Impaired insulin secretion from the β-cells characterizes both type 2 and the initial phase of type 1 diabetes (T1D). Although the two sub-forms have different causes, we postulate that the rapidly developing β-cell defect and death in T1D as well as the slowly progressing β-cell dysfunction associated with T2D share a common cellular mechanism.
Long-term elevated plasma glucose (glucotoxicity) as well as presence of inflammatory cytokines in the pancreatic islets contribute to β-cell demise in both forms of diabetes. In the initial phase of T1D, islet cell antibodies are detected, while insulin secretion is attenuated but not abolished. Existing therapies are not preventing the progression of either T1D or T2D. We have recently shown that long-term exposure of pancreatic β-cells to high glucose (glucotoxicity) as well as β-cells isolated from T2D cadaveric organ donors show increased expression of the mitochondrial voltage-dependent anion channel-1 (VDAC1). This leads toVDAC1 miss-targeting (translocation) to the cell surface. Our preliminary data showed that inflammatory cytokines also increases VDAC1, which might contribute to the loss of β-cells in T1D. VDAC1 overexpression leads to its oligomerization, which participates in cell death. In preliminary results, we also observe upregulation of VDAC1 in a rat model of T1D. Since VDAC1 is a mitochondrial ATP transporter, its translocation to the cell surface is associated with ATP loss from the β-cells, leading to energy depletion. Prevention of ATP loss withVDAC1 inhibitors restores β-cell ATP levels and insulin secretion in T2D islets. Daily injections of a VDAC1 inhibitor prevent the onset of hyperglycemia in db/db mice, a T2D model. Based on the effects of cytokines, we want to extend our investigations to include T1D. To this end, we will studyVDAC1 protein expression and co-localization with other β-cell markers on pancreatic sections from T1D organ donors. We thus envision that novel therapeutics based on VDAC1 inhibitors i.e. newly developed small molecules or a specific VDAC1 antibody, may act either as complements to existing therapies, or as novel stand-alone treatments for T2D as well as prevention of the β-cell loss in T1D.