Insulin's direct effects on the liver dominate the control of hepatic glucose production

Abstract

Insulin inhibits glucose production through both direct and indirect effects on the liver; however, considerable controversy exists regarding the relative importance of these effects. The first aim of this study was to determine which of these processes dominates the acute control of hepatic glucose production (HGP). Somatostatin and portal vein infusions of insulin and glucagon were used to clamp the pancreatic hormones at basal levels in the nondiabetic dog. After a basal sampling period, insulin infusion was switched from the portal vein to a peripheral vein. As a result, the arterial insulin level doubled and the hepatic sinusoidal insulin level was reduced by half. While the arterial plasma FFA level and net hepatic FFA uptake fell by 40-50%, net hepatic glucose output increased more than 2-fold and remained elevated compared with that in the control group. The second aim of this study was to determine the effect of a 4-fold rise in head insulin on HGP during peripheral hyperinsulinemia and hepatic insulin deficiency. Sensitivity of the liver was not enhanced by increased insulin delivery to the head. Thus, this study demonstrates that the direct effects of insulin dominate the acute regulation of HGP in the normal dog. IntroductionHepatic glucose production (HGP) accounts for the majority of whole-body glucose production and is tightly regulated by insulin in the healthy individual. Since hepatic insulin resistance in diabetic patients results in excess HGP and fasting hyperglycemia (1), it is critical to understand the mechanisms by which insulin regulates this process. Insulin reduces HGP by acting both directly and indirectly on the liver (2); however, there is considerable controversy regarding the relative importance of insulin's direct versus indirect effects under physiological conditions. Insulin acts directly by binding to hepatic insulin receptors and thereby activating insulin signaling pathways in the liver. These effects have been demonstrated in various models. In isolated rat hepatocytes, insulin inhibits glucose production through inhibition of gluconeogenesis (3) and glycogenolysis (4). In the dog, an acute selective increase (5) or decrease (6) in hepatic insulin level (so that the arterial insulin level was kept constant) resulted in very rapid suppression or stimulation, respectively, of HGP. In addition, liver-specific insulin receptor knockout (LIRKO) mice, which lack hepatic insulin receptors from birth, demonstrate severe hepatic insulin resistance (7). These studies, and others, demonstrate that insulin acts directly on the liver to regulate HGP.Insulin's indirect effects include reduction of glucagon secretion at the pancreas (8), inhibition of lipolysis in fat (which reduces circulating lipids and glycerol availability for gluconeogenesis) (9), and decreased protein catabolism in muscle (which further reduces gluconeogenic precursor availability) (10), and in addition, recent studies in the mouse and rat suggest that hypothalamic insulin signaling may also play an important role ...

Activation of KATP channels suppresses glucose production in humans

“…Factors contributing to this time course probably included the time required for central appearance of oral diazoxide (maximal by 4 hours in rats) and the effects of central signals on hepatic p-STAT3 and subsequently on gluconeogenic enzyme transcription and translation (16). This is consistent with the observation that raising carotid and vertebral artery insulin levels for 3 hours did not affect EGP in dogs (17). Moreover, intraportal insulin infusion caused rapid (45%-50% by 30 minutes), followed by marked (80%-90% by 240 minutes), decreases in hepatic PEPCK and G6Pase expression, with significant increases in hepatic p-STAT3 by 240 minutes (18).…”

Evidence for Central Regulation of Glucose Metabolism

“…Short duration pancreatic clamp studies in conscious dogs failed to show an acute impact on EGP when insulin delivery to the head was increased 4-fold (39). Further work in dogs confirmed the ability of ICV insulin infusion to increase hepatic STAT3 phosphorylation and suppress hepatic gluconeogenic enzyme expression (40).…”

The IGF system after insertion of a transjugular intrahepatic porto-systemic shunt in patients with liver cirrhosis

“…This could be due to insulin-rich portal bypassing the sinusoids via the TIPS, so that sinusoidal perfusion in that situation was mostly dependent on arterial and relatively insulindepleted blood supply (39)(40)(41). Studies in dogs with shifting of insulin release from the portal to a peripheral vein immediately doubles peripheral blood insulin concentration, halves the sinusoidal concentration (42), and doubles the hepatic glucose output. This mechanism would partly explain the observed euglycemia despite the marked peripheral hyperinsulinemia.…”