Background: Amyloid-related degenerative diseases are associated with the accumulation of misfolded proteins as amyloid fibrils in tissue. In Alzheimer disease (AD), amyloid accumulates in several distinct types of insoluble plaque deposits, intracellular Aβ and as soluble oligomers and the relationships between these deposits and their pathological significance remains unclear. Conformation dependent antibodies have been reported that specifically recognize distinct assembly states of amyloids, including prefibrillar oligomers and fibrils.

Type 2 diabetes (T2DM) is characterized by insulin resistance, defective insulin secretion, loss of beta-cell mass with increased beta-cell apoptosis and islet amyloid. The islet amyloid is derived from islet amyloid polypeptide (IAPP, amylin), a protein coexpressed and cosecreted with insulin by pancreatic beta-cells. In common with other amyloidogenic proteins, IAPP has the propensity to form membrane permeant toxic oligomers. Accumulating evidence suggests that these toxic oligomers, rather than the extracellular amyloid form of these proteins, are responsible for loss of neurons in neurodegenerative diseases. In this review we discuss emerging evidence to suggest that formation of intracellular IAPP oligomers may contribute to beta-cell loss in T2DM. The accumulated evidence permits the amyloid hypothesis originally developed for neurodegenerative diseases to be reformulated as the toxic oligomer hypothesis. However, as in neurodegenerative diseases, it remains unclear exactly why amyloidogenic proteins form oligomers in vivo, what their exact structure is, and to what extent these oligomers play a primary or secondary role in the cytotoxicity in what are now often called unfolded protein diseases.

Controversy exists regarding the potential regenerative influences of incretin therapy on pancreatic β-cells versus possible adverse pancreatic proliferative effects. Examination of pancreata from age-matched organ donors with type 2 diabetes mellitus (DM) treated by incretin therapy (n = 8) or other therapy (n = 12) and nondiabetic control subjects (n = 14) reveals an ∼40% increased pancreatic mass in DM treated with incretin therapy, with both increased exocrine cell proliferation (P < 0.0001) and dysplasia (increased pancreatic intraepithelial neoplasia, P < 0.01). Pancreata in DM treated with incretin therapy were notable for α-cell hyperplasia and glucagon-expressing microadenomas (3 of 8) and a neuroendocrine tumor. β-Cell mass was reduced by ∼60% in those with DM, yet a sixfold increase was observed in incretin-treated subjects, although DM persisted. Endocrine cells costaining for insulin and glucagon were increased in DM compared with non-DM control subjects (P < 0.05) and markedly further increased by incretin therapy (P < 0.05). In conclusion, incretin therapy in humans resulted in a marked expansion of the exocrine and endocrine pancreatic compartments, the former being accompanied by increased proliferation and dysplasia and the latter by α-cell hyperplasia with the potential for evolution into neuroendocrine tumors.

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...

OBJECTIVE The aim of this study was to elucidate whether age plays a role in the expansion or regeneration of β-cell mass. RESEARCH DESIGN AND METHODS We analyzed the capacity of β-cell expansion in 1.5- and 8-month-old mice in response to a high-fat diet, after short-term treatment with the glucagon-like peptide 1 (GLP-1) analog exendin-4, or after streptozotocin (STZ) administration. RESULTS Young mice responded to high-fat diet by increasing β-cell mass and β-cell proliferation and maintaining normoglycemia. Old mice, by contrast, did not display any increases in β-cell mass or β-cell proliferation in response to high-fat diet and became diabetic. To further assess the plasticity of β-cell mass with respect to age, young and old mice were injected with a single dose of STZ, and β-cell proliferation was analyzed to assess the regeneration of β-cells. We observed a fourfold increase in β-cell proliferation in young mice after STZ administration, whereas no changes in β-cell proliferation were observed in older mice. The capacity to expand β-cell mass in response to short-term treatment with the GLP-1 analog exendin-4 also declined with age. The ability of β-cell mass to expand was correlated with higher levels of Bmi1, a polycomb group protein that is known to regulate the Ink4a locus, and decreased levels of p16 Ink4a expression in the β-cells. Young Bmi1 −/− mice that prematurely upregulate p16 Ink4a failed to expand β-cell mass in response to exendin-4, indicating that p16 Ink4a levels are a critical determinant of β-cell mass expansion. CONCLUSIONS β-Cell proliferation and the capacity of β-cells to regenerate declines with age and is regulated by the Bmi1/p16 Ink4a pathway.