Impaired insulin secretion and glucose intolerance in synaptotagmin-7 null mutant mice

Abstract

Vertebrates express at least 15 different synaptotagmins with the same domain structure but diverse localizations and tissue distributions. Synaptotagmin-1,-2, and -9 act as calcium sensors for the fast phrase of neurotransmitter release, and synaptotagmin-12 acts as a calcium-independent modulator of release. The exact functions of the remaining 11 synaptotagmins, however, have not been established. By analogy to the role of synaptotagmin-1, -2, and -9 in neurotransmission, these other synaptotagmins may serve as Ca 2؉ transducers regulating other Ca 2؉ -dependent membrane processes, such as insulin secretion in pancreatic ␤-cells. Of these other synaptotagmins, synaptotagmin-7 is one of the most abundant and is present in pancreatic ␤-cells. To determine whether synaptotagmin-7 regulates Ca 2؉ -dependent insulin secretion, we analyzed synaptotagmin-7 null mutant mice for glucose tolerance and insulin release. Here, we show that synaptotagmin-7 is required for the maintenance of systemic glucose tolerance and glucose-stimulated insulin secretion. Mutant mice have normal insulin sensitivity, insulin production, islet architecture and ultrastructural organization, and metabolic and calcium responses but exhibit impaired glucose-induced insulin secretion, indicating a calcium-sensing defect during insulin-containing secretory granule exocytosis. Taken together, our findings show that synaptotagmin-7 functions as a positive regulator of insulin secretion and may serve as a calcium sensor controlling insulin secretion in pancreatic ␤ cells.calcium sensor ͉ exocytosis ͉ glucose tolerance ͉ insulin sensitivity ͉ NADH T he predominant form of diabetes, type 2 or non-insulindependent diabetes mellitus, develops as a result of insulin secretory dysfunction and peripheral insulin resistance (1). Secretory dysfunction in pancreatic ␤-cells (i.e., a reduction of stimulated insulin secretion) is thought to be caused by insufficient signal level secondary to impaired glucose metabolism and the resultant incomplete closure of the K ATP -channels and/or deficiencies in the exocytotic mechanism itself (2, 3). Glucosestimulated insulin secretion has a biphasic pattern, which consists of a 10-to 15-min rapid first phase and a less-prominent but sustained second phase (4). The first phase of insulin secretion requires a rapid and marked elevation of intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ), whereas the second phase requires amplifying signals from glucose metabolism in addition to oscillatory [Ca 2ϩ ] i (3). Partial or complete loss of the first phase of glucose-induced insulin release is a characteristic deterioration in early stages of type 2 diabetes (4, 5). Defects of the second phase develop at a slower time course but become equally prominent as diabetes progresses (6). Although much progress has been made in understanding the role of insulin secretion in the pathogenesis of diabetes, the molecular mechanisms of normal ␤ cell function, such as Ca 2ϩ regulation of insulin release, are poorly understood.Insulin releas...

In Vivohyperpolarized carbon-13 magnetic resonance spectroscopy reveals increased pyruvate carboxylase flux in an insulin-resistant mouse model

“…The intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (ITT) were conducted as described previously. 8 Details are available in the Supporting Materials.…”

Newcomer insulin secretory granules as a highly calcium-sensitive pool

“…One candidate for the HCSP Ca 2ϩ sensor is synaptotagmin 7 (Syt7), which has higher Ca 2ϩ sensitivity than Syt9 and Syt1 (26,27). However, Syt7 knockout mice show reductions in both first-and secondphase insulin secretion (52), not the selective reduction in second phase predicted by the model for loss of the HCSP sensor. (Fig.…”

Synaptotagmin-1 Utilizes Membrane Bending and SNARE Binding to Drive Fusion Pore Expansion

“…Syt-1 and -9 also cofunction as essential Ca 2ϩ sensors for dense-core vesicle exocytosis in PC12 cells , whereas Syt-1 and -7 contribute to Ca 2ϩ -triggered dense-core vesicle exocytosis in chromaffin cells (Schonn et al, 2008). Syts-1, -7, and -9 have also been reported to mediate Ca 2ϩ -triggered dense-core vesicle exocytosis in pancreatic ␤-cells (Iezzi et al, 2005;Xiong et al, 2006;Gustavsson et al, 2008). The function of most other members of the 17 member Syt family remains to be clarified (Craxton, 2007).…”