Apoptosis plays important roles in the pathophysiology of Type 2 diabetes mellitus (T2DM). The etiology of T2DM is multifactorial, including obesity-associated insulin resistance, defective insulin secretion, and loss of β-cell mass through β-cell apoptosis. β-cell apoptosis is mediated through a milliard of caspase family cascade machinery in T2DM. The glucose-induced insulin secretion is the principle pathophysiology of diabetes and insufficient insulin secretion results in chronic hyperglycemia, diabetes. Recently, hyperglycemia-induced β-cell apoptosis has been extensively studied on the balance of pro-apoptotic Bcl-2 proteins (Bad, Bid, Bik, and Bax) and anti-apoptotic Bcl family (Bcl-2 and Bcl-xL) toward apoptosis in vitro isolated islets and insulinoma cell culture. Apoptosis can only occur when the concentration of pro-apoptotic Bcl-2 exceeds that of anti-apoptotic proteins at the mitochondrial membrane of the intrinsic pathway. A bulk of recent research on hyperglycemia-induced apoptosis on β-cells unveiled complex details on glucose toxicity on β-cells in molecular levels coupled with cell membrane potential by adenosine triphosphate generation through K+ channel closure, opening Ca2+ channel and plasma membrane depolarization. Furthermore, animal models using knockout mice will shed light on the basic understanding of the pathophysiology of diabetes as a glucose metabolic disease complex, on the balance of anti-apoptotic Bcl family and pro-apoptotic genes. The cumulative knowledge will provide a better understanding of glucose metabolism at a molecular level and will lead to eventual prevention and therapeutic application for T2DM with improving medications.
Type 1 diabetes mellitus (T1DM) results from autoimmune destruction of pancreatic β-cells after an asymptomatic period over years. Insulitis activates antigen presenting cells, which trigger activating CD4+ helper-T cells, releasing chemokines/cytokines. Cytokines activate CD8+ cytotoxic-T cells, which lead to β-cell destruction. Apoptosis pathway consists of extrinsic (receptor-mediated) and intrinsic (mitochondria-driven) pathway. Extrinsic pathway includes Fas pathway to CD4+-CD8+ interaction, whereas intrinsic pathway includes mitochondria-driven pathway at a balance between anti-apoptotic B-cell lymphoma (Bcl)-2 and Bcl-xL and pro-apoptotic Bad, Bid, and Bik proteins. Activated cleaved caspse-3 is the converging point between extrinsic and intrinsic pathway. Apoptosis takes place only when pro-apoptotic proteins exceed anti-apoptotic proteins. Since the concordance rate of T1DM in identical twins is about 50%, environmental factors are involved in the development of T1DM, opening a door to find means to detect and prevent further development of autoimmune β-cell destruction for a therapeutic application.
As a means for increasing sympathetic activity, male weanling rats were given 8% sucrose solution to drink instead of water. After 5 weeks, systolic pressures measured with a tail-cuff method became appreciably elevated, and the elevation was verified when phasic pressures were later recorded directly from femoral catheters. Successful induction of sympathetic overactivity was considered a likely explanation because sucrose-ingesting rats, compared with untreated controls, had faster heart rates and larger hypotensive responses to alpha-adrenergic blockade with phentolamine. Upon graded electrical stimulation of the ventromedial hypothalamus under urethane anesthesia, resulting pressor and sympathetic nerve responses were also larger in sucrose-treated rats. By contrast, pressor responses to injections of norepinephrine or tyramine were unaffected, thereby indicating that cardiovascular sensitivity had not been enhanced by sucrose ingestion. During intravenous glucose tolerance tests, increases in plasma insulin were consistently lower in sucrose-treated than control rats even though corresponding increases in plasma glucose were just transiently higher. These results support the interpretation that chronic sucrose ingestion inhibits pancreatic insulin secretion and elevates blood pressure by stimulating the ventromedial hypothalamus to increase sympathetic activity.
Isolated rat islets were maintained in vitro in a simple perifusion system and the rate of insulin secretion was maintained throughout the period of perifusion. Exposure of the perifused islets to alloxan (20 mg. per cent) for a period of five minutes produced complete inhibition of subsequent glucose-induced insulin secretion with retention of basal secretion. Glucose, mannose and 3-0 methyl glucose provided complete or almost complete protection of the perifused islets from the inhibitory effect of alloxan on glucose-induced insulin release. The order of potencies of various hexoses to protect against alloxan toxicity in vitro was glucose (100 ⋝ 3−0 methyl glucose ⋝ mannose > 2-deoxyglucose > galactose > fructose ≫ L-glucose (0). Mannoheptulose diminished but did not abolish the protective effect of glucose against alloxan. The first phase of tolbutamide-induced secretion was retained after exposure to alloxan. This finding indicated that the beta cells were still viable and suggests that a separate receptor or transport site for tolbutamide may exist on the beta cell. The possible mechanisms by which the hexoses protect the beta cells from alloxan are discussed.
Increasing immunolocalization of gelatinases and TIMPs from tubular adenomas to adenocarcinomas coincides with a multistep process of colonic tumorigenesis.
Keywords: amyloid deposit, islet amyloid polypeptide, immunocytochemistry, pancreatic islets, type 2 diabetes to unfold disappearing water-soluble IAPP in secretary granules from dying β-cells to refold water-insoluble polymerized amyloid fibrils in transforming β-sheet conformation in IAPP-containing islet deposits 8,14-17 by immunocytochemical staining using different dilutions of rabbit antihuman IAPP antibody.
Results
Control islets.The mean islet cell numbers of extra-large, large and medium-sized islets were 120, 71 and 34 cells, respectively, representing 8, 44 and 48% in a total of 225 islets examined for nine age-matched control cases ( Table 1). The relative percentages of β-cells for insulin, α-cells for glucagon and δ-cells for somatostatin (SARIF) were about 60, 30 and 15% respectively, among all three sizes of islets (Table 1). By immunocytochemical staining, all three pancreatic hormone and IAPP staining was granular in the cytoplasm, in which insulin and IAPP staining was of variable staining intensity from moderately to strongly
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.