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Pathophysiology
Clinical meaning
Insulin resistance is the pathophysiological hallmark of type 2 diabetes (T2D), defined as a diminished biological response to physiological insulin concentrations in target tissues — primarily skeletal muscle, liver, and adipose tissue. Understanding the molecular mechanisms allows the NP to select targeted pharmacotherapy and counsel patients on disease modification.
In skeletal muscle (responsible for ~80% of postprandial glucose disposal), insulin normally binds its receptor tyrosine kinase, activating the IRS-1/PI3K/Akt signaling cascade, which translocates GLUT4 glucose transporters from intracellular vesicles to the cell membrane. In insulin resistance, multiple defects impair this pathway: serine phosphorylation of IRS-1 (by inflammatory kinases JNK and IKK-β, free fatty acids via PKC-θ, and ceramides) blocks the normal tyrosine phosphorylation required for downstream signaling, reducing GLUT4 translocation by 50-70%. Skeletal muscle thus fails to uptake glucose adequately after meals, causing postprandial hyperglycemia — the earliest metabolic abnormality in T2D.
In the liver, insulin normally suppresses gluconeogenesis (new glucose production from lactate, amino acids, and glycerol) and glycogenolysis (glycogen breakdown to glucose). In the insulin-resistant state, hepatic insulin signaling is selectively impaired: the glucose-regulatory pathway (suppression of gluconeogenesis) becomes resistant, but the lipogenic pathway (stimulation of de novo lipogenesis and VLDL production) remains insulin-sensitive. This 'selective hepatic insulin resistance' produces the paradox of simultaneous hyperglycemia (from ongoing gluconeogenesis despite hyperinsulinemia) and dyslipidemia (hypertriglyceridemia, low HDL, small dense LDL from ongoing lipogenesis).
Visceral adipose tissue plays a central role in insulin resistance. Enlarged, inflamed visceral adipocytes secrete pro-inflammatory adipokines: TNF-α (activates JNK and IKK-β inflammatory kinases, directly impairing insulin receptor signaling), IL-6 (activates STAT3 in hepatocytes promoting gluconeogenesis), and resistin (impairs hepatic insulin sensitivity). Simultaneously, adiponectin — an insulin-sensitizing adipokine that activates AMPK (the same target as metformin) — is markedly decreased in obesity. Free fatty acid (FFA) overflow from insulin-resistant adipocytes causes ectopic lipid accumulation in muscle and liver (lipotoxicity), further impairing insulin signaling. This creates a vicious cycle: insulin resistance causes compensatory hyperinsulinemia, which promotes weight gain and further adipocyte expansion, worsening resistance.
The natural history of T2D progresses through identifiable stages: (1) insulin sensitivity is normal, (2) insulin resistance develops (genetic + environmental factors), (3) compensatory beta cell hyperplasia and hyperinsulinemia maintain normoglycemia (this stage may last years), (4) beta cell compensation fails (beta cell mass decreases by ~50% at time of T2D diagnosis through apoptosis from glucotoxicity, lipotoxicity, ER stress, and amyloid deposition), (5) overt hyperglycemia (first postprandial, then fasting). By the time T2D is diagnosed, approximately 50% of beta cell function has already been lost.
Exam Focus
Diagnosis & workup
Diagnostics & workup:
- Fasting plasma glucose: ≥126 mg/dL on two occasions (diabetes); 100-125 mg/dL (impaired fasting glucose/prediabetes)
- HbA1c: ≥6.5% (diabetes); 5.7-6.4% (prediabetes); reflects 2-3 month average glucose exposure
- 2-hour OGTT: ≥200 mg/dL (diabetes); 140-199 mg/dL (impaired glucose tolerance/prediabetes)
- Fasting insulin level: elevated fasting insulin (>25 mcU/mL) with normal or elevated glucose indicates compensatory hyperinsulinemia from insulin resistance
- HOMA-IR calculation: (fasting insulin mcU/mL × fasting glucose mg/dL) / 405; values >2.5-3.0 indicate significant insulin resistance
- Fasting lipid panel: characteristic dyslipidemia of insulin resistance — elevated triglycerides, low HDL cholesterol, small dense LDL (pattern B), elevated total cholesterol/HDL ratio
- Hepatic steatosis assessment: elevated ALT (often 1.5-3x ULN), hepatic ultrasound showing steatosis, FIB-4 index for fibrosis assessment in NAFLD/NASH
- C-peptide: elevated in insulin-resistant T2D (compensatory beta cell secretion); distinguishes from type 1 diabetes (low C-peptide from beta cell destruction)
- Urine albumin-to-creatinine ratio: screen for diabetic nephropathy at diagnosis of T2D (many patients have had undiagnosed hyperglycemia for years)
- Screening recommendations: ADA recommends screening all adults ≥35 years, or earlier with BMI ≥25 and ≥1 additional risk factor; repeat every 3 years if normal
Risk factors:
- Obesity, especially central/visceral adiposity (waist circumference >40 inches men, >35 inches women; visceral fat is metabolically active, producing inflammatory adipokines)
- Family history of type 2 diabetes (first-degree relative confers 2-3x risk; strong polygenic inheritance)
- Ethnicity: African American, Hispanic/Latino, Native American, Asian American, Pacific Islander (2-6x higher risk than non-Hispanic whites)
- Physical inactivity (skeletal muscle is the primary glucose disposal tissue; exercise independently improves GLUT4 translocation and insulin sensitivity)
- Polycystic ovary syndrome (PCOS — insulin resistance drives ovarian androgen excess; 40-70% of women with PCOS develop prediabetes or T2D)
- Gestational diabetes history (50% develop T2D within 5-10 years; postpartum screening recommended)
- Metabolic syndrome (3 of 5: elevated waist circumference, elevated triglycerides ≥150, low HDL <40/50, elevated BP ≥130/85, elevated fasting glucose ≥100)
- Medications: corticosteroids, atypical antipsychotics (olanzapine, clozapine), thiazide diuretics, protease inhibitors — all increase insulin resistance
- Acanthosis nigricans (clinical marker of hyperinsulinemia and insulin resistance — velvety hyperpigmented plaques in skin folds)
- Non-alcoholic fatty liver disease (NAFLD/NASH — hepatic steatosis is both a consequence and amplifier of insulin resistance)
- Sleep deprivation and obstructive sleep apnea (intermittent hypoxia activates sympathetic nervous system, increases cortisol, and worsens insulin resistance)
Management
Additional clinical detail, exam hooks, and takeaways continue in the full lesson.
Prescribing & monitoring
Additional clinical detail, exam hooks, and takeaways continue in the full lesson.
Takeaways
Additional clinical detail, exam hooks, and takeaways continue in the full lesson.
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