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

Simon J. Fisher, C. Ronald Kahn

Research output: Contribution to journalArticlepeer-review

174 Scopus citations


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 [3-3H]-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 (∼50%) in LIRKO and LIRKO+STZ mice versus controls. Insulin suppressed FFAs similarly in all groups (∼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.

Original languageEnglish
Pages (from-to)463-468
Number of pages6
JournalJournal of Clinical Investigation
Issue number4
StatePublished - Feb 2003

ASJC Scopus subject areas

  • General Medicine


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