Glucose metabolism is regulated by the opposing actions of insulin and glucagon. Insulin is released from pancreatic ß cells in response to high blood glucose levels and regulates glucose metabolism through its actions on muscle, liver, and adipose tissue. The binding of insulin to its receptor activates multiple proteins including Phosphatidylinositol 3-Kinase (PI3K). PI3K activity controls pathways regulating glucose transporter 4 (Glut4) translocation to the membrane, lipolysis, and glycogen synthesis. The activation of PI3K results in the uptake of glucose into skeletal and adipose cells and the storage of excess glucose as glycogen. Insulin resistance in skeletal muscle is associated with impaired signaling through the insulin receptor/PI3K signaling axis with subsequent defects in Glut4 translocation and glycogen synthesis. In adipose tissue, insulin resistance is associated with decreased fat storage and increased fatty acid mobilization. Insulin affects two major processes within hepatocytes, gluconeogenesis and triglyceride synthesis. Upon insulin receptor signaling, the transcription factor FoxO1 becomes phosphorylated and is excluded from the nucleus. FoxO1 controls the transcription of factors involved in gluconeogenesis, and inactivation of this protein normally results in a down-regulation of gluconeogenic activities. Insulin also activates the transcription factor SREBP-1c, which controls triglyceride synthesis. Under normal conditions, insulin signaling results in decreased hepatocyte glucose production and increased triglyceride synthesis. Individuals with insulin resistance present with hyperglycemia and hypertriglyceridemia even in the presence of high plasma insulin levels (hyperinsulinemia). This strongly suggests that within the liver, insulin resistance is partial. Insulin fails to suppress gluconeogenesis while the triglyceride synthesis pathway remains sensitive to insulin. This results in hyperglycemia and hypertriglyceridemia.
Glucagon, which is released from pancreatic a cells in response to low blood glucose levels, acts on liver cells to promote glycogen breakdown (glycogenolysis) and to encourage glucose synthesis via gluconeogenesis. The net effect of glucagon signaling is an increase in blood glucose levels. For reasons that are not entirely clear, patients with type 2 diabetes often present with hyperglucagonaemia which results in continued glucose output by hepatic cells. This suggests that targeting glucagon signaling in hepatocytes may be a viable treatment option for type 2 diabetes.
Figure 1.Insulin binding to its receptor initiates multiple signaling molecules including those leading to Phosphatidylinositol (PI)-3-Kinase activation. PI-3-Kinase activation contributes to multiple tissue-specific biological processes, including Glut4 translocation from intracellular vesicles to the plasma membrane, the inhibition of lipolysis, and the upregulation of glycogen synthesis. The actions of insulin are countered by glucagon receptor signaling.
Insulin acts on hepatocyte cells to suppress gluconeogenesis, the metabolic pathway that generates glucose from non-carbohydrate sources. In insulin-resistant tissues, insulin fails to suppress gluconeogenesis resulting in chronically elevated blood glucose levels. Enzymes of the gluconeogenic pathway are attractive targets for pharmacological intervention in insulin-resistant and type 2 diabetic patients.