
      • In patients with autoimmune thyroid disease and/or GAD antibodies persisting for ≥ 5 years, APCA should be determined every 2 years due to increasing risk of development of gastric autoimmunity.
    • Reference - Biomed Res Int 2016;2016:6219730
Vitiligo
  • Vitiligo can occur in patients with type 1 diabetes.
    • Vitiligo is characterized by a loss of epidermal melanocytes, resulting in the appearance of demarcated discoloration of the skin.
    • Prevalence, disease onset, and risk factors in type 1 diabetes:
      • Vitiligo is reported in 0.5%-1% of the general population with > 50% of cases reported to be diagnosed prior to 20 years old.
      • Vitiligo may precede the development of type 1 diabetes. Type 1 diabetes is reported to develop in 16%-20% of patients with vitiligo.
      • Polyglandular autoimmune syndromes (specifically PAS-2) commonly starts with the development of vitiligo and is more common in patients with type 1 diabetes.
    • Vitiligo is likely influenced by both genetic and environmental factors, but the pathogenesis is not well-established.
      • Neural hypothesis proposes the accumulation of toxic neurochemical substances (released from nerve ending) damages melanocytes and results in reduced melanin production.
      • Biochemical hypothesis proposes the self-destruction of pigment cells is a consequence of all of:
        • Accumulation of intermediate toxic byproducts of melanin synthesis
        • Impairment of defense against free radicals
        • Build-up of excessive amounts of hydrogen peroxide
      • Alternative hypothesis emphasizes the important role of autoimmunity.
        • Vitiligo often occurs with other autoimmune diseases and the majority of patients are reported to present with reactive T cells in serum and anti-melanocyte autoantibodies.
        • Positive correlation has been established between increased level of antibodies and severity of vitiligo (increased degree of skin affected).
      • There is no curative treatment for vitiligo but management may include:
        • Topical corticosteroids
        • Vitamin D derivatives
        • Calcineurin inhibitors
        • Photochemotherapy
        • Surgical techniques
    • Reference - Biomed Res Int 2016;2016:6219730
Adrenal Autoimmunity
  • Adrenal autoimmunity can occur in patients with type 1 diabetes.
    • In high income countries, the vast majority of primary adrenal insufficiency (Addison disease) is caused by an autoimmune process.
      • The presence of antibodies against the adrenal cortex (adrenal cell antibody [ACA]) is characteristic for the autoimmune adrenal insufficiency.
      • Primary autoantigen is the microsomal cytochrome P450 enzyme 21- hydroxylase, which converts alpha progesterone and progesterone to 11-deoxycortisol and 11-deoxycorticosterone.
    • Impact of adrenal disease:
      • Damage of adrenal gland results in:
        • Impaired production of glucocorticoids, mineralocorticoids, and androgens
        • High serum levels of adrenocorticotropic hormone (ACTH) and high plasma renin activity
      • In patients with diabetes type 1, influence of adrenal insufficiency on glucose metabolism and glycemic control include a tendency toward hypoglycemia owing to combinations of:
        • Increased insulin sensitivity
        • Reduced glycogenolysis
        • Reduced gluconeogenesis
        • Increased glycolysis
    • Incidence/prevalence, and onset of disease:
      • In the general population, adrenal autoimmunity rarely occurs. It is reported to develop in 90 to 140 people/million.
      • In patients with type 1 diabetes, autoimmune adrenal disease (primary adrenal insufficiency) is reported in 1%-2% of patients.
    • Clinical presentation:
      • > 50% of patients with primary adrenal insufficiency are reported to present with other autoimmune diseases. 10%-18% are reported to develop type 1 diabetes.
      • Typical clinical presentation includes symptoms of:
        • Adrenal insufficiency, such as fatigue due to orthostatic hypotension and hypoglycemia
        • Weight loss
        • Reduced appetite
        • Nausea
        • Craving of salty foods
        • Discoloration of skin and mucous membranes
      • Hypoglycemia is not a common symptom of primary adrenal insufficiency in patients with or without type 1 diabetes; however, recurrent unexplained hypoglycemic episodes in patients with type 1 diabetes may occur and should prompt testing for potential primary adrenal insufficiency.
    • Suggested screening in patients with type 1 diabetes:
      • For assessment of ACA levels in patients ≥ 18 years old:
        • Routine screening is not typically performed.
        • ACA levels are obtained if either of:
          • Presence of clinical adrenal autoimmunity symptoms
          • First-degree relatives with Addison disease (testing should occur every 5 years)
      • For serum ACTH and cortisol levels, screen every 2-3 years or with frequent unexplained hypoglycemia.
    • Management includes chronic substitution of adrenal cortex hormones (glucocorticoids and mineralocorticoids), and administration of androgens after adolescence.
    • Reference - Biomed Res Int 2016;2016:6219730
Autoimmune Polyendocrine Syndromes
  • Autoimmune polyendocrine syndromes can occur in patients with type 1 diabetes.
    • Autoimmune polyendocrine syndromes are heterogeneous group of rare diseases defined as functional disorders in ≥ 2 of the endocrine glands and, possibly, in other organs.
    • Autoimmune polyendocrine syndromes develop in genetically predisposed persons after activation of a factor that provokes an abnormal immune response.
    • Presence of specific autoantibodies typically precedes symptoms of individual endocrinopathies, which may develop at different times.
    • Reference - Biomed Res Int 2016;2016:6219730
  • Diabetes can be a component of autoimmune polyendocrine syndromes. Type 1 diabetes is reported in:
    • 4%-18% of patients with autoimmune polyendocrine syndrome type 1 (Biomed Res Int 2016;2016:6219730)
    • 60% of patients with autoimmune polyendocrine syndrome type 2 (Biomed Res Int 2016;2016:6219730)
    • 14.5% of patients with autoimmune polyendocrine syndrome type 3 (Biomed Res Int 2016;2016:6219730)
    • 75%-85% of patients with IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome (Curr Opin Endocrinol Diabetes Obes 2013 Aug;20(4):271)
  • Clinical manifestations of disease can appear from early infancy to old age (N Engl J Med 2018 Mar 22;378(12):1132).
  • Current classification distinguishes types of autoimmune polyendocrine syndromes based on the clinical presentation, autoantibody detection, genetic background, and time of onset of disease.
    • Autoimmune polyendocrine syndrome type 1:
      • Also referred to as Autoimmune Polyendocrinopathy-candidiasis-ectodermal Dystrophy (APECED) or Blizzard syndrome.
      • Typically reported in children aged 3-5 years or younger adolescents.
      • Diagnosis requires the presence of ≥ 2 of:
        • Primary adrenal insufficiency (Addison disease)
        • Hypoparathyroidism
        • Mucocutaneous candidiasis
        • AIRE gene mutation (located on chromosome 21)
      • Usually manifests itself by mucocutaneous fungal infection (candidiasis).
      • Other diseases constituting the syndrome include autoimmune hepatitis, primary hypothyroidism, vitiligo, pernicious anemia, and type 1 diabetes.
      • Screening for disease-specific antibodies (anti-islet cell, anti-21-hydroxylase, anti-parietal cell [APCA], and anti-tissue transglutaminase antibodies) and for vitamin B12 deficiency is suggested.
      • Characterized by autosomal recessive inheritance.
      • Reference - Biomed Res Int 2016;2016:6219730
    • Autoimmune polyendocrine syndrome type 2:
      • Also called Schmidt syndrome.
      • Reported to be the most common type of autoimmune polyendocrine syndrome that affects adults.
      • Reported to affect about 3 times more female patients than male patients.
      • Diseases/conditions comprising this syndrome include:
        • Type 1 diabetes
        • Primary adrenal insufficiency (Addison disease)
        • IgA deficiency
        • Autoimmune thyroid diseases
        • Primary hypothyroidism
        • Hypogonadism
        • Hypopituitarism
        • Parkinson disease
        • Myasthenia gravis
        • Celiac disease
        • Vitiligo
        • Alopecia
        • Pernicious anemia
        • Stiff person syndrome
        • Malabsorption
        • Hepatitis
        • Asplenia
      • Initial symptoms can present in the first decade of life, but its development is reported to peak in persons aged 25-30 years.
      • Patients should be screened periodically for:
        • Diabetes (insulin autoantibodies [IAA], anti-tyrosine phosphatase [IA2], and glutamic acid decarboxylase autoantibodies [GADA])
        • Thyroid diseases (including anti-thyroglobulin [ATG], and anti-thyroid peroxidase [TPO])
        • Addison disease (21-hydroxylase)
        • Celiac disease (anti-tissue transglutaminase [ATG])
        • Autoimmune hepatitis (cytochrome P450 enzymes)
      • Characterized by polygenic inheritance and is associated with the HLA class II System.
      • Reference - Biomed Res Int 2016;2016:6219730
    • Autoimmune polyendocrine syndrome type 3:
      • Comprises the same spectrum of endocrinopathies as autoimmune polyendocrine syndrome type 2, but without adrenal insufficiency.
      • There are 3 subtypes, which include:
        • IIIA: Hashimoto disease with type 1 diabetes
        • IIIB: Hashimoto disease with pernicious anemia
        • IIIC: Hashimoto disease with vitiligo and/or alopecia and/or other organ-specific and organ-nonspecific autoimmune diseases (celiac disease, hypogonadism, myasthenia gravis, sarcoidosis, rheumatoid arthritis, and Sjogren syndrome)
      • Characterized by polygenic inheritance and is associated with the HLA class II System.
      • Reference - Biomed Res Int 2016;2016:6219730
    • IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome:
      • Rare primary immunodeficiency disorder characterized by severe multiorgan autoimmunities.
      • IPEX syndrome is caused by mutations in the FOXP3 gene, located on the X chromosome.
      • Male patients are exclusively affected due to X-linked inheritance. Female carriers are generally healthy.
      • Clinical features are highly variable at presentation and throughout the disease course, and may include a wide variety of autoimmune diseases.
      • Classic triad of IPEX manifestations includes:
        • Chronic diarrhea due to enteropathy
        • Endocrinopathies (most commonly type 1 diabetes mellitus and thyroid disease)
        • Eczematous dermatitis
      • See IPEX Syndrome for additional information.
Other Autoimmune Conditions
  • Organ nonspecific autoimmune diseases may develop in patients with type 1 diabetes.
    • Psoriasis is a chronic inflammatory disease of the skin, nails, and joints, reported in 2%-3.5% of the world population.
    • Sjogren disease is a systemic autoimmune disease. It primarily affects the lacrimal and salivary glands, and the clinical spectrum of the syndrome spans from dryness (dry mucous membranes) to systemic disease of the exocrine glands.
    • Reference - Biomed Res Int 2016;2016:6219730
Eating Disorders
  • Insulin omission resulting in glycosuria in order to lose weight is the most common reported disordered eating behavior in patients with type 1 diabetes.
    1
  • STUDY SUMMARY
    diabetes mellitus type 1 associated with increased risk for eating disorders in female adolescents
    COHORT STUDY: BMJ 2000 Jun 10;320(7249):1563

  • STUDY SUMMARY
    disordered eating behavior appears common in female adolescents with type 1 diabetes
    COHORT STUDY: N Engl J Med 1997 Jun 26;336(26):1849

Other Associated Conditions
  • STUDY SUMMARY
    diabetes mellitus associated with hearing impairment in adults
    SYSTEMATIC REVIEW: J Clin Endocrinol Metab 2013 Jan;98(1):51

  • STUDY SUMMARY
    diabetes mellitus for ≥ 10 years associated with nonrefractive visual impairment
    COHORT STUDY: JAMA 2012 Dec 12;308(22):2361

  • STUDY SUMMARY
    enterovirus infection associated with type 1 diabetes
    SYSTEMATIC REVIEW: BMJ 2011 Feb 3;342:d35

Etiology and Pathogenesis

Causes

  • Immune-mediated diabetes is caused by cellular-mediated autoimmune destruction of pancreatic beta cells.
    1
    • Beta-cell proteins are recognized as autoantigens by autoantibodies and by autoreactive CD4+ and CD8+ T cells (Clin Rev Allergy Immunol 2014 Oct;47(2):174).
    • Autoantibodies are reported to be present in 85%-90% of patients at the time of diagnosis of fasting hyperglycemia.
      2
    • Autoantibodies include:
      1
      • Islet cells
      • Insulin
      • Glutamic acid decarboxylase 65 (GAD65)
      • Tyrosine phosphatases 1A-2 and 1A-2beta
      • Zinc transporter 8 (ZnT8)
    • Other possible autoantigens include:
      • Preproinsulin
      • Imogen 38
      • Pancreatic duodenal homeobox factor 1 (PDX1)
      • Chromogranin A (CHGA)
      • Islet specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)
      • Heat shock protein 60 (hsp60)
      • Carboxypeptidase H (CPH)
      • Islet cell antigen 69 (ICA69)
      • Reference - Clin Rev Allergy Immunol 2014 Oct;47(2):174
    • Associated with human leukocyte antigen (HLA) DQ and DR genetic alleles, which may be protective or predisposing.
      1
  • Idiopathic type 1 diabetes, which is rare, has no clear underlying cause. These patients have no evidence of beta-cell autoimmunity.
    1
  • The development of type 1 diabetes following the use of immune checkpoint inhibitors has been reported.
    • 283 cases of new-onset diabetes mellitus have been reported to the World Health Organization (WHO) database of drug safety reports following treatment with immune checkpoint inhibitors for various malignancies.
      • Immune checkpoint inhibitors are effective in treating many types of malignancies but are associated with immune-related adverse events.
      • New onset insulin-dependent diabetes mellitus is reported to develop in 0.2%-1% of patients treated with immune checkpoint inhibitors.
      • In an analysis of WHO's database of individual safety reports, 283 cases (median age 64 years, 56% male patients) of new-onset diabetes mellitus were reported from April 2014 to April 2018 following treatment with immune checkpoint inhibitors.
        • Onset of diabetes mellitus ranged from 5 to 790 days after the first dose of immune checkpoint inhibitors (median 116 days).
        • 69% of patients developed diabetes within 1 month after cessation, 22% developed diabetes within 1-3 months, and 9% developed diabetes > 3 months after cessation.
        • 76% of cases were treated with anti-programmed cell death-1 (anti-PD-1) monotherapy. 2.8% of cases were treated with anti-programmed death-ligand 1 (anti-PD-L1) therapy.
        • 17% of cases were treated with dual therapy, with either anti-PD-1 or anti-PD-L1 therapy plus anti-cytotoxic T-lymphocyte-associated protein-4 (CTLA4).
        • 12 cases (4.2%) were treated with anti-CTLA-4 monotherapy.
      • Reference - Diabetes Care 2018 Dec;41(12):e150
    • 91 cases of type 1 diabetes were reported in a systematic review of case series of patients treated with immune checkpoint inhibitors.
      • 91 patients (mean age 61 years) treated with checkpoints inhibitors, including anti-PD-1 or anti-PD-L1 monotherapy (79%) or in combination with anti-CTLA-4 therapy (15%), who developed diabetes were evaluated.
      • Immunotherapies were most commonly used for the treatment of cancers including melanoma or non-small-cell lung cancer.
      • Diabetic ketoacidosis (DKA) developed in 71%.
      • Diabetes developed after a mean of 4.5 treatment cycles (range 1-17 cycles), 2.7 treatment cycles for combination therapy.
      • Reference - Eur J Endocrinol 2019 Sep;181(3):363
        • DynaMed Commentary

        Since the new onset of diabetes related to checkpoint inhibitor is a well-described phenomenon, clinicians are no longer reporting every case. The reported case numbers are likely to under-represent the frequency of this entity.

Pathogenesis

  • The pathophysiology of type 1 diabetes is not fully understood. It appears to be due to functional deficits in beta cells, the immune system, and in the bone marrow and thymus.
    • Anti-islet autoimmunity:
      • Serological evidence of beta-cell destruction (altered amino acids and autoantibodies associated with type 1 diabetes) is caused by inherent immune dysregulation.
      • > 90% of patients with newly diagnosed type 1 diabetes are reported to have ≥ 1 of the following autoantibodies at disease onset:
        • Insulin autoantibodies (IAA)
        • Glutamic acid decarboxylase autoantibodies (GADA)
        • Insulinoma-associated-2 autoantibodies (IA-2A)
        • Zinc transporter 8 autoantibodies (ZnT8A)
    • Selective destruction of insulin-secreting pancreatic beta cells:
      • About 70% of pancreatic islets are reported to lack insulin at the time of diagnosis of type 1 diabetes, and about 20% of islets still containing insulin are reported to be inflamed (insulitis).
      • Pathogenic cell populations within insulitic lesions that aid in the destruction of islet cells include:
        • CD8+ T cells (most predominant)
        • Macrophages (CD68+)
        • CD4+ T cells
        • B lymphocytes (CD20+)
        • Plasma cells (CD138+)
        • Regulatory T cells (FOXP3+ cells) and natural killer cells (rarely occurring cell populations)
      • By 5 years after diagnosis, most islets are insulin deficient but have normal numbers of alpha cells, gamma cells, and pancreatic polypeptide secreting cells.
    • Polygenic susceptibility:
      • 40 genetic loci have been identified, which affect disease susceptibility.
      • Human leukocyte antigen (HLA) region on chromosome 6 may account for about 50% of genetic susceptibility .
      • HLA class II gene haplotypes DRB1 0401-DQB1 0302 and DRB1 0301-DQB1 0201 show strongest association with type 1 diabetes susceptibility.
      • HLA haplotypes DRB1 1501 and DQA1 0102-DQB1 0602 may be associated with disease resistance.
    • Environmental exposure:
      • Environmental factors may precipitate onset and continuance of beta-cell autoimmunity in genetically susceptible persons. Environmental influences may occur as early as in utero and continue past birth.
      • Proposed environmental triggers include diet, viruses, and vitamin D.
    • Reference - Lancet 2014 Jan 4;383(9911):69
  • The disease course of type 1 diabetes may begin with early serologic evidence of beta-cell destruction.
    • Alterations in insulin secretion and glucose intolerance may present months to decades after multiple islet autoantibodies are detected.
    • Metabolic changes are typically indicated by the following:
      • Reduction in early C-peptide (a surrogate marker of insulin release) response ≥ 2 years before disease onset
      • Subsequent increase in fluctuation of plasma glucose levels as person nears disease onset
      • Ultimately, a linear rise in plasma glucose occurs with a surge in the months before disease onset
    • Once a critical mass of beta cells has been destroyed (potentially just two-thirds of cells), symptoms develop and exogenous insulin is required.
    • Not all persons with beta-cell autoantibodies progress to overt disease. The reasons for this are not known.
    • Reference - Lancet 2014 Jan 4;383(9911):69
  • Inadequate insulin secretion results in deficient action of insulin on target tissues.
    2
    • Deficient action of insulin on target tissues results in abnormal carbohydrate, fat, and protein metabolism.
    • Abnormal metabolism results in hyperglycemia.
    • Acute hyperglycemia can cause metabolic emergencies such as diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state.
    • Chronic hyperglycemia can cause vascular complications such as nephropathy, retinopathy, and cardiovascular disease.
  • The pathophysiology of vascular complications is likely multifactorial, involving prolonged exposure to hyperglycemia combined with other risk factors such as genetic susceptibility, hypertension, and dyslipidemia.
    • Mechanisms leading to micro- and macrovascular complications include:
      • High intracellular glucose concentration activates protein kinase C (PKC), which causes structural and functional changes in vasculature, including:
        • Alterations in cellular permeability
        • Inflammation
        • Angiogenesis
        • Cell growth
        • Extracellular matrix expansion
        • Apoptosis
      • Insulin resistance contributes to endothelial dysfunction and produces a prothrombotic state (increased cellular synthesis of plasminogen activator inhibitor-1 and fibrinogen, and decreased synthesis of tissue plasminogen activator). These changes result in reduced inhibition of platelet aggregation and thrombosis.
    • Reference - Eur Heart J 2013 Aug;34(31):2436
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DynaMed Levels of Evidence

Quickly find and determine the quality of the evidence.

DynaMed provides easy-to-interpret Level of Evidence labels so users can quickly find and determine the quality of the best available evidence. Evidence may be labeled in one of three levels:

1Level 1 (likely reliable) Evidence
Representing research results addressing clinical outcomes and meeting an extensive set of quality criteria which minimizes bias.
There are two types of conclusions which can earn a Level 1 label: levels of evidence for conclusions derived from individual studies and levels of evidence for conclusions regarding a body of evidence.
2Level 2 (mid-level) Evidence
Representing research results addressing clinical outcomes, and using some method of scientific investigation, but not meeting the quality criteria to achieve Level 1 evidence labeling.
3Level 3 (lacking direct) Evidence
Representing reports that are not based on scientific analysis of clinical outcomes. Examples include case series, case reports, expert opinion, and conclusions extrapolated indirectly from scientific studies.

Grades of Recommendation

Guideline producers are now frequently using classification approaches for their evidence and recommendations, and these classifications are recognized and requested by guideline users. When summarizing guideline recommendations for DynaMed users, the DynaMed Editors are using the guideline-specific classifications and providing guideline classification approach when this is done.

Download the full version of Levels of Evidence