Hormonal regulation of hepatic glucose production in health and disease

Abstract

We review mechanisms that regulate production of glucose by the liver, focusing on areas of budding consensus, and endeavoring to provide a candid assessment of lingering controversies. We also attempt to reconcile data from tracer studies in humans and large animals with the growing compilation of mouse knockouts that display changes in glucose production. A clinical hallmark of diabetes, excessive glucose production remains key to its treatment. Hence, we attempt to integrate emerging pathways into the broader goal to rejuvenate the staid antidiabetic pharmacopeia.

Figure 1. Direct and indirect control of HGP

The liver integrates cell-autonomous and cell-nonautonomous mechanisms to control glucose release into the bloodstream. The role of altered glucagon-to-insulin ratios in HGP of type 2 diabetics remains unsettled and of potential therapeutic import. Classic mechanisms of indirect control of HGP include release of gluconeogenic precursors from adipose tissue and muscle (FFA, glycerol, amino acids), adipocytokines (leptin, adiponectin, resistin), neuronal control–possibly mediated through the vagus nerve. In addition, intrahepatic fat plays an important role in promoting HGP, possibly through accumulation of complex phospholipids. Finally, intra-hepatic accumulation of resident macrophages has in recent years taken center stage as a potential mechanism of insulin resistance, leading to lipid accumulation and increased HGP.

Figure 2. Hormonal and nutrient pathways of HGP regulation in hepatocytes

Some of the main signaling pathways reviewed in this article are summarized. Insulin, glucagon, and glucocorticoids remain the central regulators of HGP. Their transcriptional effects are mediated through the Akt/Foxo and possibly Crtc2 pathways. AMPK, by virtue of its energy-sensing role, is likely to participate in several of these processes, but its upstream regulators and downstream targets are elusive. Bile acids have profound effects on HGP through complex and redundant mechanisms. Cytokines released from a variety of sources (fat cells, circulating as well as resident macrophages) also affect HGP and are likely to impair insulin sensitivity. A second level of transcriptional integration is provided by cofactors such as Sirt1, Clock genes, Src1–3. Their hormonal regulation is unknown at present. But transcriptional effects account only for part of HGP regulation. Direct control over enzymatic flux through glycolysis and gluconeogenesis, summarized on the right, is likely to be the critical mechanism for rapid regulation of this process.