Does hepatic insulin resistance increase liver glucose production and link to fatty liver and mild ALT elevation?

The claim is supported overall: impaired hepatic insulin action contributes to dysregulated glucose output, and systemic insulin resistance commonly coexists with MASLD and higher ALT. These are related metabolic phenomena, but neither ALT nor insulin-resistance estimates alone establishes an individual liver diagnosis.

Clinical and metabolic evidence

• In obese adults with impaired fasting glucose, insulin-mediated suppression of endogenous glucose production was lower than in metabolically normal participants (55% vs 68%; P<0.001). Inappropriate persistence of hepatic glucose release can therefore contribute to fasting hyperglycemia.
• Insulin resistance has a strong association with MASLD/NAFLD. A 2024 systematic review found higher HOMA-IR in NAFLD versus controls (weighted mean difference 1.28, 95% CI 1.00–1.58). In a prospective non-diabetic cohort, HOMA-IR predicted incident NAFLD (adjusted OR 1.315, 95% CI 1.214–1.424).
• ALT is also associated with insulin resistance: in Framingham, each 1-SD increase in ALT corresponded to an adjusted OR of 1.76 (95% CI 1.25–2.26) for high HOMA-IR, including ALT levels within conventional “normal” ranges.

Mechanistic explanation

• Hepatic insulin resistance weakens insulin’s suppression of gluconeogenesis and, in some settings, glycogenolysis. Tracer data attribute elevated fasting glucose production in isolated impaired fasting glucose chiefly to increased gluconeogenesis.
• Adipose insulin resistance increases portal non-esterified fatty-acid delivery; hyperinsulinemia/hyperglycemia can maintain hepatic de novo lipogenesis. Hepatic lipid and diacylglycerol accumulation, with PKCε activation, correlate with impaired hepatic insulin signaling and glucose-production suppression.

Clinical implications

• ALT is nonspecific: normal ALT does not exclude MASLD or fibrosis, while ALT ≥2× the upper limit had only 50% sensitivity and 61% specificity for steatohepatitis. Evaluate alternative liver causes and use fibrosis pathways such as FIB-4, followed when indicated by elastography.

Bottom line

• Hepatic insulin resistance plausibly raises liver glucose production and is closely linked to MASLD and mild ALT elevation, but ALT should not be used as a stand-alone diagnostic marker.