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amount of ketone production is determined by the amount of long-chain fatty acids available for oxidation. Most fatty acids oxidized in liver originate in adipose tissue, but glucagon, through cyclic AMP and protein kinase A, may also activate a lipase in liver and thereby provide fatty acids from breakdown of hepatic triglycerides.

Ureogenesis

Whenever carbon chains of amino acids are used as substrate for gluconeogenesis, amino groups must be disposed of in the form of urea, which thus becomes a by-product of gluconeogenesis. By promoting gluconeo-genesis, therefore, glucagon also increases the formation of urea (ureogenesis). Carbon skeletons of most amino acids can be converted to glucose, but because of peculiarities of peripheral metabolism, alanine is quantitatively the most important glucogenic amino acid. By accelerating conversion of pyruvate to glucose (see earlier discussion), glucagon indirectly accelerates transamination of alanine to pyruvate. Glucagon also accelerates ureogenesis by increasing transport of amino acids across hepatocyte plasma membranes by an action that requires synthesis of new RNA and protein. In addition, glucagon also promotes the synthesis of some urea cycle enzymes.

Regulation of Glucagon Secretion

The concentration of glucose in blood is the most important determinant of glucagon secretion in normal individuals. When the plasma glucose concentration exceeds 200 mg/dL, glucagon secretion is maximally inhibited. Inhibitory effects of glucose are proportionately less at lower concentrations and disappear when its concentration falls below 50 mg/dL. Except immediately after a meal rich in carbohydrate, the blood glucose concentration remains constant at around 90 mg/dL. The set point for glucose concentration thus falls well within the range over which glucagon secretion is regulated, and alpha cells can respond to changes in blood glucose with either an increase or a decrease in glucagon output. The alpha cells appear to respond directly to changes in glucose concentration, but we do not yet understand how they monitor blood glucose concentration and translate that information to an appropriate rate of glucagon secretion. Little is understood of the intracellular molecular events that bring about an increase or decrease of glucagon secretion.

Low blood glucose (hypoglycemia) not only relieves inhibition of glucagon secretion, but this life-threatening circumstance stimulates the central nervous system to signal both parasympathetic and sympathetic nerve endings within the islet to release their neurotransmitters, acetylcholine and VIP (vasoactive intestinal peptide), from parasympathetic endings and norepinephrine and NPY (neuropeptide Y) from sympathetic endings. Alpha cells express receptors for these neurotransmitters, and they secrete glucagon in response to both parasym-pathetic and sympathetic stimulation. The sympathetic response to hypoglycemia also involves secretion of epinephrine and norepinephrine from the adrenal medulla (see Chapter 40). Adrenomedullary hormones further stimulate alpha cells to secrete glucagon.

Glucagon secretion is evoked by a meal rich in amino acids. Alpha cells respond directly to increased blood levels of certain amino acids, particularly arginine. In addition, digestion of protein-rich foods triggers the release of cholecystokinin from cells in the duodenal mucosa (see Chapter 32). This gastrointestinal hormone is a secretagogue for islet hormones as well as pancreatic enzymes and may alert alpha cells to an impending influx of amino acids. Increased secretion of glucagon in response to a protein meal not only prepares the liver to dispose of excess amino acids by gluconeogenesis but also signals the liver to release glucose and thus counteracts the hypoglycemic effects of insulin, whose secretion is simultaneously increased by amino acids (see later discussion).

Glucose is not the only physiologic inhibitor of glucagon secretion. Insulin, somatostatin, GLP-1, glucose-dependent insulinotropic peptide (GIP), and free fatty acids (FFA) also exert inhibitory influences on glucagon secretion (Fig. 8). Insulin, which may reach alpha cells by either the endocrine or paracrine route, directly inhibits glucagon secretion and is required for expression of inhibitory effects of glucose. In fact, it has been suggested that glucose may inhibit gluca-gon secretion indirectly through increased secretion of insulin. In persons suffering from insulin deficiency amino acids acetyl choline epinephrine norepinephrine VIP

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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