title: Insulin signaling is required for insulin's direct and indirect action on hepatic glucose production.
abstract: 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.
authors.affiliation: Research Division, Joslin Diabetes Center, Harvard Medical School, Boston. Massachusetts 02215, USA.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Fisher
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects; D005947:Glucose / Q000096:biosynthesis*; D015309:Glucose Clamp Technique; D007328:Insulin / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051381:Rats; D011972:Receptor, Insulin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013311:Streptozocin / Q000633:toxicity
chemical_list: D007328:Insulin; D013311:Streptozocin; D011972:Receptor, Insulin; D005947:Glucose