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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]

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]

Pancreatic beta cell damage caused by pro-inflammatory cytokines interleukin-1β (IL-1β), interferon-γ (IFNγ) and tumor necrosis factor-α (TNFα) is a key event in the pathogenesis of type 1 diabetes. The suppressor of cytokine signaling-1 (SOCS-1) blocks IFNγ-induced signaling and prevents diabetes in the non-obese diabetic mouse. Here, we investigated if SOCS-1 overexpression in primary beta cells provides protection from cytokine-induced islet cell dysfunction and death. We demonstrate that SOCS-1 does not prevent increase in NO production and decrease in glucose-stimulated insulin secretion in the presence of IL-1β, IFNγ, TNFα. However, it decreases the activation of caspase-3, -8 and -9, and thereby, promotes a robust protection from cytokine-induced beta cell death. Our data suggest that SOCS-1 overexpression may not be sufficient in preventing all the biological activities of IFNγ in beta cells. In summary, we show that interference with IFNγ signal transduction pathways by SOCS-1 inhibits cytokine-stimulated pancreatic beta cell death. [ABSTRACT FROM AUTHOR]

Transthyretin (TTR) is a transport protein for thyroxine and, in association with retinol-binding protein, for retinol, mainly existing as a tetramer in vivo. We now demonstrate that TTR tetramer has a positive role in pancreatic β-cell stimulus-secretion coupling. TTR promoted glucose-induced increases in cytoplasmic free Ca²+ concentration ([Ca²+]i) and insulin release. This resulted from a direct effect on glucose-induced electrical activity and voltage- gated Ca²+ channels. TTR also protected against β-cell apoptosis. The concentration of TTR tetramer was decreased, whereas that of a monomeric form was increased in sera from patients with type 1 diabetes. The monomer was without effect on glucose-induced insulin release and apoptosis. Thus, TTR tetramer constitutes a component in normal β-cell function. Conversion of TTR tetramer to monomer may be involved in the development of β-cell failure/ destruction in type 1 diabetes. [ABSTRACT FROM AUTHOR]