Progression of Diet-Induced Diabetes in C57BL6J Mice Involves Functional Dissociation of Ca2+ Channels From Secretory Vesicles

OBJECTIVE: The aim of the study was to elucidate the cellular mechanism underlying the suppression of glucose-induced insulin secretion in mice fed a high-fat diet (HFD) for 15 weeks. RESEARCH DESIGN AND METHODS: C57BL6J mice were fed a HFD or a normal diet (ND) for 3 or 15 weeks. Plasma insulin and glucose levels in vivo were assessed by intraperitoneal glucose tolerance test. Insulin secretion in vitro was studied using static incubations and a perfused pancreas preparation. Membrane currents, electrical activity, and exocytosis were examined by patch-clamp technique measurements. Intracellular calcium concentration ([Ca(2+)](i)) was measured by microfluorimetry. Total internal reflection fluorescence microscope (TIRFM) was used for optical imaging of exocytosis and submembrane depolarization-evoked [Ca(2+)](i). The functional data were complemented by analyses of histology and gene transcription. RESULTS: After 15 weeks, but not 3 weeks, mice on HFD exhibited hyperglycemia and hypoinsulinemia. Pancreatic islet content and beta-cell area increased 2- and 1.5-fold, respectively. These changes correlated with a 20-50% reduction of glucose-induced insulin secretion (normalized to insulin content). The latter effect was not associated with impaired electrical activity or [Ca(2+)](i) signaling. Single-cell capacitance and TIRFM measurements of exocytosis revealed a selective suppression (>70%) of exocytosis elicited by short (50 ms) depolarization, whereas the responses to longer depolarizations were (500 ms) less affected. The loss of rapid exocytosis correlated with dispersion of Ca(2+) entry in HFD beta-cells. No changes in gene transcription of key exocytotic protein were observed. CONCLUSIONS: HFD results in reduced insulin secretion by causing the functional dissociation of voltage-gated Ca(2+) entry from exocytosis. These observations suggest a novel explanation to the well-established link between obesity and diabetes

A lattice gas model of II-VI(001) semiconductor surfaces

We introduce an anisotropic two-dimensional lattice gas model of metal terminated II-IV(001) seminconductor surfaces. Important properties of this class of materials are represented by effective NN and NNN interactions, which result in the competition of two vacancy structures on the surface. We demonstrate that the experimentally observed c(2x2)-(2x1) transition of the CdTe(001) surface can be understood as a phase transition in thermal equilbrium. The model is studied by means of transfer matrix and Monte Carlo techniques. The analysis shows that the small energy difference of the competing reconstructions determines to a large extent the nature of the different phases. Possible implications for further experimental research are discussed.Comment: 7 pages, 2 figure

Inhibition of Dipeptidyl Peptidase-4 by Vildagliptin During Glucagon-Like Peptide 1 Infusion Increases Liver Glucose Uptake in the Conscious Dog

OBJECTIVE—This study investigated the acute effects of treatment with vildagliptin on dipeptidyl peptidase-4 (DPP-4) activity, glucagon-like peptide 1 (GLP-1) concentration, pancreatic hormone levels, and glucose metabolism. The primary aims were to determine the effects of DPP-4 inhibition on GLP-1 clearance and on hepatic glucose uptake

Gpr40 Is Expressed in Enteroendocrine Cells and Mediates Free Fatty Acid Stimulation of Incretin Secretion

OBJECTIVE—The G-protein–coupled receptor Gpr40 is expressed in β-cells where it contributes to free fatty acid (FFA) enhancement of glucose-stimulated insulin secretion (1–4). However, other sites of Gpr40 expression, including the intestine, have been suggested. The transcription factor IPF1/PDX1 was recently shown to bind to an enhancer element within the 5′-flanking region of Gpr40 (5), implying that IPF1/PDX1 might regulate Gpr40 expression. Here, we addressed whether 1) Gpr40 is expressed in the intestine and 2) Ipf1/Pdx1 function is required for Gpr40 expression

Gynaecological morbidity among HIV positive pregnant women in Cameroon

<p>Abstract</p> <p>Objective</p> <p>To compare the prevalence of gynaecological conditions among HIV infected and non-infected pregnant women.</p> <p>Methods</p> <p>Two thousand and eight (2008) pregnant women were screened for HIV, lower genital tract infections and lower genital tract neoplasia at booking antenatal visit.</p> <p>Results</p> <p>About 10% (198/2008) were HIV positive. All lower genital tract infections except candidiasis were more prevalent among HIV positive compared to HIV negative women: vaginal candidiasis (36.9% vs 35.4%; <it>p </it>= 0.678), Trichomoniasis (21.2% vs 10.6%; <it>p </it>< 0.001), gonorrhoea (10.1% vs 2.5%; <it>p </it>< 0.001), bacterial vaginosis (21.2% vs 15.2%; <it>p </it>= 0.026), syphilis (35.9% vs 10.6%; <it>p </it>< 0.001), and <it>Chlamydia trachomatis </it>(38.4% vs 7.1%; <it>p </it>< 0.001). Similarly, HIV positive women more likely to have preinvasive cervical lesions: low-grade squamous intraepithelial lesion (SIL) (18.2% vs 4.4%; <it>p </it>< 0.001) and high-grade squamous intraepithelial lesion (12.1% vs 1.5%; <it>p </it>< 0.001).</p> <p>Conclusion</p> <p>We conclude that (i) sexually transmitted infections (STIs) are common in both HIV positive and HIV negative pregnant women in Cameroon, and (ii) STIs and preinvasive cervical lesions are more prevalent in HIV-infected pregnant women compared to their non-infected compatriots. We recommend routine screening and treatment of STIs during antenatal care in Cameroon and other countries with similar social profiles.</p

Computational capabilities of multilayer committee machines

We obtained an analytical expression for the computational complexity of many layered committee machines with a finite number of hidden layers (L < 8) using the generalization complexity measure introduced by Franco et al (2006) IEEE Trans. Neural Netw. 17 578. Although our result is valid in the large-size limit and for an overlap synaptic matrix that is ultrametric, it provides a useful tool for inferring the appropriate architecture a network must have to reproduce an arbitrary realizable Boolean function

Small Interfering RNA–Mediated Suppression of Proislet Amyloid Polypeptide Expression Inhibits Islet Amyloid Formation and Enhances Survival of Human Islets in Culture

OBJECTIVE—Islet amyloid, formed by aggregation of the β-cell peptide islet amyloid polypeptide (IAPP; amylin), is a pathological characteristic of pancreatic islets in type 2 diabetes. Toxic IAPP aggregates likely contribute to the progressive loss of β-cells in this disease. We used cultured human islets as an ex vivo model of amyloid formation to investigate whether suppression of proIAPP expression would inhibit islet amyloid formation and enhance β-cell survival and function

Multimodality Imaging of β-Cells in Mouse Models of Type 1 and 2 Diabetes

Objectiveβ-Cells that express an imaging reporter have provided powerful tools for studying β-cell development, islet transplantation, and β-cell autoimmunity. To further expedite diabetes research, we generated transgenic C57BL/6 "MIP-TF" mice that have a mouse insulin promoter (MIP) driving the expression of a trifusion (TF) protein of three imaging reporters (luciferase/enhanced green fluorescent protein/HSV1-sr39 thymidine kinase) in their β-cells. This should enable the noninvasive imaging of β-cells by charge-coupled device (CCD) and micro-positron emission tomography (PET), as well as the identification of β-cells at the cellular level by fluorescent microscopy.Research design and methodsMIP-TF mouse β-cells were multimodality imaged in models of type 1 and type 2 diabetes.ResultsMIP-TF mouse β-cells were readily identified in pancreatic tissue sections using fluorescent microscopy. We show that MIP-TF β-cells can be noninvasively imaged using microPET. There was a correlation between CCD and microPET signals from the pancreas region of individual mice. After low-dose streptozotocin administration to induce type 1 diabetes, we observed a progressive reduction in bioluminescence from the pancreas region before the appearance of hyperglycemia. Although there have been reports of hyperglycemia inducing proinsulin expression in extrapancreatic tissues, we did not observe bioluminescent signals from extrapancreatic tissues of diabetic MIP-TF mice. Because MIP-TF mouse β-cells express a viral thymidine kinase, ganciclovir treatment induced hyperglycemia, providing a new experimental model of type 1 diabetes. Mice fed a high-fat diet to model early type 2 diabetes displayed a progressive increase in their pancreatic bioluminescent signals, which were positively correlated with area under the curve-intraperitoneal glucose tolerance test (AUC-IPGTT).ConclusionsMIP-TF mice provide a new tool for monitoring β-cells from the single cell level to noninvasive assessments of β-cells in models of type 1 diabetes and type 2 diabetes