Maintaining homeostasis in plasma glucose concentrations requires a precise balance between intake, production, and delivery of glucose to cells. Glucose is needed for energy and cellular function and is transported to the cell through multiple metabolic pathways. Three primary sources: intestinal absorption of carbohydrates through digestion, glycogenolysis (conversion of glycogen stores in the liver to glucose), and gluconeogenesis (formation of new glucose from glycogen) supply glucose. Glycogen is the stored form of glucose, an important energy reserve that is broken down by the liver for mobilization of glucose in times of metabolic need. Glyconeogenesis is a complex multi-step process, whereas glycogenolysis takes place quickly and involves a single enzymatic step.
The regulation of glucose is dependent upon hormone release and feedback mechanisms that include glucagon (hyperglycemic hormone) from the alpha cells, insulin (hypoglycemic hormone) from beta cells of the pancreas, and hepatic and neural auto-regulatory mechanisms. Appendix B demonstrates normal glucose metabolism. Glucagon is a hyperglycemic hormone that accelerates the breakdown of glycogen in the liver and causes the level of blood glucose to rise within minutes. In addition to glucagon, catecholamines, cortisol, and growth hormones elevate blood glucose through stimulation of glycogenolysis, gluconeogenesis, and inhibition of insulin uptake by the cells.
Insulin is a hypoglycemic hormone that enhances cellular uptake of glucose and synthesis of glycogen by suppressing gluconeogenesis. Insulin increases the permeability of cells to glucose, facilitates the transport of glucose into the cells, and stimulates glycogen formation and causes blood glucose levels to decrease. Insulin binds to insulin receptors on the cell surface and opens the channels for glucose to enter the cells where it is then converted into energy.
Under normal conditions insulin levels fluctuate rapidly to correspond with changes in blood glucose concentrations. Central and peripheral gluco-sensors are important for regulation because they monitor the availability of glucose. In hypoglycemia, counter-regulatory hormones are secreted to elevate blood glucose increasing the rate of impulses among the neurons that stimulate the hypothalamus to increase sympathetic outflow and decrease parasympathetic activity. This elevates blood glucose by promoting glycogenolysis and inhibiting secretion of insulin. In hyperglycemia central receptors in the hypothalamus increase activity that releases the inhibitory sympathetic tone on the pancreas stimulating the release of insulin. Peripheral glucose sensors located in the portal vein, small intestine, and liver decrease the rate of impulses to neurons during times of higher glucose concentrations. These signals are transmitted from the vagus nerve to the medulla, resulting in increased secretion of insulin and hepatic uptake of glucose and inhibition of catecholamines.
Insulin is the primary regulator of fat, carbohydrate, and protein metabolism regulating the synthesis of glycogen, inhibiting the synthesis of glucose by the liver, and stimulating the storage and release of fat as well as protein needed for function, repair and growth of cells. The fundamental role of insulin is to coordinate the use of fuels in the body determining whether they get utilized or stored. Insulin signals information on the availability of fuel from the periphery to the brain and the central nervous system. Under normal conditions when glucose is elevated, insulin stores the excess glucose as fat in tissue or transfers it to muscle. Insulin then conveys a message to the mitochondria of the cell signaling it to use the glucose for energy. As blood glucose drops, insulin mobilizes the fatty acids and signals the mitochondria to utilize those as the energy source instead of glucose. In addition, insulin has properties that have been shown to reduce inflammation, proinflammatory cytokines, and oxidative stress.
When persistent elevations in blood glucose occur, the over-secretion of insulin is no longer able to compensate for combined insulin resistance and high levels of glucose. Insulin resistance is defined as a decrease in the effective response of tissues to insulin in terms of glucose uptake and inhibition of gluconeogenesis. Excess body weight and adiposity have been directly linked to this reduction in sensitivity to insulin. High levels of circulating proinflammatory cytokines Interleukin-6 (IL-6) and Tumor necrosis factor-alpha (TNFα) sustain insulin resistance and hyperglycemia. The resistance to insulin causes the pancreas to increase production of insulin resulting in high circulating levels referred to as hyperinsulinemia which, in turn, continues to perpetuate insulin resistance and hyperglycemia. Insulin resistance and hyperinsulinemia impair the entry of glucose into cells limiting the ability of cells to access fuel increasing the amount of circulating blood glucose.
Hyperinsulinemia and insulin resistance have been shown to exacerbate inflammation and are considered a major factor contributing to the association between diabetes and cancer. Elevated levels of insulin may stimulate cell proliferation and tumorigenesis (production of tumors) by increasing circulating insulin growth factors that can lead to proliferation of aberrant cells and decreased apoptosis, or controlled cell death. Modulation of circulating insulin and glucose levels by anti-diabetic medications appear to play a role in altering cancer risk and is currently being studied.