Glucagon

1. Glucagon • Glucagon has a major role in maintaining normal concentrations of glucose in blood, and is often described as having the opposite effect of insulin. That is, glucagon has the effect of increasing blood glucose levels. • Glucagon is a linear peptide of 29 amino acids. Its primary sequence is almost perfectly conserved among vertebrates, and it is structurally related to the secretin family of peptide hormones. Glucagon is synthesized as proglucagon and proteolytically processed to yield glucagon within alpha cells of the pancreatic islets. Proglucagon is also expressed within the intestinal tract, where it is processed not into glucagon, but to a family of glucagon-like peptide (enteroglucagon)

2. Effects of Glucagon • The major effect of glucagon is to stimulate an increase in blood concentration of glucose. As discussed previously, the brain in particular has an absolute dependence on glucose as a fuel, because neurons cannot utilize alternative energy sources like fatty acids to any significant extent. When blood levels of glucose begin to fall below the normal range, it is imperative to find and pump additional glucose into blood. Glucagon exerts control over two pivotal metabolic pathways within the liver, leading that organ to dispense glucose to the rest of the body:

4. Glucagon stimulates breakdown of glycogen stored in the liver. • When blood glucose levels are high, large amounts of glucose are taken up by the liver. Under the influence of insulin, much of this glucose is stored in the form of glycogen. Later, when blood glucose levels begin to fall, glucagon is secreted and acts on hepatocytes to activate the enzymes that depolymerize glycogen and release glucose

5. Glucagon activates hepatic gluconeogenesis. Gluconeogenesis is the pathway by which non-hexose substrates such as amino acids are converted to glucose. As such, it provides another source of glucose for blood. This is especially important in animals like cats and sheep that don't absorb much if any glucose from the intestine - in these species, activation of gluconeogenic enzymes is the chief mechanism by which glucagon does its job. • Glucagon also appears to have a minor effect of enhancing lipolysis of triglyceride in adipose tissue, which could be viewed as an addition means of conserving blood glucose by providing fatty acid fuel to most cells

6. Control of Glucagon Secretion • Knowing that glucagon's major effect is to increase blood glucose levels, it makes sense that glucagon is secreted in response to hypoglycemia or low blood concentrations of glucose. • Two other conditions are known to trigger glucagon secretion: • Elevated blood levels of amino acids, as would be seen after consumption of a protein-rich meal: In this situation, glucagon would foster conversion of excess amino acids to glucose by enhancing gluconeogenesis. Since high blood levels of amino acids also stimulate insulin release, this would be a situation in which both insulin and glucagon are active.

7. Exercise: In this case, it is not clear whether the actual stimulus is exercise per se, or the accompanying exercise-induced depletion of glucose. • In terms of negative control, glucagon secretion is inhibited by high levels of blood glucose. It is not clear whether this reflects a direct effect of glucose on the alpha cell, or perhaps an effect of insulin, which is known to dampen glucagon release. Another hormone well known to inhibit glucagon secretion is somatostatin

8. Regulatory mechanism • Increased secretion of glucagon is caused by: • Decreased plasma glucose (indirectly) • Increased catecholamine-epinephrine and nor epinephrine • Increased plasma amino acid (to protect from hypoglycemia if an all-protein meal is consumed) • Sympathetic nervous system • Acetylcholine • Cholecystokinine • Decreased secretion (inhibition) of glucagon is caused by: • Somatostatin . Insulin • Increased free fatty acids and keto acids into the blood • Increased urea production

9. Somatostatin • Somatostatin was first discovered in hypothalamic extracts and identified as a hormone that inhibited secretion of growth hormone. Subsequently, somatostatin was found to be secreted by a broad range of tissues, including pancreas, intestinal tract and regions of the central nervous system outside the hypothalamus

11. Structure and Synthesis • Two forms of somatostatin are synthesized. They are referred to as SS-14 and SS-28, reflecting their amino acid chain length. Both forms of somatostatin are generated by proteolytic cleavage of prosomatostatin, which itself is derived from preprosomatostatin. Two cysteine residules in SS-14 allow the peptide to form an internal disulfide bond

12. The relative amounts of SS-14 versus SS-28 secreted depends upon the tissue. For example, SS-14 is the predominant form produced in the nervous system and apparently the sole form secreted from pancreas, whereas the intestine secretes mostly SS-28. • In addition to tissue-specific differences in secretion of SS-14 and SS-28, the two forms of this hormone can have different biological potencies. SS-28 is roughly ten-fold more potent in inhibition of growth hormone secretion, but less potent that SS-14 in inhibiting glucagon release.

13. Biochemical Effects • Somatostatin acts by both endocrine and paracrine pathways to affect its target cells. A majority of the circulating somatostatin appears to come from the pancreas and gastrointestinal tract. If one had to summarize the effects of somatostatin in one phrase, it would be: "somatostatin inhibits the secretion of many other hormones".

14. Effects on the Pituitary Gland • Somatostatin was named for its effect of inhibiting secretion of growth hormone from the pituitary gland . Experimentally, all known stimuli for growth hormone secretion are suppressed by somatostatin administration. Additionally, animals treated with antisera to somatostatin show elevated blood concentrations of growth hormone, as do animals that are genetically engineered to disrupt their somatostatin gene. • Ultimately, growth hormone secretion is controlled by the interaction of somatostatin and growth hormone releasing hormone, both of which are secreted by hypothalamic neurons

15. Effects on the Pancreas • Cells within pancreatic islets secrete insulin, glucagon and somatostatin. Somatostatin appears to act primarily in a paracrine manner to inhibit the secretion of both insulin and glucagon. It also has the effect in suppressing pancreatic exocrine secretion , by inhibiting cholecystokinin-stimulated enzyme secretion and secretin-stimulated bicarbonate secretion.

16. Effects on the Gastrointestinal Tract • Somatostatin is secreted by scattered cells in the GI epithelium, and by neurons in the enteric nervous system . It has been shown to inhibit secretion of many of the other GI hormones, including ,gasterin cholecystokinin, secretin and vasoactive intestinal peptide • In addition to the direct effects of inhibiting secretion of other GI hormones, somatostatin has a variety of other inhibitory effects on the GI tract, which may reflect its effects on other hormones, plus some additional direct effects. Somatostatin suppresses secretion of gastric acid and pepsin , lowers the rate of gastric emptying, and reduces smooth muscle contractions and blood flow within the intestine. Collectively, these activities seem to have the overall effect of decreasing the rate of nutrient absorption

17. Effects on the Nervous System • Somatostatin is often referred to as having neuromodulatory activity within the central nervous system, and appears to have a variety of complex effects on neural transmission. Injection of somatostatin into the brain of rodents leads to such things as increased arousal and decreased sleep, and impairment of some motor responses