Sulphonylurea receptor

Antidiabetic Drugs other than Insulin. Figure 1 Sulphonylureas stimulate insulin release by pancreatic (3-cells. They bind to the sulphonylurea receptor (SUR-1), which closes Kir6.2 (ATP-sensitive) potassium channels. This promotes depolarisation, voltage-dependent calcium influx, and activation of calcium-sensitive proteins that control exocytotic release of insulin. 

An important location of the sulphonylurea receptor is the ATP-sensitive K+ channel. Here, in contrast to ATP action, the binding site for sulphonylureas is not on the intracellular side but on the extracellular side of this channel (Niki et al., 1990). Niki et al. (1989, 1990) have provided evidence that ADP also binds to and competitively displaces glibenclamide from high-affinity HIT-cell sulphonylurea-binding sites. They also showed that ADP inhibited 86Rb+ efflux, elicited a rapid and sustained increase in [Ca2+]j and caused insulin secretion. Since ADP is unable to cross the cytoplasmic membrane, they concluded that ADP and sulphonylureas have common binding sites on the outer cell surface. 

Recently, a- and /3-endosulfines, peptides isolated from brain, have been shown to bind to sulphonylurea receptors of brain membranes (Virsolvy-Vergine et al., 1992). The question arises whether they and/or ADP are physiological ligands of sulphonylurea receptors. 

Other Tissues. Sulphonylurea receptors have also been described for cardiac muscle, skeletal muscle and smooth muscle but do not appear to be of therapeutic benefit for lowering blood sugar (Panten et al., 1992). Specific binding to membranes isolated from other rat tissues (liver, lung, kidney, heart, spleen, diaphragm, duodenum, colon and stomach) was... 

SURl heterozygous activating mutation (sulphonylurea receptor)... 

Campbell, J. D., Sansom, M. S. R, Ashcroft, F. M. (2003). Potassium channel regulation. Structural insights into the function of the nucleotide-binding domains of the human sulphonylurea receptor, EMBO Reports, 4, 1038-1042. 

The increase in insulin concentrations produced by sulphonylureas lowers blood glucose concentrations through decreased hepatic glucose output and increased glucose utilisation, mostly by muscle ( insulin, insulin receptor). 

Acetazolamide is a carbonic anhydrase inhibitor that reduces aqueous humour production and is therefore indicated in glaucoma to reduce the intraocular pressure. Salbutamol is a selective, short-acting beta2-agonist used as a bronchodilator in asthma. Tolbutamide is a short-acting sulphonylurea used in type 2 (non-insulin dependent) diabetes mellitus. Chlorpromazine is an aliphatic neuroleptic antipsychotic drug used in schizophrenia. Zafirlukast is a leukotriene-receptor antagonist that is indicated in the prophylaxis of asthma but should not be used to relieve acute severe asthma. 

ANGIOTENSIN II RECEPTOR ANTAGONISTS -IRBESARTAN SULPHONYLUREAS Possible t hypotensive effect of irbesartan by tolbutamide Tolbutamide competitively inhibits CYP2C9-mediated metabolism of irbesartan Monitor BP at least weekly until stable. Warn patients to report symptoms of hypotension (light-headedness, dizziness on standing, etc.). 

H2 RECEPTOR BLOCKERS SULPHONYLUREAS- GUMEPIRIDE t plasma concentrations of glimepride and t risk of hypoglycaemic episodes Cimetidine and ranitidine i renal elimination of glimepride and T intestinal absorption of glimepride. Cimetidine is also an inhibitor of CYP2D6 and CYP3A4 Consider alternative acid suppression, e.g. a proton pump inhibitor (not omeprazole), and monitor more closely... 

The insulin-releasing effect of sulphonylureas is thought to result from the closing of an ATP-dependent channel in the yff-cell plasma membrane. The decrease in permeability leads to a depolarization of the membrane and activation of Ca " channels. Calcium then enters the cell and activates an effector system for the release of insulin [9, 158]. The receptor for the sulphonylureas is believed to be a part of the ATP-dependent channel or... 

Non-selective p-receptor blockers potentiate hypo-glycaemia of insulin and sulphonylureas. 

Sulphonylureas block the ATP-sensitive potassium channels on the P-islet cell plasma membrane. This results in the release of stored insulin in response to glucose. They do not increase insulin formation. Sulphonylureas appear to enhance insulin action on liver, muscle and adipose tissue by increasing insulin receptor number and by enhancing the postreceptor complex enzyme reactions mediated by insulin. The principal result is decreased hepatic... 

Glyburide, unlike other sulphonylureas, is inactivated by the liver and kidneys and excreted in the faeces and urine. It should therefore not be prescribed in patients with liver and renal disease. Glyburide appears to decrease resistance to insulin and sensitize the receptor while utilizing the patients available endogenous insulin (Krall, 1984). 

With loss of the sulphonylurea-induced hyperinsulinaemia, down-regulation of insulin receptors improved and an additional aspect of peripheral insulin resistance in NIDDM improved with sulphonylurea treatment. 

Post-receptor effects are still controversial. Kolterman and Olefsky (1984) felt that an increase in post-receptor function appears to be a crucial determinant of the clinical response to sulphonylureas (Fig. 23). Extra-pancreatic mechanisms in obese NIDDM patients may vary with the... 

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