Diabetes Mellitus Type 1 and Type 2

Immune-mediated (T1DM)

• Autoimmune beta cell destruction: HLA-DR3/DR4-DQ8 haplotypes confer susceptibility; environmental triggers (enteroviral infection, early dietary exposures) are proposed but unproven. Associates with other organ-specific autoimmunity — Hashimoto thyroiditis, celiac disease, Addison disease, vitiligo, pernicious anemia (autoimmune polyglandular syndromes).
• Non-modifiable risk: first-degree relative with T1DM, personal or family history of autoimmune disease, younger age at presentation.

Insulin resistance (T2DM) — non-modifiable

• Genetics: polygenic; family history in a first-degree relative is the single strongest stem clue (twin concordance far exceeds T1DM).
• Age and ancestry: risk rises with age; higher prevalence in Black, Hispanic/Latino, American Indian, Asian American, and Pacific Islander populations. The ADA Standards of Care recommend screening all adults beginning at age 35, and the USPSTF recommends screening adults 35–70 years with overweight or obesity.
• Obstetric history: prior gestational diabetes or delivery of a macrosomic infant; low birth weight (thrifty phenotype).

Insulin resistance (T2DM) — modifiable

• Central (visceral) adiposity: free fatty acid flux and adipokine shifts (↓adiponectin, ↑TNF-α, IL-6) impair IRS-1 signaling. ADA uses a lower BMI threshold for screening Asian Americans because visceral fat accrues at lower BMI.
• Physical inactivity: muscle contraction recruits GLUT4 independently of insulin, so inactivity removes the main insulin-independent glucose sink.
• Metabolic comorbidities: hypertension, low HDL/high triglycerides, MASLD (fatty liver), obstructive sleep apnea, smoking.

Secondary and monogenic causes examiners plant

• Pancreatic destruction: chronic pancreatitis, cystic fibrosis, hemochromatosis (bronze diabetes), pancreatic adenocarcinoma — new diabetes in a thin older adult with weight loss should prompt thought of malignancy.
• Counter-regulatory hormone excess: Cushing syndrome, acromegaly, pheochromocytoma, glucagonoma (necrolytic migratory erythema), somatostatinoma.
• Drugs: glucocorticoids, thiazides, atypical antipsychotics (olanzapine, clozapine), calcineurin inhibitors (tacrolimus), protease inhibitors, and immune checkpoint inhibitors (which can cause fulminant autoimmune insulin-deficient diabetes).
• MODY: autosomal dominant, young, non-obese, antibody-negative, C-peptide preserved — the classic distractor for both T1DM and T2DM.

Type 1 Diabetes

• Autoimmune beta cell destruction: T-cell mediated attack against pancreatic islet cells; associated with HLA-DR3 and HLA-DR4 alleles; antibodies to GAD65, IA-2, and insulin are pathognomonic
• Absolute insulin deficiency: Progressive loss of beta cells (>90% destruction required for hyperglycemia) leads to complete dependence on exogenous insulin; no endogenous insulin production
• Accelerated ketogenesis: Without insulin, lipolysis increases dramatically, producing ketone bodies (acetoacetate, beta-hydroxybutyrate) faster than tissues can metabolize them, predisposing to diabetic ketoacidosis (DKA)
• Genetic predisposition with environmental triggers: Monozygotic twin concordance ~50%; environmental factors (viral infections, dietary factors) likely trigger autoimmunity in genetically susceptible individuals

Type 2 Diabetes

• Insulin resistance: Impaired cellular response to insulin at receptor and post-receptor levels (GLUT4 translocation defects, IRS-1 signaling abnormalities); primarily affects muscle, liver, and adipose tissue
• Progressive beta cell dysfunction: Initially, pancreatic beta cells compensate with hyperinsulinemia, but chronic hyperglycemia and lipotoxicity cause beta cell apoptosis and secretory dysfunction over time; insulin levels eventually decline
• Hepatic glucose overproduction: Increased gluconeogenesis and glycogenolysis due to inadequate hepatic insulin signaling; impaired suppression of glucagon
• Incretin dysfunction: Reduced GLP-1 secretion and impaired incretin effect (diminished postprandial insulin secretion in response to oral glucose)
• Strong genetic component: Monozygotic twin concordance ~90%; polygenic inheritance with >100 susceptibility loci identified; environmental factors (obesity, sedentary lifestyle, poor diet) play major role

Type 1 Diabetes

• Acute onset of symptoms: Polyuria, polydipsia, polyphagia, and rapid weight loss over days to weeks; typically presents in children and young adults
• Diabetic ketoacidosis (DKA): Often the presenting manifestation; presents with Kussmaul respirations (deep, rapid breathing), fruity-smelling breath (acetone), nausea, vomiting, abdominal pain, and altered mental status; can progress to coma and death if untreated
• Absence of prodromal symptoms: Unlike T2DM, symptoms appear suddenly without prior metabolic derangement
• Thin body habitus: Weight loss is prominent due to loss of anabolic effects of insulin and increased catabolism

Type 2 Diabetes

• Insidious onset: Often asymptomatic and discovered incidentally on screening; patients may have hyperglycemia for years before diagnosis
• Nonspecific symptoms: Fatigue, blurred vision, recurrent infections (due to impaired immune function from hyperglycemia); when present, polyuria and polydipsia are usually mild
• Associated features of metabolic syndrome: Central obesity, hypertension, dyslipidemia, nonalcoholic fatty liver disease (NAFLD)
• Subtle presentation in many cases: 25% of patients unaware of diagnosis at time of discovery
• Hyperosmolar hyperglycemic state (HHS): Rare presenting manifestation; occurs with severe hyperglycemia (>600 mg/dL) without significant ketosis in elderly patients

Important Clinical Pearls

• T1DM typically presents before age 30; T2DM typically after age 45, but both are increasing in younger populations
• Family history is more prominent in T2DM; T1DM has strong HLA associations
• Latent autoimmune diabetes in adults (LADA) presents as T2DM but is actually T1DM; identified by positive autoantibodies; progresses to insulin dependence

Diagnostic Criteria (any one of the following establishes diagnosis)

• Fasting plasma glucose ≥126 mg/dL (fasting defined as no caloric intake for ≥8 hours)
• 2-hour plasma glucose ≥200 mg/dL during 75-g oral glucose tolerance test (OGTT)
• Hemoglobin A1C ≥6.5% (reflects average glucose over 2-3 months; highly specific and convenient; accounts for RBC lifespan)
• Random plasma glucose ≥200 mg/dL plus symptoms (polyuria, polydipsia, weight loss)

Diagnostic Approach

• Initial labs: Fasting glucose, random glucose, or A1C; OGTT reserved for borderline cases or gestational diabetes screening
• Prediabetes: Fasting glucose 100-125 mg/dL, A1C 5.7-6.4%, or 2-hour OGTT 140-199 mg/dL; requires lifestyle intervention and annual screening
• Type differentiation:
• Autoantibodies (GAD65, IA-2, ICA, insulin antibodies) present in T1DM but absent in T2DM
• C-peptide level: Low or undetectable in T1DM; normal or elevated in early T2DM (reflects endogenous insulin production)
• Clinical presentation and age of onset helpful but not definitive
• Baseline complications assessment: Comprehensive metabolic panel, lipid panel, urine albumin-to-creatinine ratio (UACR), retinal exam, foot exam, EKG in patients >40 years or with cardiovascular risk factors

Important Diagnostic Considerations

• A1C may be falsely low in hemolytic anemias, hemoglobinopathies, or with high RBC turnover; unreliable in pregnancy
• OGTT is most sensitive but least practical; mainly used for research and gestational diabetes screening
• Repeat testing on different day recommended unless symptomatic presentation with markedly elevated glucose

Type 1 Diabetes

• Insulin therapy: MANDATORY and lifesaving; all T1DM patients require exogenous insulin from diagnosis
• Basal-bolus regimen (preferred): Long-acting insulin once or twice daily (basal; e.g., glargine, detemir) plus rapid-acting insulin with meals (bolus; e.g., lispro, aspart, glulisine); allows flexibility and better glycemic control
• Insulin pump therapy: Continuous subcutaneous insulin infusion (CSII); delivers basal insulin continuously and patient-initiated boluses; advantageous in motivated patients, improves A1C by 0.5-1%
• Target A1C: <7% for nonpregnant adults; <6.5% in children if achievable without hypoglycemia; <6% in pregnancy
• Medical nutrition therapy (MNT): Carbohydrate counting essential for insulin dosing; balanced macronutrient distribution (45-65% carbohydrate, 25-35% fat, 10-35% protein)
• Exercise: 150 minutes/week moderate-intensity aerobic activity; increases insulin sensitivity and cardiovascular fitness
• Psychosocial support: Diabetes education, mental health screening for depression and eating disorders (higher prevalence in T1DM), support groups
• Glucose monitoring: Self-monitoring of blood glucose (SMBG) 4+ times daily; continuous glucose monitors (CGMs) increasingly used to improve time-in-range and reduce hypoglycemia
• Prevention of autoimmunity: No proven interventions to prevent T1DM in at-risk relatives; teplizumab (anti-CD3 monoclonal antibody) recently approved to delay symptom onset in high-risk individuals

Acute — emergencies

• Diabetic ketoacidosis: absolute insulin deficiency plus counter-regulatory surge → unrestrained lipolysis and ketogenesis. Anion-gap metabolic acidosis, Kussmaul respirations, fruity breath, abdominal pain; total-body potassium is depleted even when serum K⁺ looks normal. Precipitants: infection, missed insulin, MI, new-onset T1DM.
• Hyperosmolar hyperglycemic state: residual insulin suppresses ketogenesis, so profound hyperglycemia and osmotic diuresis dominate → severe hypovolemia, hyperosmolality, obtundation, seizures. Mortality exceeds DKA.
• Hypoglycemia (treatment complication): insulin and sulfonylureas (glipizide, glyburide) are the culprits; metformin, GLP-1 receptor agonists, and SGLT2 inhibitors rarely cause it alone. Adrenergic symptoms precede neuroglycopenia unless hypoglycemia unawareness from autonomic neuropathy or beta blockade blunts them.
• Cerebral edema: feared complication of pediatric DKA, linked to overly rapid osmolar correction — deteriorating mental status during treatment.
• Euglycemic DKA: SGLT2 inhibitors (empagliflozin) shift substrate toward ketogenesis; glucose may be near-normal, so check ketones/anion gap. ADA advises holding these agents before surgery.

Microvascular (chronic hyperglycemia → polyol accumulation, advanced glycation end-products, PKC activation)

• Retinopathy: microaneurysms, dot-blot hemorrhages, then neovascularization; ADA recommends dilated retinal exams with anti-VEGF or laser for proliferative disease.
• Nephropathy: hyperfiltration → albuminuria → declining eGFR; Kimmelstiel-Wilson nodular glomerulosclerosis on biopsy. Type IV renal tubular acidosis (hyporeninemic hypoaldosteronism) causes hyperkalemia.
• Neuropathy: distal symmetric stocking-glove sensory loss (foot ulcers, Charcot joint); autonomic forms give gastroparesis, orthostatic hypotension, erectile dysfunction, and silent MI. Mononeuropathies include pupil-sparing CN III palsy.

• DKA sequencing is the most tested management stem: isotonic IV fluids first, then insulin infusion, with potassium repletion before insulin if serum K⁺ is below the low-normal threshold — insulin drives K⁺ intracellularly and can precipitate fatal arrhythmia. Add dextrose to the fluids once glucose falls into the intermediate range while continuing insulin, because the endpoint is closure of the anion gap, not normoglycemia. Bicarbonate is not routine; it is reserved for extreme acidemia per ADA guidance.
• Do not stop the insulin drip until the gap closes and overlapping subcutaneous basal insulin has been given — premature discontinuation causes rebound ketoacidosis. This is the classic distractor.
• Black nasal turbinate eschar with facial pain in DKA = rhinocerebral mucormycosis: emergent surgical debridement plus amphotericin B, not antibiotics alone.
• Antibody-negative, C-peptide-preserved young lean patient with a strong autosomal dominant family history = MODY, not T1DM; sulfonylureas may suffice in the HNF1A subtype.
• Organ-protective agents are chosen independent of A1C: per the ADA Standards of Care and KDIGO, an SGLT2 inhibitor (empagliflozin) is indicated in T2DM with heart failure or albuminuric CKD, and a GLP-1 receptor agonist (semaglutide) in established ASCVD. GLP-1 receptor agonists are contraindicated with personal/family history of medullary thyroid carcinoma or MEN2.
• Every diabetic with albuminuria and hypertension gets an ACE inhibitor or ARB (never both together), and ACC/AHA recommends at least moderate-intensity statin therapy for adults with diabetes in the 40–75 age range. Note that ACE inhibitors are contraindicated in pregnancy.
• The A1C can lie: falsely low with hemolysis or blood loss (shortened RBC survival), falsely high with iron-deficiency anemia; use fructosamine or glucose-based criteria when hemoglobinopathy is present.
• Painless foot ulcer over a pressure point signals sensory neuropathy — the next step is probe-to-bone assessment and imaging for osteomyelitis, plus offloading, not simply topical care.