| First Author | Fisher SJ | Year | 2003 |
| Journal | J Clin Invest | Volume | 111 |
| Issue | 4 | Pages | 463-8 |
| PubMed ID | 12588884 | Mgi Jnum | J:81895 |
| Mgi Id | MGI:2450202 | Doi | 10.1172/JCI16426 |
| Citation | Fisher SJ, et al. (2003) Insulin signaling is required for insulin's direct and indirect action on hepatic glucose production. J Clin Invest 111(4):463-8 |
| abstractText | 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. |
