Does hepatic insulin resistance raise blood glucose despite substantial insulin secretion?

Hepatic insulin resistance is a well-established driver of dysglycemia, particularly fasting hyperglycemia in type 2 diabetes and metabolic liver disease. It describes inadequate hepatic response to insulin—not necessarily inadequate insulin availability.

Clinical evidence

• Hyperinsulinemic–euglycemic clamp studies with glucose tracers show that, at matched insulin concentrations, people with obesity, type 2 diabetes, MASLD, or NAFLD maintain higher endogenous (largely hepatic) glucose production than comparator groups. This directly demonstrates impaired insulin-mediated suppression of liver glucose output.
• Excess hepatic glucose production is a major determinant of fasting hyperglycemia in type 2 diabetes. Thus, elevated glucose can persist despite fasting hyperinsulinemia and substantial endogenous insulin secretion: insulin is present, but its glucose-lowering hepatic action is inadequate.

Mechanistic basis

• Insulin normally suppresses hepatic glucose output chiefly through strong inhibition of glycogenolysis and also through reduction of gluconeogenesis. Failure to restrain either process can sustain excessive glucose release into the circulation.
• Pathway-selective impairment of hepatic AKT–FOXO1 signaling provides a mechanistic explanation for insufficient suppression of gluconeogenic and glycogenolytic programs.
• Indirect insulin actions also matter: impaired suppression of adipose lipolysis can increase delivery of glycerol and nonesterified fatty acids to the liver, supporting gluconeogenesis.

Clinical interpretation

• Preserved or high C-peptide during hyperglycemia can support substantial endogenous insulin secretion; random or stimulated values >0.60 nmol/L generally indicate substantial residual secretion. Interpretation requires simultaneous glucose, fasting versus stimulated conditions, treatment exposure, and renal function, since reduced renal clearance raises C-peptide.
• Bottom line: The claim is strongly supported. Hepatic insulin resistance permits inappropriately high liver glucose production—via inadequate control of glycogenolysis and gluconeogenesis—thereby contributing to hyperglycemia even when endogenous insulin secretion is substantial.