Insulin

Insulin is a protein consisting of 51 amino acids contained within two peptide chains: an A chain, with 21 amino acids; and a B chain, with 30 amino acids. The chains are connected by two disulfide bridges. In addition, there is an intrachain disulfide bridge. The molecular weight of human insulin is 5808.

Human insulin differs only slightly in amino acid composition from the two mammalian insulins, which have been used for therapeutic insulin replacement. Pork insulin differs from human by only one amino acid-alanine instead of threonine at the carboxyl terminus of the B chain. Beef insulin differs by three amino acids-alanine instead of threonine and valine instead of isoleucine.

Endogenous insulin has a circulatory half-life of 3-5 minutes. It is catabolized chiefly by insulinases in liver, kidney, and placenta. Approximately 50% of insulin is removed in a single pass through the liver.

Insulin Resistance Syndrome (IRS)

Secretion

The human pancreas secretes about 40-50 units of insulin per day in normal adults. The basal concentration of insulin in the blood of fasting humans averages 10 μU/mL (0.4 ng/mL, or 61 pmol/L). In normal control subjects, insulin seldom rises above 100 μU/mL (610 pmol/L) after standard meals. There is an increase in peripheral insulin concentration beginning 8-10 minutes after ingestion of food and reaching peak concentration in peripheral blood by 30-45 minutes. This is followed by a rapid decline in postprandial plasma glucose concentration, which returns to baseline values by 90-120 minutes.

Basal insulin secretion, which occurs in the absence of exogenous stimuli, is the quantity of insulin secreted in the fasting state. Although it is known that plasma glucose levels below 80-100 mg/dL (4.4-5.6 mmol/L) do not stimulate insulin release, it has also been demonstrated that the presence of glucose is necessary (in in vitro systems) for most other known regulators of insulin secretion to be effective.

Stimulated insulin secretion is that which occurs in response to exogenous stimuli. In vivo, this is the response of the B cell to ingested meals. Glucose is the most potent stimulant of insulin release. The perfused rat pancreas has demonstrated a biphasic release of insulin in response to glucose. When the glucose concentration in the system is increased suddenly, an initial short-lived burst of insulin release occurs (the early phase); if the glucose concentration is held at this level, the insulin release gradually falls off and then begins to rise again to a steady level (the late phase). However, sustained levels of high glucose stimulation results in a reversible desensitization of the B cell response to glucose but not to other stimuli.

Glucose is known to enter the pancreatic B cell by passive diffusion, which is facilitated by a specific membrane protein termed glucose transporter-2. By virtue of its relatively low affinity for glucose, this protein more effectively facilitates transport of glucose during the hyperglycemia after meals than at the lower levels of blood glucose during an overnight fast. There is a body of data suggesting that metabolism of glucose is essential in stimulating insulin release. Indeed, agents such as 2-deoxyglucose that inhibit the metabolism of glucose interfere with release of insulin. The rate-limiting step in glucose metabolism by the pancreatic B cell appears to be the phosphorylation of glucose by the low-affinity enzyme glucokinase.

Insulin release has been shown to require calcium. It has been proposed that mature insulin-containing granules in the B cell attach linearly to microtubules that contract after exposure to high intracellular calcium, thereby ejecting the granules.

Insulin receptors & insulin action

Insulin action begins with binding of insulin to a receptor on the surface of the target cell membrane. Many cells of the body appear to have specific cell surface insulin receptors. In fat, liver, and muscle cells, binding of insulin to these receptors is associated with the biologic response of these tissues to the hormone. These receptors bind insulin rapidly, with high specificity and with an affinity high enough to bind picomolar amounts.

It has been demonstrated that insulin receptors are membrane glycoproteins composed of two subunits, a larger alpha subunit (MW 130,000), which extends extracellularly and is involved in binding the insulin molecule, and a smaller beta subunit (MW 90,000), which is predominantly cytoplasmic and contains a tyrosine kinase that becomes activated during insulin binding and results in autophosphorylation of the beta subunit itself. This activated complex in turn phosphorylates a network of as many as nine intracellular substrates, beginning with insulin receptor substrate-1 (IRS-1) and insulin receptor substrate-2 (IRS-2). These activated substrates each lead to activation of one of the seven identified forms of phosphatidylinositol-3-kinase, all of which then phosphorylate other intracellular substances to further propagate the insulin signal-leading to increased glucose transport, increased glycogen and lipid synthesis, and stimulation of other metabolic pathways. After insulin is bound to its receptor, a number of insulin-receptor complexes are internalized. However, it remains controversial whether these internalized complexes contribute to further action of insulin or whether they limit continued insulin action by exposing insulin to intracellular scavenger lysosomes.

Abnormalities of insulin receptors-in concentration, affinity, or both - will affect insulin action. "Down-regulation" is a phenomenon in which the number of insulin receptors is decreased in response to chronically elevated circulating insulin levels, probably by increased intracellular degradation. When insulin levels are low, on the other hand, receptor binding is up-regulated. Conditions associated with high insulin levels and lowered insulin binding to the receptor include obesity, high intake of carbohydrates, and (perhaps) chronic exogenous overinsulinization. Conditions associated with low insulin levels and increased insulin binding include exercise and fasting. The presence of excess amounts of cortisol decreases insulin binding to the receptor, although it is not clear if this is a direct effect of the hormone itself or one that is mediated through accompanying increases in the insulin level.

Metabolic effects of insulin

The major function of insulin is to promote storage of ingested nutrients. Although insulin directly or indirectly affects the function of almost every tissue in the body, the discussion below will be limited to a brief overview of the effects of insulin on the three major tissues specialized for energy storage: liver, muscle, and adipose tissue.

• Paracrine Effects: The effects of the products of endocrine cells on surrounding cells are termed "paracrine" effects, in contrast to actions that take place at sites distant from the secreting cells, which are termed "endocrine" effects. Paracrine effects of the B and D cells on the close-lying A cells are of considerable importance in the endocrine pancreas. The first target cells reached by insulin are the pancreatic A cells at the periphery of the pancreatic islets. In the presence of insulin, A cell secretion of glucagon is reduced. In addition, somatostatin, which is released from D cells in response to most of the same stimuli that provoke insulin release, also acts to inhibit glucagon secretion.
  Because glucose stimulates only B and D cells (whose products then inhibit A cells) whereas amino acids stimulate glucagon as well as insulin, the type and amounts of islet hormones released during a meal depend on the ratio of ingested carbohydrate to protein. The higher the carbohydrate content of a meal, the less glucagon will be released by any amino acids absorbed. In contrast, a predominantly protein meal will result in relatively greater glucagon secretion, because amino acids are less effective at stimulating insulin release in the absence of concurrent hyperglycemia but are potent stimulators of A cells.
• Endocrine Effects:
  • Liver-The first major organ reached by insulin via the bloodstream is the liver. Insulin exerts its action on the liver in two major ways:
    • Insulin promotes anabolism-Insulin promotes glycogen synthesis and storage at the same time it inhibits glycogen breakdown. These effects are mediated by changes in the activity of enzymes in the glycogen synthesis pathway. The liver has a maximum storage capacity of 100-110 g of glycogen, or approximately 440 kcal of energy. Insulin increases both protein and triglyceride synthesis and VLDL formation by the liver. It also inhibits gluconeogenesis and promotes glycolysis through its effects on enzymes of the glycolytic pathway.
    • Insulin inhibits catabolism-Insulin acts to reverse the catabolic events of the postabsorptive state by inhibiting hepatic glycogenolysis, ketogenesis, and gluconeogenesis.
  • Muscle-Insulin promotes protein synthesis in muscle by increasing amino acid transport as well as by stimulating ribosomal protein synthesis. In addition, insulin promotes glycogen synthesis to replace glycogen stores expended by muscle activity. This is accomplished by increasing glucose transport into the muscle cell, enhancing the activity of glycogen synthase, and inhibiting the activity of glycogen phosphorylase. Approximately 500-600 g of glycogen is stored in the muscle tissue of a 70-kg man, but because of the lack of glucose 6-phosphatase in this tissue, it cannot be used as a source of blood glucose, except by indirectly supplying the liver with lactate for conversion to glucose.
  • Adipose tissue-Fat, in the form of triglyceride, is the most efficient means of storing energy. It provides 9 kcal per gram of stored substrate, as opposed to the 4 kcal/g generally provided by protein or carbohydrate. In the typical 70-kg man, the energy content of adipose tissue is about 100,000 kcal. Insulin acts to promote triglyceride storage in adipocytes by a number of mechanisms: (1) It induces the production of lipoprotein lipase (this is the lipoprotein lipase that is bound to endothelial cells in adipose tissue and other vascular beds), which leads to hydrolysis of triglycerides from circulating lipoproteins. (2) By increasing glucose transport into fat cells, insulin increases the availability of a-glycerol phosphate, a substance used in the esterification of free fatty acids into triglycerides. (3) Insulin inhibits intracellular lipolysis of stored triglyceride by inhibiting intracellular lipase (also called "hormone sensitive lipase"). This reduction of fatty acid flux to the liver appears to be a key regulatory factor in the action of insulin to lower hepatic gluconeogenesis and hepatic glucose output.

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