l-783281 and Diabetes-Mellitus--Type-2

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

Topics: Administration, Oral; Animals; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Indoles; Insulin; Insulin Resistance; Molecular Mimicry; Receptor, Insulin; Structure-Activity Relationship

Epidemiological studies suggest a positive relationship between phthalate exposure and diabetes. However, little is known about the impact of dibutyl phthalate (DBP) exposure on the development of diabetes. To determine the role of DBP exposure on the development of type 2 diabetes, mice were orally exposed to DBP dosages of 0.5, 5, 50 mg/kg/day for 7 weeks, combined with a high fat diet and injections of a low dose of streptozotocin (STZ). The results showed that exposure to 50 mg/kg/day DBP alone induced a marked decrease in insulin secretion and glucose intolerance, but had no influence on insulin resistance. However, combined with a high fat diet and STZ treatment, DBP exposure markedly aggravated glucose intolerance, insulin tolerance and insulin resistance and induced lesions in the pancreas and kidney. Investigation of the role of DBP on the insulin signaling pathway, we found that DBP exposure could disrupt the PI3K expression and AKT phosphorylation, and decrease the level of GLUT-2 in the pancreas. Administering demethylasterriquinone B1, significantly increased the level of PI3K, AKT phosphorylation and GLUT-2 expression, effectively inhibiting the aggravation of diabetes. Our results suggested that DBP aggravated type 2 diabetes by disrupting the insulin signaling pathway and impairing insulin secretion.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dibutyl Phthalate; Indoles; Insulin; Insulin Resistance; Insulin Secretion; Male; Mice; Mice, Inbred BALB C; Pancreas; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction

L-783,281, an antidiabetic fungal metabolite that has previously been shown to activate insulin signaling in CHO cells, was tested for its effect on intracellular Ca(2+) ([Ca(2+)](i)) and insulin secretion in single mouse pancreatic beta-cells. Application of 10 micromol/l L-783,281 for 40 s to isolated beta-cells in the presence of 3 mmol/l glucose increased [Ca(2+)](i) to 178 +/- 10% of basal levels (n = 18) as measured by fluo-4 fluorescence. L-767,827, an inactive structural analog of the insulin mimetic, had no effect on beta-cell [Ca(2+)](i). The L-783,281-evoked [Ca(2+)](i) increase was reduced by 82 +/- 4% (n = 6, P < 0.001) in cells incubated with 1 micromol/l of the SERCA (sarco/endoplasmic reticulum calcium ATPase) pump inhibitor thapsigargin and reduced by 33 +/- 6% (n = 6, P < 0.05) in cells incubated with 20 micromol/l of the L-type Ca(2+)-channel blocker nifedipine. L-783,281-stimulated [Ca(2+)](i) increases were reduced to 31 +/- 3% (n = 9, P < 0.05) and 48 +/- 10% (n = 6, P < 0.05) of control values by the phosphatidylinositol 3-kinase (PI3-K) inhibitors LY294002 (25 micromol/l) and wortmannin (100 nmol/l), respectively. In beta-cells from IRS-1-/- mice, 10 micromol/l L-783,281 had no significant effect on [Ca(2+)](i) (n = 5). L-783,281 also resulted in insulin secretion at single beta-cells. Application of 10 micromol/l L-783,281 for 40 s resulted in 12.2 +/- 2.1 (n = 14) exocytotic events as measured by amperometry, whereas the inactive structural analog had no stimulatory effect on secretion. Virtually no secretion was evoked by L-783,281 in IRS-1-/- beta-cells. LY294002 (25 micromol/l) significantly reduced the effect of the insulin mimetic on beta-cell exocytosis. It is concluded that L-783,281 evokes [Ca(2+)](i) increases and exocytosis in beta-cells via an IRS-1/PI3-K-dependent pathway and that the [Ca(2+)](i) increase involves release of Ca(2+) from intracellular stores.

Topics: Animals; Calcium; Cells, Cultured; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Indoles; Insulin; Insulin Receptor Substrate Proteins; Insulin Secretion; Islets of Langerhans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Mimicry; Phosphatidylinositol 3-Kinases; Phosphoproteins; Signal Transduction; Thapsigargin

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

Topics: Animals; Ascomycota; CHO Cells; Cricetinae; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Hypoglycemic Agents; Indoles; Insulin; Mice; Mice, Mutant Strains; Receptor, Insulin

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Indoles; Insulin; Molecular Mimicry; Receptor, Insulin