Lynch C.J.,Pennsylvania State University |
Zhou Q.,Oregon Health And Science University |
Shyng S.-L.,Oregon Health And Science University |
Heal D.J.,RenaSci Consultancy |
And 9 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2012
Here, we examined the chronic effects of two cannabinoid receptor-1 (CB1) inverse agonists, rimonabant and ibipinabant, in hyperinsulinemic Zucker rats to determine their chronic effects on insulinemia. Rimonabant and ibipinabant (10 mg·kg -1·day -1) elicited body weightindependent improvements in insulinemia and glycemia during 10 wk of chronic treatment. To elucidate the mechanism of insulin lowering, acute in vivo and in vitro studies were then performed. Surprisingly, chronic treatment was not required for insulin lowering. In acute in vivo and in vitro studies, the CB1 inverse agonists exhibited acute K channel opener (KCO; e.g., diazoxide and NN414)-like effects on glucose tolerance and glucose-stimulated insulin secretion (GSIS) with approximately fivefold better potency than diazoxide. Followup studies implied that these effects were inconsistent with a CB1- mediated mechanism. Thus effects of several CB1 agonists, inverse agonists, and distomers during GTTs or GSIS studies using perifused rat islets were unpredictable from their known CB1 activities. In vivo rimonabant and ibipinabant caused glucose intolerance in CB1 but not SUR1-KO mice. Electrophysiological studies indicated that, compared with diazoxide, 3 μM rimonabant and ibipinabant are partial agonists for K channel opening. Partial agonism was consistent with data from radioligand binding assays designed to detect SUR1 K ATP KCOs where rimonabant and ibipinabant allosterically regulated 3Hglibenclamide- specific binding in the presence of MgATP, as did diazoxide and NN414. Our findings indicate that some CB1 ligands may directly bind and allosterically regulate Kir6.2/SUR1 K ATP channels like other KCOs. This mechanism appears to be compatible with and may contribute to their acute and chronic effects on GSIS and insulinemia. © 2012 the American Physiological Society.
Poucher S.M.,Astrazeneca |
Cheetham S.,RenaSci Consultancy |
Francis J.,Astrazeneca |
Zinker B.,Bristol Myers Squibb |
And 2 more authors.
Diabetes, Obesity and Metabolism | Year: 2012
Aims: We examined the effects of the oral dipeptidyl peptidase-4 (DPP-4) inhibitor saxagliptin on glycaemic control and pancreatic β-cell mass and morphology in a mouse model of type 2 diabetes mellitus (T2DM). Methods: Male C57BL/6 mice (n=12/group) aged 4 to 6weeks and weighing >15g received a high-fat diet throughout this 45-day study. After a 7-day handling period, baseline levels of plasma glucose, plasma insulin and glycated haemoglobin (HbA1c) were assessed. Animals were allocated to one of six groups: compound vehicle control, intraperitoneal streptozotocin (STZ, 50mg/kg)-treated control and saxagliptin (10mg/kg) or sitagliptin (10mg/kg, positive control) initiated 7days before or 1day after STZ administration. Endpoints included changes in body weight, food and water consumption, glucose tolerance (approximately 3 weeks post-STZ), fasting glucose and HbA1c and immunohistochemical analyses of the pancreas. Results: Body weight, weight gain and food intake were reduced in STZ versus control mice. DPP-4 inhibitor treatment did not affect these changes, but the increase in water intake observed post-STZ administration was significantly attenuated with DPP-4 inhibitors whether initiated before or after STZ injury. Small but significant improvements in glycaemic control were observed with DPP-4 inhibitors versus the STZ control. Improved β-cell mass and morphology were observed with saxagliptin given pre- or post-STZ and sitagliptin given post-STZ. Conclusions: Saxagliptin mitigated damage to β-cells and improved glycaemic control in this mouse model of T2DM. © 2012 Blackwell Publishing Ltd.