OBJECTIVE-Endoplasmic reticulum (ER) stress-induced apoptosis may be a common cause of cell attrition in diseases characterized by misfolding and oligomerisation of amyloidogenic proteins. The islet in type 2 diabetes is characterized by islet amyloid derived from islet amyloid polypeptide (IAPP) and increased ␤-cell apoptosis. We questioned the following: 1) whether IAPP-induced ␤-cell apoptosis is mediated by ER stress and 2) whether ␤-cells in type 2 diabetes are characterized by ER stress. RESEARCH DESIGN AND METHODS-The mechanism of IAPP-induced apoptosis was investigated in INS-1 cells and human IAPP (HIP) transgenic rats. ER stress in humans was investigated by ␤-cell C/EBP homologous protein (CHOP) expression in 7 lean nondiabetic, 12 obese nondiabetic, and 14 obese type 2 diabetic human pancreata obtained at autopsy. To assure specificity for type 2 diabetes, we also examined pancreata from eight cases of type 1 diabetes.RESULTS-IAPP induces ␤-cell apoptosis by ER stress in INS-1 cells and HIP rats. Perinuclear CHOP was rare in lean nondiabetic (2.6 Ϯ 2.0%) and more frequent in obese nondiabetic (14.6 Ϯ 3.0%) and obese diabetic (18.5 Ϯ 3.6%) pancreata. Nuclear CHOP was not detected in lean nondiabetic and rare in obese nondiabetic (0.08 Ϯ 0.04%) but six times higher (P Ͻ 0.01) in obese diabetic (0.49 Ϯ 0.17%) pancreata. In type 1 diabetic pancreata, perinuclear CHOP was rare (2.5 Ϯ 2.3%) and nuclear CHOP not detected. B oth type 1 and type 2 diabetes are characterized by deficits in ␤-cell mass and increased ␤-cell apoptosis (1-6). The mechanism that initiates ␤-cell apoptosis in type 1 diabetes is believed to be autoimmune-mediated cytokine production (5). Several mechanisms have been proposed for increased ␤-cell apoptosis in type 2 diabetes, including oxygen free radicals (7), free fatty acid toxicity (8), interleukin-1␤ (9), and formation of islet amyloid polypeptide (IAPP) toxic oligomers (10 -12). CONCLUSIONS-ERProgrammed cell death, or apoptosis, is important in multicellular organisms to permit organ development and remodeling (13). In disease states, apoptosis permits selective removal of cells that are damaged, particularly in relation to cell cycle, so that damage is not propagated (3,14). Apoptosis may be initiated by a wide variety of cellular insults, which are currently thought to act through at least three pathways that converge to accomplish irreversible destruction of the cell's chromosomes. These three major pathways have been designated as the extrinsic and intrinsic pathways and endoplasmic reticulum (ER) stress pathway (15,16). The extrinsic pathway is classically exemplified by cytokine-induced cell death, mediated through cell surface death receptors (17). The intrinsic pathway is most often described as a response to mitochondrial disruption, for example, secondary to oxygen free radicals (18). ER stress-induced apoptosis is classically ascribed to aggregates of misfolded protein that are believed to compromise the ER membrane (15).The human pancreatic ␤-cell is vulnerable to al...

One-dimensional cobalt sulfide (CoS) acicular nanorod arrays (ANRAs) were obtained on a fluorine-doped tin oxide (FTO) substrate by a two-step approach. First, Co(3)O(4) ANRAs were synthesized, and then they were converted to CoS ANRAs for various periods. The compositions of the films obtained after various conversion periods were verified by X-ray diffraction, UV-visible spectrophotometry, and X-ray photoelectron spectroscopy; their morphologies were examined at different periods by scanning electron microscopic and transmission electron microscopic images. Electrocatalytic abilities of the films toward I(-)/I(3)(-) were verified through cyclic voltammetry (CV) and Tafel polarization curves. Long-term stability of the films in I(-)/I(3)(-) electrolyte was studied by CV. The FTO substrates with CoS ANRAs were used as the counter electrodes for dye-sensitized solar cells; a maximum power conversion efficiency of 7.67% was achieved for a cell with CoS ANRAs, under 100 mW/cm(2), which is nearly the same as that of a cell with a sputtered Pt counter electrode (7.70%). Electrochemical impedance spectroscopy was used to substantiate the photovoltaic parameters.

Type 2 diabetes mellitus (T2DM) is characterized by an ∼60% deficit in β-cell mass, increased β-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). Human IAPP (hIAPP) forms oligomers, leading to either amyloid fibrils or toxic oligomers in an aqueous solution in vitro. Either application of hIAPP on or overexpression of hIAPP in cells induces apoptosis. It remains controversial whether the fibrils or smaller toxic oligomers induce β-cell apoptosis. Rifampicin prevents hIAPP amyloid fibril formation and has been proposed as a potential target for prevention of T2DM. We examined the actions of rifampicin on hIAPP amyloid fibril and toxic oligomer formation as well as its ability to protect β-cells from either application of hIAPP or endogenous overexpression of hIAPP (transgenic rats and adenovirus-transduced β-cells). We report that rifampicin (Acocella G. Clin Pharmacokinet 3: 108–127, 1978) prevents hIAPP fibril formation, but not formation of toxic hIAPP oligomers (Bates G. Lancet 361: 1642–1644, 2003), and does not protect β-cells from apoptosis induced by either overexpression or application of hIAPP. These data emphasize that toxic hIAPP oligomers, rather than hIAPP fibrils, initiate β-cell apoptosis and that screening tools to identify inhibitors of amyloid fibril formation are likely to be less useful than those that identify inhibitors of toxic oligomer formation. Finally, rifampicin and related molecules do not appear to be useful as candidates for prevention of T2DM.

Therapeutic, V.