The principal function ofinsulin is toincrease therate of glucose transport into certain cells in the body (Fig. 20.21 ). These are the striated muscle cells (including myocardial cells) and, to a lesser extent, adipocytes, representing collectively about two thirds of total body weight. Glucose uptake in other peripheral tissues, most notably the brain, is insulin-independent. In muscle cells, glucose is then either stored as glycogen or oxidized to generate adenosine triphosphate (ATP) and metabolic intermediates needed for cell growth. In adipose tissue, glucose is metabolized to lipids, which are stored as fat. Besides promoting lipid synthesis (lipogenesis), insulin also inhibits lipid degradation (lipolysis) in adipocytes. Similarly, insulin promotes amino acid uptake and protein synthesis while inhibiting protein degradation. Thus, the metabolic effects of insulin can be summarized as anabolic, with increased synthesis and reduced degradation of glycogen, lipid, and protein. In addition to these metabolic effects, insulin has several mitogenic functions, including initiation of DNA synthesis in certain cells and stimulation of their growth and differentiation.
Insulin reduces the production of glucose from the liver. Insulin and glucagon have opposing regulatory effects on glucose homeostasis. During fasting states, low
Fig.20.21Metabolicactionsofinsulininstriatedmuscle,adiposetissue,andliver.
http://ebooksmedicine.net insulin and high glucagon levels facilitate hepatic gluconeogenesis and glycogenolysis (glycogen breakdown) while decreasing glycogen synthesis, thereby preventing hypoglycemia. Thus, fasting plasma glucose levels are determined primarily by hepatic glucose output. After a meal, insulin levels rise and glucagon levels fall in response to the large glucose load.
The most important stimulus that triggers insulin release from pancreatic beta cells is glucose itself. Oral intake of food leads to secretion of multiple hormones, notably the incretins produced by cells in the intestines. These hormones stimulate insulin secretion from beta cells, and also reduce glucagon secretion and delay gastric emptying, which promotes satiety. The incretin effect is significantly blunted in patients with type 2 diabetes, and restoring incretin function can lead to improved glycemic control and loss of weight (through restoration of satiety). These observations have resulted in the development of new classes of drugs for patients with type 2 diabetes that mimic incretins or enhance the levels of endogenous incretins through delaying their degradation.
In peripheral tissues (skeletal muscle and adipose tissue), secreted insulin binds to the insulin receptor, triggering a number of intracellular responses that promote glucose uptake and postprandial glucose utilization, thereby maintaining glucose homeostasis. Abnormalities at various points along this complex signaling cascade, from synthesis and release of insulin by beta cells to insulin receptor interactions in peripheral tissues, can result in the diabetic phenotype.
Type 1 diabetes is an autoimmune disease in which islet destruction is caused primarily by immune effector cells reacting against endogenous beta cell antigens. Although type 1 diabetes is the most common form of diabetes in childhood, it is important to remember that it can present at any age. Most patients with type 1 diabetes depend on exogenous insulin for survival; without insulin they develop serious metabolic complications such as ketoacidosis and coma. Although the clinical onset of type 1 diabetes is abrupt, it results from a chronic autoimmune attack on beta cells that usually starts years before the disease becomes evident (
Fig. 20.22 ). The classic manifestations of the disease (such as ketoacidosis) occur late in its course, after more than 90% of the beta cells have been destroyed.