Insulin Inhibits Glucose Synthesis and Enhances Storage of Glucose as Glycogen

Within minutes, insulin stimulation of muscle cells enhances the conversion of glucose to glycogen, and PKB, activated downstream of the insulin receptor, plays a crucial role in this process as well. Active PKB phosphorylates GSK3 (the same enzyme that functions in the Wnt and Hh pathways). In resting (non-insulin-stimulated) cells, GSK3 phosphorylates glycogen synthase and thus inhibits its activity. In contrast, in insulin-treated muscle, GSK3 is phosphorylated by PKB and cannot phosphorylate glycogen synthase; thus insulin-stimulated activation of PKB results in net short-term activation of glycogen synthase and glycogen synthesis.

Insulin also acts on hepatocytes (liver cells) to inhibit glucose synthesis from smaller molecules (gluconeogenesis), such as lactate, pyruvate, and acetate (see Chapter 12) and to enhance glycogen synthesis from glucose. Many of these effects are manifest at the level of gene transcription because insulin signaling reduces the expression of genes whose encoded enzymes simulate synthesis of glucose from small metabolites. The net effect of all these actions is to lower blood glucose to the fasting concentration of about 5 mM while storing the excess glucose intracellularly as glycogen for future use.

If the blood glucose level falls below about 5 mM—for example, due to sudden muscular activity—reduced insulin secretion from pancreatic β cells induces pancreatic α cells to increase their secretion of glucagon into the blood and quickly trigger an increase in blood glucose levels.

Unfortunately, these intricate and powerful control systems sometimes fail, causing serious, even life-threatening, disease, mainly diabetes mellitus. In diabetes, the regulation of blood glucose is impaired, leading to persistent elevated blood glucose concentrations (hyperglycemia) that, if left untreated, lead to major complications, including blindness, kidney failure, and limb amputations. Type 1 diabetes mellitus, common in children and young adults, is caused by an autoimmune process that destroys the insulin-producing β cells in the pancreas. Sometimes called insulin-dependent diabetes, this form of the disease is generally responsive to regulated lifelong insulin injections and constant monitoring of blood glucose levels.

Most adults in developed countries with diabetes mellitus have type 2, sometimes called non-insulin-independent diabetes; this condition results from a decrease in the ability of muscle, fat, and liver cells to respond to insulin and from a loss of insulin-producing cells as the body tries to compensate for an elevated glucose level by overproducing insulin. While the underlying causes of this form of the disease are not well understood, obesity is correlated with a huge increase in the incidence of diabetes. As we see in the next section, obesity also contributes to the malfunction of adipocytes, the cells that store fatty acids as triglycerides. The resulting accumulation of lipids (particularly diacylglycerols and sphingolipids) in muscle and liver impairs insulin action in these tissues. Further identification of the signaling pathways that control energy metabolism is expected to provide insight into the pathophysiology of diabetes, hopefully leading to new methods for its prevention and treatment.