Glucagons

Glucagon is a single-chain polypeptide of 29 amino acid residues and a molecular mass of 3500 Da. It is synthesized by the A cells of the Islets of Langerhans, and also by related cells found in the digestive tract. Like insulin, it is synthesized as a high molecular mass polypeptide from which the mature hormone is released by selective proteolysis. 

Hypoglycaemia remains the most frequent complication of insulin administration to diabetics. It usually occurs due to (a) administration of an excessive amount of insulin (b) administration of insulin prior to a mealtime, but with subsequent omission of the meal or (c) due to increased physical activity. In severe cases, this can lead to loss of consciousness and even death. Although it may be treated by oral or i.v. administration of glucose, insulin-induced hypoglycaemia is sometimes treated by administration of glucagon. 

Traditionally, glucagon preparations utilized therapeutically are chromatographically purified from bovine or porcine pancreatic tissue (the structure of bovine, porcine and human glucagon is identical, thus eliminating the possibility of direct immunological complications). Such commercial preparations are generally formulated with lactose and sodium chloride and sold in freeze-dried form 0.5-1.0 units of glucagon (approximately 0.5-1.0 mg freeze-dried hormone) are administered to the patient by s.c. or i.m. injection. 

Glucagon is considered to be the hormonal antagonist of insulin.29,35 The primary effect of glucagon is to increase blood glucose to maintain normal blood glucose levels and to prevent hypoglycemia.35,93 Glucagon pro- 

Glucagon appears to exert its effects on liver cells by a classic adenyl cyclase-cyclic adenosine monophosphate (cAMP) second messenger system (see Chapter 4).93 Glucagon binds to a specific receptor located on the hepatic cell membrane. This stimulates the activity of the adenyl cyclase enzyme that transforms adeno- 

Glucagon is an oligopeptide pancreatic hormone of 29 amino acids with a single tryptophan residue in position 25 of the sequence. This peptide constituted a special synthetic problem, because of the His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp- 

The successful synthesis of this pentadecapeptide by the solid phase technique is particularly remarkable in view of the high tryptophan content. All four residues were completely resistant to repetitive acid treatment with trifluoroacetic acid used to remove the N-protecting -butyloxy- 

The closed-loop system (often termed the artificial pancreas ) is essentially a more sophisticated version of the system described above. It consists not only of a pump and infusion device, but also of an integral glucose sensor and computer that analyses the blood glucose data obtained and adjusts the flow rate accordingly. The true potential of such systems remains to be assessed. 

Although infusion pumps can go some way towards mimicking normal control of blood insulin levels, transplantation of insulin-producing pancreatic cells should effectively cure the diabetic patient, and research aimed at underpinning this approach continues. 

It stimulates breakdown of glycogen, fat, and protein. It inhibits synthesis of glycogen, fat, and protein. 

The G-protein serves as a timekeeper and binds GTP, and with GTP bound, it can couple the receptor and activate the adenylate cyclase. However, the G-protein slowly hydrolyzes the bound GTP to GDP and Pj. When this happens, the whole complex falls apart and the adenylate kinase is inactivated. 

The PROTEIN KINASE CASCADE amplifies the original extracellular signal by increasing levels of cAMP, which activates cAMP-dependent protein kinase, which phosphorylates specific proteins. 

When glucagon levels fall, cAMP phosphodiesterase destroys the accumulated cAMP, and specific protein phosphatases remove the phosphate from the phosphoproteins. These phosphatases themselves are often regulated hy phosphorylation—yes, there are phosphatase kinases and phosphatase phosphatases. It s readly easy to lose it here, hut the key factor is that increased glucagon levels lead to increased protein phosphorylation, and decreased glucagon levels lead to decreased protein phosphorylation. 

Primary drug BISPHOSPHONATES Secondary drug Effect Mechanism Precautions 

ALENDRONATE ANALGESICS-NSAIDs Risk of oesophagitis/peptic ulceration Additive effect Avoid co-administration 

BISPHOSPHONATES ANTACIDS 1 bisphosphonate levels 1 absorption Separate doses by at least 30 minutes 

SODIUM CLODRONATE ANTIBIOTICS -AMINOGLYCOSIDES Risk of symptomatic hypocalcaemia Uncertain Monitor calcium levels closely 

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It now appears that many hormones (e.g. glucagon and adrenaline) in both animals and plants exert their effects by, as a first step, decreasing or increasing cyclic AMP within the cell. This may possibly occur by modification of the activity of the enzyme AMP cyclase which generates cyclic AMP from ATP. 

Glucagon also has been used to diagnose insulinoma and pheochromocytoma. For the former, the rise in plasma insulin concentration following... 

Vitamin D withdrawal is an obvious treatment for D toxicity (219). However, because of the 5—7 d half-life of plasma vitamin D and 20—30 d half-life of 25-hydroxy vitamin D, it may not be immediately successful. A prompt reduction in dietary calcium is also indicated to reduce hypercalcemia. Sodium phytate can aid in reducing intestinal calcium transport. Calcitonin glucagon and glucocorticoid therapy have also been reported to reduce semm calcium resulting from D intoxication (210). 

The situation is different for other examples—for example, the peptide hormone glucagon and a small peptide, metallothionein, which binds seven cadmium or zinc atoms. Here large discrepancies were found between the structures determined by x-ray diffraction and NMR methods. The differences in the case of glucagon can be attributed to genuine conformational variability under different experimental conditions, whereas the disagreement in the metallothionein case was later shown to be due to an incorrectly determined x-ray structure. A re-examination of the x-ray data of metallothionein gave a structure very similar to that determined by NMR. 

Pyruvate kinase possesses allosteric sites for numerous effectors. It is activated by AMP and fructose-1,6-bisphosphate and inhibited by ATP, acetyl-CoA, and alanine. (Note that alanine is the a-amino acid counterpart of the a-keto acid, pyruvate.) Furthermore, liver pyruvate kinase is regulated by covalent modification. Flormones such as glucagon activate a cAMP-dependent protein kinase, which transfers a phosphoryl group from ATP to the enzyme. The phos-phorylated form of pyruvate kinase is more strongly inhibited by ATP and alanine and has a higher for PEP, so that, in the presence of physiological levels of PEP, the enzyme is inactive. Then PEP is used as a substrate for glucose synthesis in the pathway (to be described in Chapter 23), instead... 

Storage and utilization of tissue glycogen, maintenance of blood glucose concentration, and other aspects of carbohydrate metabolism are meticulously regulated by hormones, including insulin, glucagon, epinephrine, and the glucocorticoids. 

Stimulation of glycogen breakdown involves consumption of molecules of ATP at three different steps in the hormone-sensitive adenylyl cyclase cascade (Figure 15.19). Note that the cascade mechanism is a means of chemical amplification, because the binding of just a few molecules of epinephrine or glucagon results in the synthesis of many molecules of cyclic / MP, which, through the action of c/ MP-dependent protein kinase, can activate many more molecules of phosphorylase kinase and even more molecules of phosphorylase. For example, an extracellular level of 10 to 10 M epinephrine prompts the for-... 

Glucagon Glukagon Glucagon Glucagon Glucagon Novo... 

Alprenolol HCl Bromelain Ciprofibrate Clortermine HCl Desonide Fenofibrate Flucloronide Flunisolide Fluocinonide Flurandrenolide Glucagon Gramicidin Hetacillin potassium I proniazid Kebuzone Methyltestosterone Niaprazine Probucol Relaxin Somatotropin Triamcinolone acetonide Acetonitrile... 

Appetite-suppressing. Neuropqrtide modulators and gut hormones with anorexigenic effects are a-melanocortin-stimulating hormone (a-MSH), cocaine- and amphetamine-regulated transcript (CART), glucagon-like peptide-1 (GLP-1), leptin, insulin, oxyntomodulin, pancreatic peptide PP, peptide YY and PYY3 36, and others. 

Amylin analogue Pramlintide Suppress glucagon secretion and slow gastric emptying SC injection6... 

Antidiabetic Drugs other than Insulin. Table 3 Actions of the incretin hormones GIP (glucose-dependent insulinotropic polypeptide, gastric inhibitory peptide) and GLP-1 (glucagon-like peptide-1)... 

In clinical studies, selective DPP-4 inhibition increased active circulating concentrations of GLP-1 and GEP by two- to threefold. This was associated with increased glucose-induced insulin secretion and suppression of glucagon secretion, although changes in satiety and gastric emptying have not been repotted. 

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