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...
Obesity and atherosclerosis-related diseases account for over one-third of deaths in the western world. Controlling these conditions remains a major challenge due to an incomplete understanding of the molecular pathways involved. Here, we show that Wip1 phosphatase, a known negative regulator of Atm-dependent signaling, plays a major role in controlling fat accumulation and atherosclerosis in mice; specifically, Wip1 deficiency prevents both conditions. In the course of atherosclerosis, deletion of Wip1 results in suppression of macrophage conversion into foam cells, thus preventing the formation of atherosclerotic plaques. This process appears to be independent of p53 but rely on a noncanonical Atm-mTOR signaling pathway and on selective autophagy in regulation of cholesterol efflux. We propose that the Wip1-dependent control of autophagy and cholesterol efflux may provide avenues for treating obesity and atherosclerosis.
By adapting OPT to include the capability of imaging in the near infrared (NIR) spectrum, we here illustrate the possibility to image larger bodies of pancreatic tissue, such as the rat pancreas, and to increase the number of channels (cell types) that may be studied in a single specimen. We further describe the implementation of a number of computational tools that provide: 1/ accurate positioning of a specimen's (in our case the pancreas) centre of mass (COM) at the axis of rotation (AR) 2 ; 2/ improved algorithms for post-alignment tuning which prevents geometric distortions during the tomographic reconstruction 2 and 3/ a protocol for intensity equalization to increase signal to noise ratios in OPT-based BCM determinations 3. In addition, we describe a sample holder that minimizes the risk for unintentional movements of the specimen during image acquisition. Together, these protocols enable assessments of BCM distribution and other features, to be performed throughout the volume of intact pancreata or other organs (e.g. in studies of islet transplantation), with a resolution down to the level of individual islets of Langerhans.
Mouse models of Streptozotocin (STZ) induced diabetes represent the most widely used preclinical diabetes research systems. We applied state of the art optical imaging schemes, spanning from single islet resolution to the whole organ, providing a first longitudinal, 3D-spatial and quantitative account of β-cell mass (BCM) dynamics and islet longevity in STZ-treated mice. We demonstrate that STZ-induced β-cell destruction predominantly affects large islets in the pancreatic core. Further, we show that hyperglycemic STZ-treated mice still harbor a large pool of remaining β-cells but display pancreas-wide downregulation of glucose transporter type 2 (GLUT2). Islet gene expression studies confirmed this downregulation and revealed impaired β-cell maturity. Reversing hyperglycemia by islet transplantation partially restored the expression of markers for islet function, but not BCM. Jointly our results indicate that STZ-induced hyperglycemia results from β-cell dysfunction rather than β-cell ablation and that hyperglycemia in itself sustains a negative feedback loop restraining islet function recovery.
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