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Results for “INSULIN INHIBITORS”

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At least 19 recordsLinked to original sources
PubMed1971

Removal of an insulin inhibitor from the rat heart by perfusion.

1. Insulin-stimulated efflux of galactose from the perfused rat heart increased when the Krebs bicarbonate medium was prepared with gassing with CO(2).2. Analysis of the kinetics of efflux in the light of the carrier theory is used to justify the interpretation of the increased rate of efflux as an increased response to insulin.3. With medium prepared with CO(2) gassing, the photoperiodic reduction in insulin response seen previously was not found; but it was seen when cardiac contractility was reduced or eliminated during the period of galactose loading.4. The relation between the increase in galactose efflux with insulin and the insulin concentration conforms to the Michaelis-Menten equation, for perfusates prepared both with and without CO(2) gassing, indicating in the latter case the presence of a competitive inhibitor of insulin.5. It has been previously shown that preparing the perfusate with CO(2) gassing results in increased contractility of the perfused heart and a much increased rate of interstitial washout. The conditions of the enhanced response to insulin are consistent with the removal of the inhibitor from the heart due to the increased rate of interstitial washout. The possible role of the inhibitor in the control of lipid and carbohydrate metabolism is discussed.

Animals↗
PubMed2005

Diabetes: the latest developments in inhibitors, insulin sensitisers, new drug targets and novel approaches. October 18-19, 2004, The Hatton, London, UK.

The 6th annual conference on diabetes, organised by the SMI group, was held on 18th-19th October 2004 in London, followed by a one-day symposium on an executive briefing entitled Type 2 diabetes and beyond: the untapped commercial potential. More than 100 delegates from both academic and industrial institutes attended the two meetings. The presentations provided insights into the understanding of mechanisms and developments of novel drugs for treatments of insulin resistance, diabetes, and metabolic syndrome, as well as new approaches for therapeutic intervention including the development of dipeptidyl peptidase IV inhibitors and glucagon-like peptide-1 analogues. This review offers a general overview of the fields in metabolic diseases and different strategies to develop new drugs. Discussions focused on several emerging therapeutic areas, including novel compound developments and target identification with the use of conventional methods and recently emerged technologies, such as siRNA, genomics and proteomics.

Diabetes Mellitus, Type 2↗
PubMedDate not supplied

Compound M & B 39890A [N-(3-imidazol-1-ylpropyl)- 2-(3-trifluoromethylbenezensulphonamido)-benzamide hydrochloride], a glucagon and insulin secretion inhibitor, improves insulin sensitivity in viable yellow obese-diabetic mice.

Compound M & B 39890A [N-(3-imidazol-1-ylpropyl)-2- (3-trifluoromethylbenzenesulphonamido)benzamide hydrochloride] had no effect on cellular cAMP and cGMP levels but significantly inhibited insulin and glucagon secretion from freshly isolated normal rat islets stimulated with 10 mM glucose and 20 mM arginine. Daily gavage of the compound for three days lowered the elevated blood glucose and plasma insulin levels in fed, male viable yellow obese-diabetic mice; the minimum effective dose was 25 mg/kg. However, M & B 39890A did not affect the blood glucose level of fasted diabetic mice. In addition, it had no effect on blood glucose levels of normal mice and streptozotocin-diabetic rats. M & B 39890A, fed in the diet at the concentration of 1 mg/g for 42 days, reversed the hyperglycemia of the fed diabetic mice without causing tachyphylaxis and improved the sensitivity to exogenous insulin as demonstrated by the lowering of blood glucose. When M & B 39890A was fed to young male mice destined to become diabetic, the development of hyperglycemia was prevented. Thus, M & B 39890A represents a new class of pharmacological agents that may prove to be effective for the chronic treatment of type II diabetics without the risk of hypoglycemia.

Animals↗
PubMed1991

Purification and preliminary characterization of new peptide inhibitor of insulin from pork pancreas.

A new active peptide was purified from the acid-alcohol extract of pork pancreas. It markedly suppressed the insulin activity detected by either in vivo mouse convulsion assay or in vitro free-fat cell assay. When the extract was subjected to chromatography on a carboxymethylcellulose column, the insulin fraction completely passed through the column, whereas the glucagon fraction was absorbed. The fact that the total apparent biological activity of insulin in the exclusive eluate was higher than in the original extract and the insulin radioimmunoactivity remained unchanged led to the discovery of a potent insulin inhibitor in the extract. The inhibitor was separated from glucagon and insulin in the extract by ion-exchange chromatography on a carboxymethylcellulose column followed by gel filtration on a Bio-Gel P-6 column and finally purified by reverse-phase high-performance liquid chromatography (HPLC) on a C-18 column. The antagonistic effect of this inhibitor on insulin was dose dependent with an ED50 of 2 x 10(-10) M, which was the same level used for insulin in vitro assay (1.7 x 10(-10) M). Amino acid analysis of the inhibitor showed that it was rich in arginine and glycine. It was estimated to be approximately 3000 Mr. The NH2-terminal of the peptide was proved to be blocked because it could not be degraded by Edman degradation. Based on the physicochemical and biochemical characteristics of the inhibitor and compared with other active peptides known to be in the pancreas, the inhibitor is probably a new active peptide that might play an important role in homeostasis of carbohydrate metabolism.

Adipose Tissue↗
PubMed1988

Characterization of rat skeletal muscle sarcolemmal insulin receptors and a sarcolemmal insulin binding inhibitor.

When insulin receptors of rat skeletal muscle sarcolemmal vesicles were solubilized with Triton X-100, the specific binding of 125I-labeled insulin increased by more than 10-fold over that seen in the intact vesicles. Partial purification of the skeletal muscle insulin receptors on wheat germ agglutinin affinity columns increased the total insulin binding activity by 7-fold and reduced the Kd for insulin binding from 1.92 to 0.20 nM, suggesting that an inhibitor of insulin binding was removed by this purification step. This was confirmed when the unbound fractions of the affinity column were dialyzed and reconstituted with the insulin receptors. The inhibitory activity in the sarcolemmal extract could not be accounted for by the presence of Triton X-100. The skeletal muscle inhibitor was more potent in inhibiting insulin binding to skeletal muscle insulin receptors than to liver or adipose receptors. The inhibitor was very effective in inhibiting insulin binding to wheat germ agglutinin-purified IM-9 receptors, but had negligible effects on insulin binding to intact IM-9 cells. The properties of the alpha and beta subunits of the skeletal muscle insulin receptors appear to be the same as those of insulin receptors of other tissues: cross-linking of 125I-labeled insulin to the receptor revealed a band of 130,000 daltons, and insulin stimulated the phosphorylation of bands of 90,000 and 95,000 daltons in the receptor preparation. The skeletal muscle insulin binding inhibitor elutes from molecular sieves in a major 160,000-dalton peak and minor 75,000-dalton peak. The binding inhibitor is not inactivated by heat, by mercaptoethanol, or by trypsin, pepsin, or proteinase K. Collectively, these data suggest that the inhibitor may be a small molecule that aggregates with itself, with larger proteins, or with detergent micelles.

Adipose Tissue↗
PubMed1984

Potentiation of the hypoglycemic effect of insulin by thiorphan, an enkephalinase inhibitor.

Insulin administration to rats produced a dose-related hypoglycemia. When insulin and the enkephalinase (Enk'ase) inhibitor thiorphan (30 or 100 mg/kg s.c.) were co-administered, there was a potentiation of the hypoglycemic response to insulin; these doses of thiorphan alone had no significant effect on plasma glucose. When tested in vitro against isolated Enk'ase, both insulin and its beta-chain inhibited the catabolism of [Met5]enkephalin. Theoretically, thiorphan blocked the catabolism of insulin by inhibiting Enk'ase. Alternatively, thiorphan acted as an inhibitor of another insulin-catabolizing enzyme having similar substrate requirements as Enk'ase.

Amino Acids, Sulfur↗
PubMed1983

Decreased insulin-generation of pyruvate dehydrogenase inhibitor in insulin resistant states.

Insulin resistance produced in rats by feeding a high fat diet or by dexamethasone administration (50 micrograms/day, sc for 4 days) resulted in 50-70% decrease in the generation of pyruvate dehydrogenase inhibitor by insulin exposed liver particulate fractions. The inhibition was dose dependent. Treatment of insulin mediator preparations with neuraminidase and B-D-galactosidase resulted in inactivation of the pyruvate dehydrogenase inhibitor. Presence of exogenous enzyme substrates during enzyme digestion partially protected the inhibitor from inactivation. Protease treatment did not affect the inhibitor while the stimulatory activity of the insulin mediator was abolished by trypsin treatment. These results together with the previous report suggest that insulin resistance results in a decrease in the generation of both of the mediators of insulin action. This may result from a decrease in insulin binding, shown earlier, or from a decrease in precursor availability.

Animals↗