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The β-cell is equipped with at least six voltage-gated Ca2+ (Cav) channel α1-subunits designated Cav1.2, Cav1.3, Cav2.1, Cav2.2, Cav2.3, and Cav3.1. These principal subunits, together with certain auxiliary subunits, assemble into different types of Cav channels conducting L-, P/Q-, N-, R-, and T-type Ca2+ currents, respectively. The β cell shares customary mechanisms of Cav channel regulation with other excitable cells, such as protein phosphorylation, Ca2+-dependent inactivation, and G protein modulation How ever, the β-cell displays some characteristic features to bring these mechanisms into play. In islet β-cells. Cav channels can be highly phosphorylated under basal conditions and thus marginally respond to further phosphorylation. In β-cell lines, Cav channels can be surrounded by tonically activated protein phosphatases dominating over protein kinases; thus their activity is dramatically enhanced by inhibition of protein phosphatases. During the last 10 years, we have revealed some novel mechanisms of β-cell Cav channel regulation under physiological and pathophysiological conditions, including the involvement of exocytotic proteins, inositol hexakisphosphate, and type 1 diabetic serum. This minireview highlights characteristic features of customary mechanisms of Cav channel regulation in β-cells and also reviews our studies on newly identified mechanisms of β-cell Cav channel regulation. [ABSTRACT FROM AUTHOR]

Abstract: Pancreatic β-cells release insulin in appropriate amounts in order to keep blood glucose levels within physiological limits. Failure to do so leads to the most common metabolic disorder in man, diabetes mellitus. The glucose-stimulus/insulin-secretion coupling represents a sophisticated interplay between glucose and a variety of modulatory factors. These factors are provided by the blood supply (such as nutrients, vitamins, incretins etc.), the nerval innervations, cell-cell contacts as well as by paracrine and autocrine feedback loops within the pancreatic islet of Langerhans. However, the underlying mechanisms of their action remain poorly understood. In the present mini-review we discuss novel aspects of selective insulin signaling in the β-cell and novel insights into the role of higher inositol phosphates in insulin secretion. Finally we present a newly developed experimental platform that allows non-invasive and longitudinal in vivo imaging of pancreatic islet/β-cell biology at single-cell resolution. [Copyright &y& Elsevier]

The appropriate function of insulin-producing pancreatic β-cells is crucial for the regulation of glucose homeostasis, and its impairment leads to diabetes mellitus, the most common metabolic disorder in man. In addition to glucose, the major nutrient factor, inputs from the nervous system, humoral components, and cell-cell communication within the islet of Langerhans act together to guarantee the release of appropriate amounts of insulin in response to changes in blood glucose levels. Data obtained within the past decade in several laboratories have revitalized controversy over the autocrine feedback action of secreted insulin on β-cell function. Although insulin historically has been suggested to exert a negative effect on β-cells, recent data provide evidence for a positive role of insulin in transcription, translation, ion flux, insulin secretion, proliferation, and β-cell survival. Current insights on the role of insulin on pancreatic β-cell function are discussed. [ABSTRACT FROM AUTHOR]

Pancreatic β-cell function is essential for the regulation of glucose homeostasis and its impairment leads to diabetes mellitus. Besides glucose, the major nutrient factor, inputs from neural and humoral components and intraislet cell–cell communication act together to guarantee an appropriate pancreatic β-cell function. Data obtained over the last 5 years in several laboratories have revitalized a controversial concept, namely the autocrine feedback action of secreted insulin on β-cell function. While, historically, insulin was suggested to exert a negative effect on β-cells, recent data provide evidence for a positive role of insulin in transcription, translation, ion flux, insulin secretion and β-cell survival. [Copyright &y& Elsevier]

The voltage-gated Ca (Ca) channel acts as a key player in β cell physiology and pathophysiology. β cell Ca channels undergo hyperactivation subsequent to exposure to type 1 diabetic (T1D) serum resulting in increased cytosolic free Ca concentration and thereby Ca-triggered β cell apoptosis. The present study was aimed at revealing the subtypes of Ca1 channels hyperactivated by T1D serum as well as the biophysical mechanisms responsible for T1D serum-induced hyperactivation of β cell Ca1 channels. Patch-clamp recordings and single-cell RT-PCR analysis were performed in pancreatic β cells from Ca1 channel knockout and corresponding control mice. We now show that functional Ca1.3 channels are expressed in a subgroup of islet β cells from Ca1.2 knockout mice (Ca1.2). T1D serum enhanced whole-cell Ca currents in islet β cells from Ca1.3 knockout mice (Ca1.3). T1D serum increased the open probability and number of functional unitary Ca1 channels in Ca1.2 and Ca1.3 β cells. These data demonstrate that T1D serum hyperactivates both Ca1.2 and Ca1.3 channels by increasing their conductivity and number. These findings suggest Ca1.2 and Ca1.3 channels as potential targets for anti-diabetes therapy. [ABSTRACT FROM AUTHOR]

Defects in pancreatic β-cell function and survival are key components in type 2 diabetes (T2D). An age-dependent deterioration in β-cell function has also been observed, but little is known about the molecular mechanisms behind this phenomenon. Our previous studies indicate that the regulation of cytoplasmic free Ca 2+ concentration ([Ca 2+ ] i ) may be critical and that this is dependent on the proper function of the mitochondria. The [Ca 2+ ] i dynamics of the pancreatic β-cell are driven by an interplay between glucose-induced influx of extracellular Ca 2+ via voltage-dependent Ca 2+ channels and the inositol 1,4,5-trisphosphate (Ins(1,4,5) P 3 )-mediated liberation of Ca 2+ from intracellular stores. Our previous work has indicated a direct relationship between disruption of Ins(1,4,5) P 3 -mediated Ca 2+ regulation and loss of β-cell function, including disturbed [Ca 2+ ] i dynamics and compromised insulin secretion. To investigate these processes in aging we used three mouse models, a premature aging mitochondrial mutator mouse, a mature aging phenotype (C57BL/6) and an aging-resistant phenotype (129). Our data suggest that age-dependent impairment in mitochondrial function leads to modest changes in [Ca 2+ ] i dynamics in mouse β-cells, particularly in the pattern of [Ca 2+ ] i oscillations. These changes are driven by modifications in both PLC/Ins(1,4,5) P 3 -mediated Ca 2+ mobilization from intracellular stores and decreased β-cell Ca 2+ influx over the plasma membrane. Our findings underscore an important concept, namely that even relatively small, time-dependent changes in β-cell signal-transduction result in compromised insulin release and in a diabetic phenotype. [ABSTRACT FROM AUTHOR]

Pancreatic islet transplantation has emerged as a therapy for type 1 diabetes and is today performed using both freshly isolated and cultured islets. Islet blood vessels are disrupted during islet isolation; therefore, proper revascularization of the transplanted islets is of great importance for islet graft function and survival. We have studied intraislet endothelial cells after islet isolation, during islet culture, and following islet transplantation. By isolating islets from the transgenic Tie2-GFP (green fluorescent protein) mouse, characterized by an endothelial cell--specific expression of GFP, living endothelial cells could be studied in intact islets utilizing two-photon laser-scanning microscopy (TPLSM). Intraislet endothelial cells were found to survive islet transplantation but to rapidly disappear during islet culture. By transplanting freshly isolated Tie2-GFP islets and applying a novel ex vivo model for simultaneous perfusion and TPLSM imaging of the graft-bearing kidneys, GFP fluorescent endothelial cells were found to extensively contribute to vessels within the islet graft vasculature. Real-time imaging of the flow through the islet graft vasculature confirmed that the donor-derived vessels were functionally integrated. Hence, intraislet endothelial cells have the capability of participating in revascularization of pancreatic islets subsequent to transplantation. Therefore, preservation of intraislet endothelial cell mass may improve long-term graft function. Diabetes 54:2287-2293, 2005 [ABSTRACT FROM AUTHOR]