Type 2 Diabetes Mellitus

Risk factors

• Modifiable: obesity (especially central/visceral adiposity, BMI ≥25 or ≥23 in Asian populations), physical inactivity, hypertension, dyslipidemia, smoking
• Non-modifiable: age ≥35, family history, race/ethnicity (Hispanic, Black, Native American, Asian, Pacific Islander)
• Obstetric: history of gestational diabetes, PCOS, delivery of infant >9 lb
• Metabolic: metabolic syndrome, NAFLD, prediabetes (A1c 5.7-6.4%)
• Medications: glucocorticoids, atypical antipsychotics, thiazides, statins (mild effect)

Pathophysiology

Pathogenesis involves the 'ominous octet': (1) impaired insulin secretion, (2) decreased incretin effect, (3) increased glucagon, (4) increased hepatic glucose output, (5) increased lipolysis, (6) increased renal glucose reabsorption, (7) neurotransmitter dysfunction (CNS), (8) muscle insulin resistance. Hyperinsulinemia compensates initially, but beta cells eventually fail.

Clinical presentation

Differential diagnosis

• Type 1 diabetes mellitus — Lean, younger, acute onset, may present with DKA; positive autoantibodies; low C-peptide
• LADA — Initially appears as T2DM but progresses rapidly to insulin requirement; positive GAD-65
• MODY — Autosomal dominant family pattern, onset <25, non-obese, preserved C-peptide
• Cushing syndrome — Centripetal obesity, striae, moon facies, hypertension, hyperglycemia; elevated cortisol
• Acromegaly — Coarse features, enlarged hands/feet, sweating; elevated IGF-1
• Pancreatic disease — Chronic pancreatitis, hemochromatosis, pancreatic cancer; may cause secondary diabetes
• Drug-induced hyperglycemia — Glucocorticoids, atypical antipsychotics, HIV protease inhibitors, immunosuppressants

Diagnostic workup

Diagnostic algorithm

flowchart TD
  A[New T2DM diagnosis<br/>A1c ≥6.5%] --> B[Lifestyle modification<br/>+ Metformin]
  B --> C{Comorbidities?}
  C -->|ASCVD| D["GLP-1 RA and/or SGLT2i<br/>with proven CV benefit<br/>(regardless of A1c or metformin)"]
  C -->|HF or CKD| E["Add SGLT2i<br/>empagliflozin, dapagliflozin<br/>(CKD: start if eGFR ≥20)"]
  C -->|Obesity| F[Add GLP-1 RA<br/>or tirzepatide]
  C -->|None| G[Continue metformin<br/>reassess A1c in 3 mo]
  D --> H{At A1c goal?}
  E --> H
  F --> H
  G --> H
  H -->|No| I[Add second agent<br/>DPP-4i, SU, TZD, basal insulin]
  I --> J{"A1c >10%, glucose ≥300,<br/>or catabolic symptoms?"}
  J -->|Yes| K[Initiate basal insulin<br/>± prandial]
  H -->|Yes| L[Continue regimen<br/>recheck q3-6mo]

Treatment

Complications

• Microvascular: retinopathy (leading cause of adult blindness in US), nephropathy (leading cause of ESRD), neuropathy (peripheral, autonomic, mononeuropathies)
• Macrovascular: CAD (2-4× risk), stroke, peripheral arterial disease, amputation
• Acute: HHS, DKA (uncommon but possible), severe hypoglycemia (especially with insulin/sulfonylureas)
• Hepatic: NAFLD/NASH, cirrhosis, hepatocellular carcinoma
• Infections: foot ulcers, cellulitis, osteomyelitis, mucormycosis

PANCE pearls

• Metformin's most feared (but rare) complication: lactic acidosis. Hold for iodinated contrast if eGFR <30 or AKI.
• Vitamin B12 deficiency develops in ~10-30% of long-term metformin users; check B12 annually.
• SGLT2 inhibitors can cause euglycemic DKA — hold prior to surgery and during acute illness.
• GLP-1 RAs and tirzepatide delay gastric emptying (aspiration risk with anesthesia): most patients may continue them before elective surgery; higher-risk patients (dose-escalation phase, high dose, GI symptoms) get a 24-h liquid diet or an individualized hold (2024 multisociety guidance).
• Patients with established ASCVD, HF, or CKD should get GLP-1 RA or SGLT2 inhibitor regardless of A1c.
• Diabetic foot exam: 10-g monofilament, 128-Hz tuning fork, ankle reflexes, visual inspection — annually at minimum.
• Preconception: target A1c <6.5% if achievable without significant hypoglycemia; insulin is the preferred agent in pregnancy; stop GLP-1 RAs (semaglutide at least 2 months before), SGLT2 inhibitors, and DPP-4 inhibitors before conception; start a prenatal vitamin with at least 400-800 mcg folic acid; get a baseline dilated eye exam.
• Hypoglycemia on insulin: localize it by timing (fasting or overnight lows = basal dose; lows 2-4 h after a meal = that meal's prandial dose) and cut that component by about 10-20%. Falling eGFR slows insulin clearance, so doses often need reduction; relax the A1c goal (e.g., <8.0%) in older adults with complex health or high hypoglycemia risk.

References

• ADA 2026 — American Diabetes Association Professional Practice Committee. Standards of Care in Diabetes—2026 (Diabetes Care 2026;49 Suppl 1)
• AACE 2023 — AACE Consensus Statement: Comprehensive Type 2 Diabetes Management Algorithm — 2023 Update (Endocr Pract 2023)
• UKPDS — Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment (UKPDS 33, Lancet 1998)
• EMPA-REG OUTCOME — Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (Zinman et al., NEJM 2015)
• LEADER — Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes (Marso et al., NEJM 2016)