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.
Simon J. Fisher, C. Ronald Kahn
Title and authors | Publication | Year |
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Insulin’s Direct Effects on the Liver Dominate the Control of Hepatic Glucose Production
Dale S. Edgerton, Margaret Lautz, Melanie Scott, Carrie A. Everett, Kathryn M. Stettler, Doss W. Neal, Chang A. Chu, Alan D. Cherrington |
Journal of Clinical Investigation | 2006 |
Liver-specific deletion of insulin receptor substrate 2 does not impair hepatic glucose and lipid metabolism in mice
M Simmgen, C Knauf, M Lopez, AI Choudhury, M Charalambous, J Cantley, DC Bedford, M Claret, MA Iglesias, H Heffron, PD Cani, A Vidal-Puig, R Burcelin, DJ Withers |
Diabetologia | 2006 |
The Genetic Basis of Type 2 Diabetes
SK Das, SC Elbein |
Cellscience | 2006 |
Aberrant Forkhead box O1 function is associated with impaired hepatic metabolism
S Qu, J Altomonte, G Perdomo, J He, Y Fan, A Kamagate, M Meseck, HH Dong |
Endocrinology | 2006 |
Central nervous system and control of endogenous glucose production
G Demuro, S Obici |
Current Diabetes Reports | 2006 |
Phosphoinositide 3-kinase regulatory subunit p85alpha suppresses insulin action via positive regulation of PTEN
CM Taniguchi, TT Tran, T Kondo, J Luo, K Ueki, LC Cantley, CR Kahn |
Proceedings of the National Academy of Sciences | 2006 |
Insulin’s effect on the liver: “Direct or indirect?” continues to be the question
J Girard |
Journal of Clinical Investigation | 2006 |