Insulin and Glucagon System

In skeletal muscle, insulin stimulates glucose uptake and storage (glycogen synthesis by Glycogen Synthase, or GS), thus lowering blood glucose levels. In the liver, insulin blocks the release and neogenesis of glucose and stimulates glucose storage. In addition, insulin stimulates protein synthesis, regulates mitochondrial biogenesis and blocks autophagy. One of the most important metabolic events that accompany the intake of nutrients is the suppression of hepatic glucose output. During fasting, the liver maintains blood glucose levels by producing glucose, thus providing energy to organs, such as brain, that are dependent on carbohydrates. Glucose produced and released from liver derives from de novo synthesis from substrates like glycerol, lactate, and amino acids (gluconeogenesis) and the breakdown of stored glycogen (glycogenolysis). In the postprandial state (i.e. satiety, the increased availability of glucose and insulin), these processes are largely suppressed by the increase in insulin and glucose and the decrease in glucagon. Liver ceases to produce glucose and takes up excess circulating glucose to replenish glycogen and triglyceride (TG) stores.

Insulin is the major hormone controlling the fasted to postprandial transition. In type 2 diabetes, hepatic insulin resistance leads to impaired glucose metabolism and thereby hyperglycaemia. The glycaemic excursion is determined both by the insulin dependent clearance of glucose as well as the suppression of hepatic glucose output. The immediate response of the liver to insulin or feeding is to redirect glucose-6-phosphate derived from gluconeogenesis and blood glucose to glycogen, thus effectively suppressing glycogenolysis.

In humans, who have residual hepatic glycogen after an overnight fast, feeding both stimulates glycogen synthesis and suppresses glycogenolysis. Given the substantive level of recycling of glycogen, it is likely that a coordinated regulation of both synthesis and degradation underlie the postprandial regulation of hepatic glycogen metabolism even when the normal coupling between glycogen synthesis and glucose production is disrupted (1).

Glucagon antagonises the action of insulin, mostly in the liver, where it stimulates gluconeogenesis, leading to increased blood glucose levels. The secretion of insulin and glucagon is regulated in a reciprocal manner, which avoids glycaemic volatility because of their opposing effects. It is suggested that the glucose-induced secretion of insulin inhibits glucagon secretion from α-cells in a paracrine manner. Furthermore, incretin hormones [e.g. glucagon-like peptide 1 (GLP-1)] secreted postprandially by the gut potentiate glucose mediated insulin secretion and block glucagon secretion. In addition, physiological conditions such as low intracellular energy level and cellular stress affect whole-body glucose homeostasis by interfering with insulin action (1).

Signal transduction pathways responsible for the regulation of cellular processes, including those involved in glucose homeostasis, mainly, depend on protein kinase signalling. On activation, protein kinases determine the output of metabolic processes by transcriptional and post-translational regulation of rate-limiting enzymes. The tyrosine kinase insulin receptor (IR) activates various downstream pathways that control energy homeostasis, including phosphoinositide-3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue [AKT, also known as protein kinase B (PKB)] and the mitogen-activated protein kinase 3/1 (MAPK3/ 1, ERK1/2). Whereas the PI3K/AKT pathway is considered to be the major regulator of insulin action on metabolic processes, insulin-independent kinases also contribute to metabolic control. AMP-activated protein kinase (AMPK) is mainly activated by low intracellular energy levels and inhibits anabolic processes, stimulates energy-producing catabolic processes and lowers blood glucose levels. Correct function of the PI3K/ AKT, MAPK and AMPK pathways is crucial for proper control of metabolic processes. Thus their dysfunction often leads to impaired glucose homeostasis and therefore, these pathways are attractive therapeutic targets. Notably, PI3K/AKT, MAPK and AMPK are also involved in additional fundamental cellular processes, including cell proliferation and survival, and thus global therapeutic modification of their activities could induce severe side effects (1).

References

Schultze, S. M., Hemmings, B. A., Niessen, M., and Tschopp, O. (2012) Expert reviews in molecular medicine 14.

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