Unraveling the Regulation of Hepatic Metabolism by Insulin

Abstract

During insulin-resistant states such as type 2 diabetes mellitus (T2DM), insulin fails to suppress hepatic glucose production yet promotes lipid synthesis leading to hyperglycemia and hypertriglyceridemia. Defining the downstream signaling pathways underlying the control of hepatic metabolism by insulin is necessary for understanding both normal physiology and the pathogenesis of metabolic disease. Here, we summarize recent literature highlighting the importance of both hepatic and extra-hepatic mechanisms in insulin’s regulation of liver glucose and lipid metabolism. We posit that a failure of insulin to inappropriately regulate liver metabolism during T2DM is not exclusively from an inherent defect in canonical liver insulin signaling but, rather, due to a combination of hyperinsulinemia, altered substrate supply, and the input of several extra-hepatic signals.

Fast‐acting insulin aspart in people with type 2 diabetes: Earlier onset and greater initial exposure and glucose‐lowering effect compared with insulin aspart

“…It was recently shown that the improved postprandial glucose control seen with faster aspart during the first hour after a meal is attributable to a combination of greater early suppression of endogenous glucose production and greater increase in glucose disappearance; thus, the mechanisms explaining the reduced postprandial glucose concentration with faster aspart mimic the physiological dual response to increased circulating insulin after meal initiation, consisting of a rapid reduction in hepatic glucose output combined with an increased peripheral glucose uptake . The present finding of earlier suppression of FFA concentration with faster aspart versus IAsp is intriguing because reduced FFA availability to the liver may lead to suppression of hepatic glucose output via decreased hepatic FFA oxidation and, in turn, inhibition of gluconeogenesis . It was recently suggested, based on a study in people with T1D, that the greater early suppression of endogenous glucose production with faster aspart might be partly attributable to larger initial suppression of the FFA level in the circulation .…”

“…2 The present finding of earlier suppression of FFA concentration with faster aspart versus IAsp is intriguing because reduced FFA availability to the liver may lead to suppression of hepatic glucose output via decreased hepatic FFA oxidation and, in turn, inhibition of gluconeogenesis. [18][19][20] It was recently suggested, based on a study in people with T1D, that the greater early suppression of endogenous glucose production with faster aspart might be partly attributable to larger initial suppression of the FFA level in the circulation. 7 It follows that the earlier suppression of FFA in the present study in T2D may contribute to the early improved postprandial glycaemic control seen with faster aspart versus IAsp.…”

Asprosin: A Novel Player in Metabolic Diseases

“…The essential pathological features of T2DM are the increased fasting and postprandial blood glucose caused by the continued excess release of glucose from the liver, IR, and β-cell dysfunction (21,22). Romere et al noticed that a single dose of recombinant asprosin injected subcutaneously in mice led to hyperglycemia and hyperinsulinemia; neutralization of asprosin by asprosinspecific antibodies resulted in ameliorated IR and dropped plasma glucose, insulin levels as well as body weight.…”

Mitogen-Activated Protein Kinase Regulation in Hepatic Metabolism

“…In the liver, T2DM manifests as insulin resistance, altered glucose homeostasis and the accumulation of fat (hepatosteatosis) [2]. The progressive increase in hepatic fat content leads to non-alcoholic fatty liver disease (NAFLD) which, can subsequently be accompanied by hepatic inflammation leading to non-alcoholic steatohepatitis (NASH) [3].…”