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

Abstract

IntroductionThe failure of insulin to inhibit hepatic glucose production (HGP) is a cardinal feature of insulin resistance in the liver and a major factor contributing to hyperglycemia in diabetic states. Classically, the HGP-suppressing effect of insulin is thought to occur via signaling through the hepatic insulin receptor to inhibit glycogenolysis and gluconeogenesis. This classical paradigm has been challenged by in vivo studies suggesting that much of insulin's action on the liver may be indirect, and related to systemic, rather than hepatic, insulin effects (1-6). Thus, extrahepatic actions of insulin on muscle and adipose tissue to inhibit release of gluconeogenic substrates (e.g., lactate, alanine, and glycerol) and gluconeogenic energy substrates (e.g., FFAs) result in a subsequent inhibition of HGP (7-10). These mechanisms may be particularly important in the diabetic state, in which gluconeogenesis is considerably increased (11)(12)(13)(14), and in which hyperglycemia per se has been shown to potentiate the indirect actions of insulin (15). Furthermore, since up to 75% of basal HGP is driven by glucagon (16), insulin-induced suppression of glucagon release may be another indirect mechanism by which insulin suppresses HGP (2, 3, 17, 18).We have recently developed a unique model to investigate direct versus indirect insulin actions. Liver-specific insulin receptor knockout (LIRKO) mice have an approximately 95% reduction in insulin receptor content in the liver, and only in the liver (19). Since the Alb-Cre transgene is only expressed in hepatocytes, and since hepatocytes make up only about 85% of the total number of cells in the liver, it is likely that the knockout of insulin receptor in LIRKO hepatocytes is essentially complete. LIRKO mice have an absence of insulin-stimulated receptor tyrosine phosphorylation and insulin signaling in the hepatocyte (19). Since the livers of LIRKO mice cannot respond directly to insulin, any effect of insulin administered in vivo must be mediated by indirect actions of insulin on extrahepatic tissues.In this study, in an attempt to clarify indirect effects of insulin on the suppression of HGP, we assessed the regulation of HGP in both control and LIRKO mice by performing high-dose hyperinsulinemic-euglycemic clamps to maximally stimulate insulin-sensitive peripheral tissues. We speculated that the marked chronic hyperinsulinemia in the LIRKO mice might have led to secondary insulin resistance in muscle and fat (20)(21)(22) and perhaps limited insulin action on these extrahepatic tissues. We therefore treated a second group of LIRKO mice with streptozotocin (LIRKO+STZ mice) to reduce hyperinsulinemia in an 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 ...

In Vivo Mutagenesis of the Insulin Receptor

“…Measurements of hepatic glucose fluxes using hyperinsulinemic-euglycemic clamps reveal that insulin fails to suppress gluconeogenesis in LIRKO mice, consistent with the view that Insr signaling is required for both indirect and direct effects of insulin on the liver in mice (36).…”

Central Resistin Induces Hepatic Insulin Resistance via Neuropeptide Y

“…The mice were killed at the end of the experiment and gastrocnemius, perigonadal adipose, brown adipose tissue and liver were harvested, frozen in liquid nitrogen and stored at Ϫ80°C until processing. The glucose infusion rate, hepatic glucose production, R d and tissue glucose uptake were determined (Fisher and Kahn, 2003;Qi et al, 2006). For experiments examining the effects of antagonism of NPY signaling, NPY Y1 receptor antagonist, BIBP3226 (2 nmol) (Doods et al, 1996), NPY Y5 receptor antagonist, CGP71683 (5 nmol) (Criscione et al, 1998), or vehicle (1 l of artificial CSF) was injected intracerebroventricularly 2 h before central resistin or vehicle.…”

Ectopic expression of glucagon receptor in skeletal muscles improves glucose homeostasis in a mouse model of diabetes

“…Insulin signalling in the liver is critical for the proper maintenance of metabolic homeostasis [49]. Particularly, in the absence of insulin signalling, insulin cannot suppress hepatic glucose production in liver-specific insulin receptor knockout (LIRKO) mice [50]. The Mck/Gcgr mice have both elevated glucagon and insulin, thus maintaining an appropriate ratio of glucagon to insulin, which represents an important mechanism for maintaining glycaemic stability, particularly in extremes of glucose influx or efflux [9] (Fig.…”