l-783281 and Hyperglycemia

The increasing prevalence, variable pathogenesis, progressive natural history, and complications of type 2 diabetes emphasise the urgent need for new treatment strategies. Longacting (eg, once weekly) agonists of the glucagon-like-peptide-1 receptor are advanced in development, and they improve prandial insulin secretion, reduce excess glucagon production, and promote satiety. Trials of inhibitors of dipeptidyl peptidase 4, which enhance the effect of endogenous incretin hormones, are also nearing completion. Novel approaches to glycaemic regulation include use of inhibitors of the sodium-glucose cotransporter 2, which increase renal glucose elimination, and inhibitors of 11β-hydroxysteroid dehydrogenase 1, which reduce the glucocorticoid effects in liver and fat. Insulin-releasing glucokinase activators and pancreatic-G-protein-coupled fatty-acid-receptor agonists, glucagon-receptor antagonists, and metabolic inhibitors of hepatic glucose output are being assessed. Early proof of principle has been shown for compounds that enhance and partly mimic insulin action and replicate some effects of bariatric surgery.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Allylamine; Anticholesteremic Agents; Bariatric Surgery; Bile Acids and Salts; Cardiovascular System; Colesevelam Hydrochloride; Comorbidity; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glucokinase; Humans; Hyperglycemia; Hypoglycemic Agents; Indoles; Insulin; Insulin Resistance; Insulin-Secreting Cells; Liver; Obesity; Peptides; Randomized Controlled Trials as Topic; Receptors, Dopamine D2; Signal Transduction; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome; Venoms

We recently described the identification of a non-peptidyl fungal metabolite (l-783,281, compound 1), which induced activation of human insulin receptor (IR) tyrosine kinase and mediated insulin-like effects in cells, as well as decreased blood glucose levels in murine models of Type 2 diabetes (Zhang, B., Salituro, G., Szalkowski, D., Li, Z., Zhang, Y., Royo, I., Vilella, D., Diez, M. T. , Pelaez, F., Ruby, C., Kendall, R. L., Mao, X., Griffin, P., Calaycay, J., Zierath, J. R., Heck, J. V., Smith, R. G. & Moller, D. E. (1999) Science 284, 974-977). Here we report the characterization of an active analog (compound 2) with enhanced IR kinase activation potency and selectivity over related receptors (insulin-like growth factor I receptor, epidermal growth factor receptor, and platelet-derived growth factor receptor). The IR activators stimulated tyrosine kinase activity of partially purified native IR and recombinant IR tyrosine kinase domain. Administration of the IR activators to mice was associated with increased IR tyrosine kinase activity in liver. In vivo oral treatment with compound 2 resulted in significant glucose lowering in several rodent models of diabetes. In db/db mice, oral administration of compound 2 elicited significant correction of hyperglycemia. In a streptozotocin-induced diabetic mouse model, compound 2 potentiated the glucose-lowering effect of insulin. In normal rats, compound 2 improved oral glucose tolerance with significant reduction in insulin release following glucose challenge. A structurally related inactive analog (compound 3) was not effective on insulin receptor activation or glucose lowering in db/db mice. Thus, small molecule IR activators exert insulin mimetic and sensitizing effects in cells and in animal models of diabetes. These results have implications for the future development of new therapies for diabetes mellitus.

Topics: Animals; CHO Cells; Cricetinae; Humans; Hyperglycemia; Hypoglycemic Agents; Indoles; Insulin; Male; Mice; Mice, Inbred Strains; Models, Chemical; Protein-Tyrosine Kinases; Rats; Rats, Sprague-Dawley; Receptor, Insulin; Signal Transduction; Structure-Activity Relationship

Insulin elicits a spectrum of biological responses by binding to its cell surface receptor. In a screen for small molecules that activate the human insulin receptor tyrosine kinase, a nonpeptidyl fungal metabolite (L-783,281) was identified that acted as an insulin mimetic in several biochemical and cellular assays. The compound was selective for insulin receptor versus insulin-like growth factor I (IGFI) receptor and other receptor tyrosine kinases. Oral administration of L-783,281 to two mouse models of diabetes resulted in significant lowering in blood glucose levels. These results demonstrate the feasibility of discovering novel insulin receptor activators that may lead to new therapies for diabetes.

Topics: Adenosine Triphosphate; Animals; Ascomycota; Binding Sites; Blood Glucose; CHO Cells; Cricetinae; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Enzyme Activation; ErbB Receptors; Glucose Tolerance Test; Hyperglycemia; Hypoglycemic Agents; Indoles; Insulin; Insulin Receptor Substrate Proteins; Mice; Mice, Mutant Strains; Mice, Obese; Molecular Mimicry; Phosphoproteins; Phosphorylation; Protein Conformation; Receptor, IGF Type 1; Receptor, Insulin; Signal Transduction