Insulin signaling is required for insulin's direct and indirect action on hepatic glucose production

J Clin Invest. 2003 Feb;111(4):463-8. doi: 10.1172/JCI16426.


We and others have suggested that insulin predominantly acts indirectly to inhibit hepatic glucose production (HGP) via suppression of gluconeogenic precursors, FFAs, and glucagon. To test that hypothesis, we performed high-dose hyperinsulinemic-euglycemic clamps using [3-(3)H]-glucose in liver-specific insulin receptor knockout (LIRKO) mice, LIRKO mice treated with streptozotocin (LIRKO+STZ), and controls. In LIRKO mice, fasted glucose was normal, but insulin levels were elevated tenfold. STZ treatment reduced insulinemia by 60% with resulting hyperglycemia. Interestingly, basal HGP was similar in all three groups. During the clamp, HGP was suppressed by 82 +/- 17% in controls, but was not suppressed in either LIRKO or LIRKO+STZ mice. Glucose infusion and utilization were impaired ( approximately 50%) in LIRKO and LIRKO+STZ mice versus controls. Insulin suppressed FFAs similarly in all groups ( approximately 46%). Glucagon was not significantly suppressed during the clamp. Thus, in LIRKO mice, (a) high-dose insulin fails to suppress HGP indicating that both direct and indirect effects of insulin require an intact insulin-signaling pathway in the liver; (b) primary hepatic insulin resistance leads to hyperinsulinemia and secondary extrahepatic insulin resistance; and (c) lowering insulin levels with STZ tended to improve extrahepatic insulin sensitivity but failed to reveal the previously postulated indirect role of insulin in suppressing HGP.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Diabetes Mellitus, Experimental / blood
  • Diabetes Mellitus, Experimental / metabolism
  • Gluconeogenesis / drug effects
  • Glucose / biosynthesis*
  • Glucose Clamp Technique
  • Insulin / blood
  • Insulin / metabolism*
  • Insulin / pharmacology
  • Insulin Resistance
  • Liver / drug effects
  • Liver / metabolism*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Rats
  • Receptor, Insulin / deficiency
  • Receptor, Insulin / genetics
  • Receptor, Insulin / metabolism*
  • Signal Transduction
  • Streptozocin / toxicity


  • Insulin
  • Streptozocin
  • Receptor, Insulin
  • Glucose