Diabetes Mellitus - Types and Classification

Diagnostic Criteria (All Types)

• Impaired Fasting Glucose (IFG): 5.6-6.9 mmol/L (100-125 mg/dL)
• Impaired Glucose Tolerance (IGT): 7.8-11.1 mmol/L at 2-hour OGTT

Type I: Type 1 Diabetes Mellitus (T1DM)

Pathobiology

• A complex interplay of genetic, environmental, and autoimmune factors selectively targets and destroys insulin-producing islet β-cells
• Over 90% of newly diagnosed patients have ≥1 autoantibody:
  • Anti-GAD65 (glutamic acid decarboxylase)
  • Anti-IA-2 (tyrosine phosphatase)
  • Anti-ZnT8 (zinc transporter 8)
  • Anti-insulin antibodies
• β-cell destruction is largely mediated by CD8+ and CD4+ T cells, macrophages (insulitis), leading to apoptosis

Genetics

• ~60 genes involved; HLA genes on chromosome 6p contribute ~50% of genetic susceptibility
• High-risk haplotypes: DR4-DQ8 and DR3-DQ2 (present in ~90% of affected children)
• Protective haplotype: DR15-DQ6 (found in only 1% of T1DM vs. 20% of general population)
• Twin concordance: 30-40% in identical twins (indicating a significant environmental trigger as well)
• Fathers with T1DM carry higher risk to offspring (6-9%) than affected mothers (1-3%)

Epidemiology

• Incidence peaks around puberty
• Incidence as high as 60/100,000/year in Scandinavia; ~3/100,000/year in China
• Worldwide incidence increasing by 3-4% per year over the past 50-60 years

Subtypes

• Immune-mediated (Type 1A): Classic autoimmune - most common
• Idiopathic (Type 1B): No evidence of autoimmunity; some patients have intermittent insulinopenia and are prone to ketoacidosis

Clinical Features

• Typically younger onset (though can occur at any age)
• Lean body habitus
• Acute onset with polyuria, polydipsia, polyphagia, weight loss
• Prone to diabetic ketoacidosis (DKA)
• Requires lifelong insulin therapy
• Goldman-Cecil Medicine, pp. 682-695

Type II: Type 2 Diabetes Mellitus (T2DM)

Pathobiology

• Impaired insulin secretion: β-cell failure is progressive, with decreasing insulin output over time
• Insulin resistance: Peripheral tissues (especially skeletal muscle, liver, adipose) fail to respond appropriately to insulin
• Nearly 90% of T2DM patients are overweight or obese
• Women with BMI ≥35 have over a 90-fold higher odds of developing diabetes vs. BMI <22

Key Risk Factors

• Obesity (especially central/abdominal adiposity)
• Family history (strong hereditary component)
• Physical inactivity / sedentary lifestyle
• Age >45 years
• Hypertension, dyslipidemia
• History of gestational diabetes
• High-risk ethnicity (Native Americans, Hispanic Americans, non-Hispanic Blacks)
• Sleep deprivation, cigarette smoking

Epidemiology

• Affects >34 million in the USA (~10.5% of population as of 2020)
• Globally, ~537 million affected in 2021; projected 783 million by 2045
• Countries with most cases: China (140M), India (74M), Pakistan (33M)

Clinical Features

• Often asymptomatic for years - detected on routine testing
• Classic symptoms (polyuria, polydipsia, weight loss) only when glucose >180-200 mg/dL
• Long-term microvascular complications: retinopathy (~12%), nephropathy (>40%), neuropathy (~50%)
• Macrovascular complications are the leading cause of mortality: ischemic heart disease, heart failure, stroke, peripheral vascular disease (2-2.5-fold higher cardiovascular risk)
• Goldman-Cecil Medicine, pp. 811-922

Type III: Other Specific Types

A. Monogenic Disorders of β-Cell Function (MODY - Maturity-Onset Diabetes of the Young)

• Also includes: Permanent neonatal diabetes (KCNJ11/Kir6.2 mutations, insulin gene), Mitochondrial DNA mutations (maternally inherited diabetes + deafness)
• Accounts for 1-5% of all diabetes cases; ≥14 subtypes identified

B. Genetic Defects in Insulin Action

• Type A insulin resistance
• Leprechaunism (Donohue syndrome)
• Rabson-Mendenhall syndrome
• Lipodystrophy syndromes

C. Diseases of the Exocrine Pancreas

• Pancreatitis, pancreatectomy, neoplasia
• Cystic fibrosis
• Hemochromatosis ("bronze diabetes")
• Fibrocalculous pancreatopathy
• Mutations in carboxyl ester lipase

D. Endocrinopathies (counter-regulatory hormone excess)

• Acromegaly (excess GH)
• Cushing syndrome (excess cortisol)
• Glucagonoma
• Pheochromocytoma (excess catecholamines)
• Hyperthyroidism
• Somatostatinoma, aldosteronoma

E. Drug or Chemical-Induced

• Glucocorticoids (most common)
• Calcineurin inhibitors (tacrolimus, cyclosporine) and mTOR inhibitors
• Atypical antipsychotics (olanzapine, clozapine)
• HIV protease inhibitors
• Beta-adrenergic agonists (e.g., epinephrine)

F. Infections

• Congenital rubella
• Cytomegalovirus (CMV)

G. Uncommon Immune-Mediated Forms

• "Stiff-person" syndrome
• Anti-insulin receptor antibodies

H. Other Genetic Syndromes Associated with Diabetes

• Wolfram syndrome (DIDMOAD)
• Down syndrome
• Klinefelter syndrome
• Turner syndrome
• Laurence-Moon-Biedl, Prader-Willi syndromes
• Friedreich ataxia, Huntington disease
• Myotonic dystrophy, porphyria
• Goodman & Gilman's Pharmacological Basis of Therapeutics, Table 51-2, p. 1047

Type IV: Gestational Diabetes Mellitus (GDM)

• Defined as glucose intolerance first identified during pregnancy
• Considered a form of T2DM precipitated by pregnancy-induced insulin resistance and physiologic changes in glucose metabolism
• Women with GDM are at significantly increased risk of developing T2DM later in life
• Also associated with adverse pregnancy outcomes: congenital malformations, macrosomia, neonatal hypoglycemia
• Diagnosed by OGTT at 24-28 weeks of gestation

Quick Comparison Table

• Goldman-Cecil Medicine - Chapters 208 & 210
• Goodman & Gilman's Pharmacological Basis of Therapeutics, 14e, Chapter 51 (pp. 1046-1047)
• ADA Standards of Care 2024 - Classification & Diagnosis (Section 2)