Endocrinology · PANCE / PANRE

Type 2 Diabetes Mellitus

Insulin resistance with progressive beta-cell dysfunction; most common form of diabetes.

Also known as: T2DM, type 2 diabetes, adult-onset diabetes, NIDDM, insulin resistance

Overview

Chronic metabolic disorder characterized by peripheral insulin resistance and progressive pancreatic beta-cell dysfunction, leading to hyperglycemia. Accounts for ~90-95% of all diabetes cases.

Epidemiology

Affects ~37 million Americans (11% of adults); ~96 million have prediabetes. Disproportionately affects Hispanic, Black, Native American, and South Asian populations. Increasing incidence in adolescents paralleling childhood obesity epidemic.

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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

Symptoms

  • Often asymptomatic; diagnosed on screening labs
  • Polyuria, polydipsia, polyphagia (less prominent than T1DM)
  • Fatigue, blurred vision, slow wound healing
  • Recurrent infections (yeast, UTI, skin)
  • May present with complications: neuropathy, retinopathy, CAD, or HHS

Signs / physical exam

  • Overweight or obese (~80%); central adiposity
  • Acanthosis nigricans — hyperpigmented velvety plaques on neck/axillae (insulin resistance)
  • Skin tags
  • Diminished pedal pulses, decreased monofilament/vibration sensation
  • Diabetic foot ulcers, fungal infections

Classic findings

Acanthosis nigricans on the posterior neck in an overweight adult is a classic sign of insulin resistance.

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 criteria

A1c ≥6.5%, fasting glucose ≥126 mg/dL (8-hr fast), 2-hr OGTT ≥200 mg/dL (75 g load), or random ≥200 mg/dL with symptoms. Prediabetes: A1c 5.7-6.4%, fasting 100-125, OGTT 140-199.

Labs

  • Screening: USPSTF recommends screening adults 35-70 with overweight/obesity; ADA recommends starting at age 35 for all, earlier with risk factors
  • A1c ≥6.5%, fasting glucose ≥126 mg/dL, 2-hr OGTT ≥200 mg/dL, or random ≥200 mg/dL with symptoms
  • Confirm with repeat testing unless unequivocal hyperglycemia
  • Lipid panel, comprehensive metabolic panel, urine albumin/creatinine ratio
  • TSH, LFTs (NAFLD screening), CBC

Imaging

  • Not routine for diagnosis
  • Dilated retinal exam at diagnosis and annually
  • Consider liver imaging if AST/ALT elevated (NAFLD evaluation)

Diagnostic algorithm

flowchart TD
  A[New T2DM diagnosis<br/>A1c ≥6.5%] --> B[Lifestyle modification<br/>+ Metformin]
  B --> C{Comorbidities?}
  C -->|ASCVD| D[Add GLP-1 RA<br/>semaglutide, liraglutide]
  C -->|HF or CKD| E[Add SGLT2i<br/>empagliflozin, dapagliflozin]
  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 >9% or symptomatic?}
  J -->|Yes| K[Initiate basal insulin<br/>± prandial]
  H -->|Yes| L[Continue regimen<br/>recheck q3-6mo]
T2DM treatment algorithm — choice of second agent driven by comorbidities (ADA 2025).

Treatment

First-line

  • Lifestyle modification: 5-10% weight loss, Mediterranean/DASH diet, 150 min/week moderate aerobic exercise + resistance training, smoking cessation
  • Biguanide — metformin: first-line for most patients (unless contraindicated); start 500 mg daily, titrate to 1000 mg BID; reduces hepatic gluconeogenesis; weight neutral; low hypoglycemia risk; contraindicated if eGFR <30
  • GLP-1 RA — semaglutide, liraglutide, dulaglutide, tirzepatide (dual GIP/GLP-1): weight loss, CV benefit (LEADER, REWIND, SUSTAIN-6); first-line if ASCVD, HF, CKD, or obesity present
  • SGLT2 inhibitor — empagliflozin, dapagliflozin, canagliflozin: CV and renal benefit (EMPA-REG, DAPA-HF, CREDENCE); first-line if HF or CKD; risk of euglycemic DKA, genital mycotic infection

Second-line / adjunct

  • DPP-4 inhibitor — sitagliptin, linagliptin, saxagliptin: weight neutral, low hypoglycemia risk
  • Sulfonylurea — glipizide, glimepiride, glyburide: inexpensive but cause hypoglycemia and weight gain
  • Thiazolidinedione — pioglitazone: insulin sensitizer; weight gain, edema, HF exacerbation, bladder cancer concern
  • Insulin: indicated if A1c >10%, glucose >300, symptomatic hyperglycemia, or failure of oral/injectable agents; basal insulin (glargine, detemir, degludec) first, then add prandial
  • Bariatric/metabolic surgery: BMI ≥35 or ≥30 with inadequate glycemic control; can induce remission

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: hold for elective surgery (delayed gastric emptying → aspiration risk).
  • 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.

References

  • ADA 2025 — American Diabetes Association Standards of Care in Diabetes—2025 (Diabetes Care 2025; 48 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)

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