Abstract
A small nonpeptidyl compoud extracted from Pseudomassaria sp. was found to induce the activity of human insulin receptor tyrosine kinase in vitro. The compound was identified as demethylasterriquinone B-1 (DMAQ-B1). DMAQ- B1 also induced an increase in [Ca2+]i and insulin secretion in mice pancreatic beta-cells at low glucose (3 mM) concentration via insulin receptor substrate-1/phosphatidylinositol-3-kinase (PI3 kinase) pathway. By using rat pancreatic perfusion technique, we found that 10 μM DMAQ-B1 directly stimulated insulin secretion up to 240% in normal rat pancreas. In the dosage from 1 to 20 μM, DMAQ-B1 stimulated insulin secretion in a dose dependent manner. Furthermore, DMAQ-B1 enhanced glucose-induced insulin secretion by 17.6% (first stage) and 19.0% (second stage), respectively. The PI3 kinase inhibitors, LY 294002 (3.9 μM) or wortmannin (100 nM), inhibited DMAQ-B1-induced insulin secretion by 46.3% and 57.4%, respectively. LY 294002 or wortmannin also inhibited DMAQ-B1 with10 mMglucose-induced insulin secretion by 70.3% and 79.0%, respectively. All the results suggested that DMAQ-B1 directly stimulated insulin secretion and enhanced glucose-induced insulin secretion. The effect of DMAQ-B1 may mediate through the activation of PI3 kinase pathway to stimulate insulin secretion in normal rat pancreas.
Highlights
Oral therapies for type 2 diabetes mellitus are widely used until today
The results indicated a possible role of the PI3 kinase pathway involving the effect of demethylasterriquinone B-1 (DMAQ-B1) on insulin secretion
Zhang et al found that the interaction of DMAQ-B1 with IR kinase domain appears to alter the conformation of the protein in the region encompassing the ATP binding site [1]
Summary
Oral therapies for type 2 diabetes mellitus are widely used until today. the development of an orally insulin mimetic drug was the way for the treatment of diabetes mellitus. DMAQ-B1 increased the activity of human insulin receptor tyrosine kinase and increased the tyrosine phosphorylation of IR subunit. DMAQ-B1 induced an increase in [Ca2+]i involved release of Ca2+ from intracellular stores and stimulated insulin secretion in mice pancreatic beta-cells at nonstimulatory glucose (3 mM) concentrations via insulin receptor substrate-1/phosphatidylinositol-3-kinase (PI3 kinase) pathway [4]. Strowski et al found that administration of DMAQ-B1 could decrease hyperglycemia and obesity in a nongenetic mouse model of type 2 diabetes mellitus [5]. Velliquette et al found that the oral treatment of DMAQ-B1 didn’t increase body weight and food intake in the spontaneously hypertensive obese rat model of metabolic syndrome X [6].
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