Search

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]