Diabetes Mellitus

• Definition: a group of metabolic disorders unified by chronic hyperglycemia resulting from defective insulin secretion, defective insulin action, or both. The hyperglycemia itself is the toxin — it drives the microvascular and macrovascular end-organ damage that defines the disease's morbidity.
• Why it matters: diabetes is the leading cause of end-stage renal disease, non-traumatic lower-extremity amputation, and new-onset blindness in working-age adults in the United States, and it roughly doubles cardiovascular mortality. Most therapeutic decisions in modern diabetes care are made to prevent these outcomes, not merely to lower a number.

Epidemiology worth recalling

• Prevalence: per CDC surveillance, roughly one in ten Americans has diabetes and more than a third of adults meet criteria for prediabetes; a substantial minority of cases are undiagnosed at any given time.
• Type 2 predominance: type 2 accounts for the large majority of cases (~90–95%). Incidence rises steeply with age, BMI, and duration of obesity, and is disproportionately high in Black, Hispanic/Latino, American Indian/Alaska Native, and South Asian populations.
• Type 1: bimodal incidence peaks in early childhood (~4–6 years) and around puberty, though it can present at any age; incidence is highest in populations of Northern European ancestry. Unlike type 2, it is not driven by obesity.
• Pediatric type 2 DM is increasingly common in parallel with childhood obesity — a stem describing an obese adolescent with acanthosis nigricans is pointing at type 2, not type 1.
• Screening: the USPSTF recommends screening for prediabetes and type 2 diabetes in adults aged 35–70 years who are overweight or obese; the ADA Standards of Care recommends screening all adults beginning at age 35, and earlier in those with overweight/obesity plus an additional risk factor, repeating at least every 3 years if normal.

Autoimmune (type 1)

• T-cell–mediated insulitis destroys β-cells while α, δ, and PP cells are spared. Islet autoantibodies (GAD65, IA-2, insulin autoantibody, ZnT8) are markers, not the effector mechanism.
• Genetic: strongest association is with the HLA class II region (HLA-DR3-DQ2 and DR4-DQ8); certain haplotypes such as DQB1\*0602 are protective. Concordance in monozygotic twins is incomplete, so environment matters.
• Environmental triggers: enteroviral infection (coxsackievirus B) is the classically tested association; congenital rubella is another.

Insulin resistance (type 2)

• Visceral adiposity → increased free fatty acid flux and adipokine dysregulation → post-receptor insulin signaling defects in muscle and liver, with β-cell exhaustion superimposed.

Monogenic and secondary causes

• MODY: autosomal dominant defects in β-cell transcription factors or glucokinase.
• Pancreatic destruction: chronic pancreatitis, cystic fibrosis, hemochromatosis (bronze diabetes), pancreatectomy, pancreatic cancer.
• Endocrinopathies of counterregulation: Cushing syndrome, acromegaly, pheochromocytoma, glucagonoma, hyperthyroidism.
• Drug-induced: glucocorticoids, thiazides, atypical antipsychotics (olanzapine, clozapine), protease inhibitors, tacrolimus/cyclosporine, statins (small effect), niacin.

Non-modifiable risk factors

• Age ≥35, first-degree relative with diabetes (family history is stronger in type 2 than type 1), high-risk race/ethnicity, prior gestational diabetes, PCOS, low birth weight.

Modifiable risk factors

• Overweight/obesity (especially central), physical inactivity, hypertension, atherogenic dyslipidemia (high triglycerides, low HDL), smoking, and diets high in refined carbohydrate and sugar-sweetened beverages. The ADA Standards of Care stresses that intensive lifestyle intervention in prediabetes substantially reduces progression to overt type 2 diabetes — the modifiable list is the intervention list.

• Insulin's normal job: in the fed state it drives GLUT4-mediated glucose uptake into muscle and adipose, suppresses hepatic gluconeogenesis and glycogenolysis, and — critically — suppresses hormone-sensitive lipase, halting lipolysis. Loss of insulin therefore produces both a glucose problem and a fat problem.

From insulin deficit to symptoms

• Hyperglycemia develops from unopposed hepatic glucose output plus failed peripheral uptake. Once serum glucose exceeds the renal tubular reabsorptive threshold (~180 mg/dL), glucosuria creates an osmotic diuresis → polyuria, volume depletion, and hypotonic fluid loss → thirst and polydipsia.
• Weight loss and polyphagia reflect cells that are functionally starved: unopposed glucagon drives proteolysis and lipolysis for gluconeogenic substrate despite abundant extracellular glucose.
• Ketogenesis requires near-absolute insulin deficiency with glucagon excess. Free fatty acids reach the liver, are shunted into β-oxidation via carnitine palmitoyltransferase-1 (normally inhibited by insulin), and generate acetoacetate and β-hydroxybutyrate → anion-gap metabolic acidosis with Kussmaul respirations (respiratory compensation) and fruity breath (acetone). This is why DKA is the type 1 phenotype: residual insulin in type 2 is usually enough to restrain lipolysis, so those patients instead drift toward the profound hyperosmolar dehydration of HHS.

From hyperglycemia to end-organ damage

• Non-enzymatic glycation of proteins forms advanced glycation end products → basement membrane thickening, cross-linked collagen, and glycated hemoglobin (the basis of HbA1c).
• Polyol pathway: in insulin-independent tissues (lens, retina, Schwann cells, renal papilla) aldose reductase converts glucose to sorbitol, consuming NADPH; osmotic and oxidative stress follow — the mechanism behind cataract and neuropathy.
• Protein kinase C activation and oxidative stress → endothelial dysfunction, hyperfiltration with intraglomerular hypertension (mesangial expansion, Kimmelstiel–Wilson nodules), and accelerated atherosclerosis.
• Total body potassium depletion coexists with normal or high serum potassium in DKA because acidosis and insulin lack shift K⁺ extracellularly — the reason insulin therapy unmasks dangerous hypokalemia.

Classic hyperglycemic symptoms (any type)

• Polyuria and nocturia: osmotic diuresis once glucose exceeds the renal threshold.
• Polydipsia: hypertonicity stimulates hypothalamic osmoreceptors.
• Weight loss with polyphagia: catabolism of fat and muscle despite caloric intake; far more prominent in type 1.
• Blurred vision: osmotic swelling of the lens changing refractive index — fluctuates with glycemic control and is reversible.
• Fatigue and poor wound healing; recurrent candidal vulvovaginitis or balanitis from glucose-rich secretions.

Presentations that signal a hyperglycemic emergency

• HHS: an elderly patient, often with limited free-water access or a recent infection, with profound dehydration, focal neurologic deficits or seizure, and obtundation — mental status tracks serum osmolality, not glucose per se.

Findings pointing to a specific etiology

• Necrobiosis lipoidica diabeticorum (yellow-brown shin plaques) and diabetic dermopathy.
• Hyperpigmentation with arthropathy and hepatomegaly → hemochromatosis.
• Migratory necrolytic erythema → glucagonoma.
• Steatorrhea with prior alcohol use → pancreatogenic diabetes.
• Vitiligo, goiter, or unexplained hypotension → the autoimmune cluster accompanying type 1.

Confirming diabetes (ADA Standards of Care criteria)

• Fasting plasma glucose ≥126 mg/dL (no caloric intake for ≥8 hours).
• 2-hour plasma glucose ≥200 mg/dL during a 75-g oral glucose tolerance test.
• HbA1c ≥6.5%, using an NGSP-certified, DCCT-standardized assay.
• Random plasma glucose ≥200 mg/dL plus classic hyperglycemic symptoms or hyperglycemic crisis.
• In the absence of unequivocal hyperglycemia, the abnormal result must be confirmed — either by repeating the same test on a new sample or by a second different test. Two abnormal results from a single sample are also sufficient.

• Falsely low when red cell survival is shortened: hemolytic anemia, recent transfusion, erythropoietin therapy, advanced CKD, pregnancy, splenomegaly.
• Falsely high when red cells are long-lived: iron-deficiency anemia, B12/folate deficiency, splenectomy, asplenia.
• Hemoglobin variants (HbS, HbC) interfere with certain assays.

Classifying the type once diagnosed

• Islet autoantibodies (GAD65, IA-2, insulin autoantibody, ZnT8) confirm autoimmune type 1 — the key test when an adult with a "type 2" phenotype fails oral agents rapidly (LADA).
• C-peptide with a simultaneous glucose distinguishes endogenous insulin reserve: low/undetectable in type 1, normal-to-high in early type 2, and low in surreptitious exogenous insulin administration (where insulin is high but C-peptide is suppressed).

Hyperglycemic crises

• DKA: hyperglycemia (often >250 mg/dL, but euglycemic DKA occurs with SGLT2 inhibitors, pregnancy, or starvation), anion-gap metabolic acidosis with low bicarbonate, and positive serum β-hydroxybutyrate — the preferred ketone test, since nitroprusside urine dipsticks detect acetoacetate but not β-hydroxybutyrate.
• HHS: marked hyperglycemia (often >600 mg/dL) with effective serum osmolality above roughly 320 mOsm/kg, minimal ketosis, and no significant acidosis.
• Always send a workup for the precipitant: infection, infarction, and insulin omission.

Immediate stabilization — DKA/HHS (ADA hyperglycemic crisis guidance)

• IV isotonic crystalloid first: volume depletion drives the hyperosmolality and impairs insulin delivery to tissue. Fluids alone lower glucose substantially.
• Potassium before insulin if K⁺ is low: hold insulin until serum K⁺ exceeds ~3.3 mEq/L and add K⁺ to fluids once it falls below the upper normal range — insulin drives K⁺ intracellularly and can precipitate fatal arrhythmia.
• Continuous IV regular insulin infusion (~0.1 units/kg/hr) titrated to close the anion gap, not to normalize glucose. Add dextrose to the fluids once glucose approaches ~200 mg/dL so the infusion can continue safely.
• Overlap the insulin drip with the first subcutaneous basal dose by 1–2 hours before stopping it, or the gap reopens. Bicarbonate is reserved for severe acidemia (pH <6.9); routine use is not recommended.

Type 2 DM escalation

• Comorbidity-driven agent selection now takes precedence over a purely A1c-driven ladder. The ADA recommends an SGLT2 inhibitor (empagliflozin) or GLP-1 receptor agonist (semaglutide) for patients with established ASCVD, heart failure, or CKD, independent of A1c or metformin use — SGLT2 inhibitors are favored for HF and CKD progression, echoed by KDIGO for diabetic kidney disease.
• Other add-ons: DPP-4 inhibitors (weight-neutral, modest efficacy), sulfonylureas and insulin (potent but cause hypoglycemia and weight gain), thiazolidinediones (fluid retention, HF, fracture risk).
• Metabolic surgery is recommended by the ADA for selected patients with obesity and inadequately controlled type 2 diabetes.
• Risk-factor control is not optional: statin therapy per ADA/ACC-AHA, blood pressure control, ACE inhibitor or ARB for albuminuria, and smoking cessation.

Acute — emergencies

• DKA: anion-gap acidosis from ketogenesis; emergency. In children, overly rapid fluid/osmolality correction risks cerebral edema — headache, bradycardia, and declining consciousness during treatment demand immediate attention.
• HHS: extreme hyperosmolar dehydration with obtundation; mortality exceeds that of DKA.
• Hypoglycemia (treatment complication): sulfonylureas and insulin are the culprits. Adrenergic warning symptoms are blunted by autonomic neuropathy (hypoglycemia unawareness) and by non-selective beta blockers — a classic exam trap.

Microvascular (glycemic-control dependent)

• Retinopathy: nonproliferative (microaneurysms, dot-blot hemorrhages, hard exudates) progressing to proliferative neovascularization; vitreous hemorrhage or traction retinal detachment is a sight-threatening emergency. ADA recommends dilated eye exams at diagnosis in type 2 and within 5 years of onset in type 1, then periodically.
• Nephropathy: hyperfiltration → albuminuria → declining eGFR; biopsy shows Kimmelstiel–Wilson nodules. Monitor with annual urine albumin-to-creatinine ratio and eGFR (ADA, KDIGO).
• Neuropathy: distal symmetric stocking-glove sensory loss (longest axons first) causing painless foot ulceration and Charcot arthropathy; autonomic forms cause gastroparesis, orthostatic hypotension, neurogenic bladder, and erectile dysfunction. Mononeuropathies include a pupil-sparing CN III palsy (ischemia spares peripheral parasympathetic fibers).

Macrovascular

• Accelerated atherosclerosis → MI (often silent due to autonomic denervation), stroke, and peripheral arterial disease with amputation risk.

Infectious

• Rhinocerebral mucormycosis in DKA (acidosis frees iron and impairs neutrophils), malignant otitis externa from Pseudomonas, emphysematous pyelonephritis and cholecystitis, necrotizing soft-tissue infection.

Drug-specific

• Metformin: GI intolerance, B12 malabsorption, rare lactic acidosis in renal failure.
• SGLT2 inhibitors: genital mycotic infection, volume depletion, euglycemic DKA, Fournier gangrene.
• GLP-1 RA: nausea, delayed gastric emptying, pancreatitis.
• Insulin: weight gain, lipohypertrophy at unrotated injection sites.

• Anion-gap acidosis + hyperglycemia + vomiting in a thin teenager = DKA. The single best next step is IV isotonic fluids, not insulin — and check potassium before starting the insulin drip. Serum K⁺ may be normal or high while total body K⁺ is profoundly depleted.
• β-hydroxybutyrate, not urine ketones. The nitroprusside dipstick detects acetoacetate only; early in DKA the ratio favors β-hydroxybutyrate, so urine ketones can paradoxically appear to rise as the patient improves.
• Euglycemic DKA on an SGLT2 inhibitor is the modern trap: normal or mildly elevated glucose with a wide anion gap and positive ketones. Do not exclude DKA because glucose is <250 mg/dL.
• Low C-peptide + positive GAD65 in a lean adult failing oral agents = LADA, not "poorly controlled type 2." Contrast with factitious insulin use: high insulin, suppressed C-peptide.
• Pupil-sparing CN III palsy = ischemic diabetic mononeuropathy; a pupil-involving third nerve palsy is a posterior communicating artery aneurysm until proven otherwise. This distinction is tested constantly.
• Comorbidity picks the second drug. ADA Standards of Care: heart failure or CKD → SGLT2 inhibitor; established ASCVD or need for weight loss → GLP-1 receptor agonist. Choosing a sulfonylurea for a patient with heart failure is the intended wrong answer.
• A discordant HbA1c means check the red cells. Iron deficiency falsely raises it; hemolysis, recent transfusion, and pregnancy falsely lower it — use fasting glucose or OGTT instead.
• Necrotic black eschar on the palate or turbinates in a patient with DKA = rhinocerebral mucormycosis; the next step is urgent surgical debridement plus amphotericin B, not observation.
• Do not use ACE inhibitors or ARBs in pregnancy — including captopril, whose short half-life makes it useful for rapid titration in non-pregnant patients, never for pregnancy.

• Type 1 DM: autoimmune destruction of pancreatic β-cells; presents in children; absolute insulin deficiency; HLA-associated (HLA-DR3/DR4)
• Type 2 DM: insulin resistance + relative insulin deficiency; accounts for 90% of cases; strong genetic/lifestyle component
• Diagnostic criteria: fasting glucose ≥126 mg/dL, 2-hour glucose ≥200 mg/dL on OGTT, HbA1c ≥6.5%, or random glucose ≥200 mg/dL with symptoms
• Gestational DM: glucose intolerance first identified during pregnancy; 50% progress to Type 2 DM within 10 years
• HbA1c target: generally <7% (individualize based on age, comorbidities, hypoglycemia risk)

• Type 1: Child/young adult with polyuria, polydipsia, polyphagia, weight loss over weeks; DKA at presentation (fruity breath, Kussmaul respirations, altered mental status)
• Type 2: Asymptomatic or insidious onset in obese middle-aged/older adult; discovered incidentally on labs; may present with complications (neuropathy, vision changes)
• Gestational: Glucose intolerance detected on 50-g glucose challenge or 75-g OGTT at 24-28 weeks gestation; usually asymptomatic

• Type 1 DM associations: Celiac disease, Graves disease, Addison disease, pernicious anemia (autoimmune polyglandular syndrome); increased infection risk
• Type 2 DM associations: Metabolic syndrome, NAFLD, PCOS, obstructive sleep apnea, acanthosis nigricans
• Complications mnemonic "4 Vs": Vision (retinopathy), Vessels (macrovascular disease), Vascular (microvascular), Voidance issues (neuropathy, sexual dysfunction)
• Maturity Onset Diabetes of the Young (MODY): monogenic diabetes; presents <25 years; autosomal dominant inheritance
• LADA ("Type 1.5"): Latent Autoimmune Diabetes in Adults; slow autoimmune β-cell destruction; initially appears Type 2; positive GAD/IA-2 antibodies

• Confusing prediabetes with DM: Prediabetes = fasting glucose 100-125 mg/dL or HbA1c 5.7-6.4%; does NOT require pharmacotherapy; lifestyle modification is first-line
• Missing DKA in Type 1 presentations: Up to 25% present with DKA; requires aggressive IV fluids, insulin, and electrolyte monitoring; use anion-gap metabolic acidosis as clue
• Delaying insulin in Type 2 when needed: "Insulin resistance" is NOT contraindication to insulin; withholding insulin when C-peptide depleted worsens outcomes; treat to target glucose

• Type 1 DM: Insulin (basal-bolus regimen or pump); mandatory from diagnosis; education on carb counting, sick-day rules, hypoglycemia recognition
• Type 2 DM: Lifestyle modification (weight loss, exercise, diet) first; if HbA1c target not met in 3 months → Metformin (first-line agent: improves insulin sensitivity, cardioprotective, weight-neutral); add second agent (GLP-1 RA, SGLT2i, DPP-4i, sulfonylureas) based on comorbidities; insulin reserved for advanced disease or acute illness
• Gestational DM: Dietary management, self-monitoring of blood glucose; insulin if targets not met (preferred over oral agents in pregnancy)