Insulin increases H2O2-induced pancreatic beta cell death (original) (raw)
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Prolonged insulin treatment sensitizes apoptosis pathways in pancreatic beta cells
Journal of Endocrinology, 2016
Insulin resistance results from impaired insulin signaling in target tissues that leads to increased levels of insulin required to control plasma glucose levels. The cycle of hyperglycemia and hyperinsulinemia eventually leads to pancreatic cell deterioration and death by a mechanism that is yet unclear. Insulin induces ROS formation in several cell types. Furthermore, death of pancreatic cells induced by oxidative stress could be potentiated by insulin. Here, we investigated the mechanism underlying this phenomenon. Experiments were done on pancreatic cell lines (Min-6, RINm, INS-1), isolated mouse and human islets, and on cell lines derived from nonpancreatic sources. Insulin (100nM) for 24h selectively increased the production of ROS in pancreatic cells and isolated pancreatic islets, but only slightly affected the expression of antioxidant enzymes. This was accompanied by a time- and dose-dependent decrease in cellular reducing power of pancreatic cells induced by insulin and al...
Cellular death, reactive oxygen species (ROS) and diabetic complications
Cell death & disease, 2018
Chronic or intermittent hyperglycemia is associated with the development of diabetic complications. Several signaling pathways can be altered by having hyperglycemia in different tissues, producing oxidative stress, the formation of advanced glycation end products (AGEs), as well as the secretion of the pro-inflammatory cytokines and cellular death (pathological autophagy and/or apoptosis). However, the signaling pathways that are directly triggered by hyperglycemia appear to have a pivotal role in diabetic complications due to the production of reactive oxygen species (ROS), oxidative stress, and cellular death. The present review will discuss the role of cellular death in diabetic complications, and it will suggest the cause and the consequences between the hyperglycemia-induced signaling pathways and cell death. The signaling pathways discussed in this review are to be described step-by-step, together with their respective inhibitors. They involve diacylglycerol, the activation o...
Apoptosis of beta cells in diabetes mellitus
DNA and cell biology, 2014
Diabetes mellitus is a multifactorial metabolic disorder characterized by hyperglycemia. Apoptosis in beta cells has been observed in response to diverse stimuli, such as glucose, cytokines, free fatty acids, leptin, and sulfonylureas, leading to the activation of polyol, hexosamine, and diacylglycerol/protein kinase-C (DAG/PKC) pathways that mediate oxidative and nitrosative stress causing the release of different cytokines. Cytokines induce the expression of Fas and tumor necrosis factor-alpha (TNF-α) by activating the transcription factor, nuclear factor-κb, and signal transducer and activator of transcription 1 (STAT-1) in the β cells in the extrinsic pathway of apoptosis. Cytokines produced in beta cells also induce proapoptotic members of the intrinsic pathway of apoptosis. The genetic alterations in apoptosis signaling machinery and the pathogenesis of diabetes include Fas, FasL, Akt, caspases, calpain-10, and phosphatase and tensin homolog (Pten). The other gene products tha...
Diabetes, 2005
Type 1 and type 2 diabetes are characterized by progressive -cell failure. Apoptosis is probably the main form of -cell death in both forms of the disease. It has been suggested that the mechanisms leading to nutrient-and cytokine-induced -cell death in type 2 and type 1 diabetes, respectively, share the activation of a final common pathway involving interleukin (IL)-1, nuclear factor (NF)-B, and Fas. We review herein the similarities and differences between the mechanisms of -cell death in type 1 and type 2 diabetes. In the insulitis lesion in type 1 diabetes, invading immune cells produce cytokines, such as IL-1, tumor necrosis factor (TNF)-␣, and interferon (IFN)-␥.
Beta-Cell Apoptosis and Defense Mechanisms: Lessons from Type 1 Diabetes
Diabetes, 2001
Increased evidence suggests that apoptosis is the main mode of beta-cell death in early type 1 diabetes. Cytokines mediate beta-cell apoptosis, and in this article, we discuss some of the cytokine-modified genes that may contribute to beta-cell survival or death. The gene encoding for the inducible form of nitric oxide synthase is induced by interleukin (IL)-1beta or IL-1beta plus gamma-interferon in rodent and human islets, respectively. This leads to nitric oxide (NO) formation, which contributes to a major extent to beta-cell necrosis and to a minor extent to the process of beta-cell apoptosis. The main mode of cell death induced by cytokines in human beta-cells is apoptosis, whereas cytokines lead to both necrosis and apoptosis in rat and mouse beta-cells. It is suggested that the necrotic component in rodent islets is due to NO-induced mitochondrial impairment and consequent decreased ATP production. Human islets, possessing better antioxidant defenses, are able to preserve glu...
Pancreatic Beta Cell Death: Novel Potential Mechanisms in Diabetes Therapy
Journal of diabetes research, 2018
Describing the diverse molecular mechanisms (particularly immunological) involved in the death of the pancreatic beta cell in type 1 and type 2 diabetes mellitus. Beta cell death is the final event in a series of mechanisms that, up to date, have not been entirely clarified; it represents the pathophysiological mechanism in the natural history of diabetes mellitus. These mechanisms are not limited to an apoptotic process only, which is characteristic of the immune-mediated insulitis in type 1 diabetes mellitus. They also include the action of proinflammatory cytokines, the production of reactive oxygen species, DNA fragmentation (typical of necroptosis in type 1 diabetic patients), excessive production of islet amyloid polypeptide with the consequent endoplasmic reticulum stress, disruption in autophagy mechanisms, and protein complex formation, such as the inflammasome, capable of increasing oxidative stress produced by mitochondrial damage. Necroptosis, autophagy, and pyroptosis a...
Β-Cell Apoptosis in Type 2 Diabetes: Quantitative and Functional Consequences
Diabetes & Metabolism, 2008
Type 2 diabetes, the most common form of diabetes in humans, is characterized by impaired insulin secretion paralleled by a progressive decline in β-cell function and chronic insulin resistance. Several authors have showed that in type 2 diabetes there is a reduction of islet and/ or insulin-containing cell mass or volume. Regulation of the β-cell mass appears to involve a balance of β-cell replication and apoptosis but, at the molecular level, pancreatic β-cell loss by apoptosis appears to play an important role in the development of insulin deficiency and the onset and/or progression of the disease. The mechanisms favoring apoptosis in type 2 diabetic pancreatic islets and new potential therapeutic approaches to prevent β-cell death and maintain β-cell mass are discussed.
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2011
Pro-inflammatory cytokine-mediated beta cell apoptosis is activated through multiple signaling pathways involving mitochondria and endoplasmic reticulum. Activation of organelle-specific caspases has been implicated in the progression and execution of cell death. This study was therefore performed to elucidate the effects of pro-inflammatory cytokines on a possible cross-talk between the compartment-specific caspases 9 and 12 and their differential contribution to beta cell apoptosis. Moreover, the occurrence of ROS-mediated mitochondrial damage in response to beta cell toxic cytokines has been quantified. ER-specific caspase-12 was strongly activated in response to pro-inflammatory cytokines; however, its inhibition did not abolish cytokine-induced mitochondrial caspase-9 activation and loss of cell viability. In addition, there was a significant induction of oxidative mitochondrial DNA damage and elevated cardiolipin peroxidation in insulin-producing RINm5F cells and rat islet cells. Overexpression of the H 2 O 2 detoxifying enzyme catalase effectively reduced the observed cytokine-induced oxidative damage of mitochondrial structures. Taken together, the results strongly indicate that mitochondrial caspase-9 is not a downstream substrate of ERspecific caspase-12 and that pro-inflammatory cytokines cause apoptotic beta cell death through activation of caspase-9 primarily by hydroxyl radical-mediated mitochondrial damage.
Mechanisms of Pancreatic β-Cell Death in Type 1 and Type 2 Diabetes
Diabetes, 2005
Type 1 and type 2 diabetes are characterized by progressive β-cell failure. Apoptosis is probably the main form of β-cell death in both forms of the disease. It has been suggested that the mechanisms leading to nutrient- and cytokine-induced β-cell death in type 2 and type 1 diabetes, respectively, share the activation of a final common pathway involving interleukin (IL)-1β, nuclear factor (NF)-κB, and Fas. We review herein the similarities and differences between the mechanisms of β-cell death in type 1 and type 2 diabetes. In the insulitis lesion in type 1 diabetes, invading immune cells produce cytokines, such as IL-1β, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ. IL-1β and/or TNF-α plus IFN-γ induce β-cell apoptosis via the activation of β-cell gene networks under the control of the transcription factors NF-κB and STAT-1. NF-κB activation leads to production of nitric oxide (NO) and chemokines and depletion of endoplasmic reticulum (ER) calcium. The execution of β-cell...
Beta-cell apoptosis in the pathogenesis of human type 2 diabetes mellitus
European Journal of Endocrinology, 2003
Type 2 diabetes is accompanied by chronic insulin resistance and a progressive decline in b-cell function (1). Obesity is a major risk factor for the development of type 2 diabetes (2, 3) and is thought to confer increased risk for type 2 diabetes through obesity-associated insulin resistance (4). However, most people who are obese do not develop diabetes but compensate their relative insulin resistance by increasing insulin secretion (5). In rodent models of obesity without diabetes there is (as opposed to non-obese littermates) an adaptive increase in b-cell mass to meet metabolic demands (6). Although not many data are available, studies suggest that b-cell mass is also adaptively increased in non-diabetic obese humans . b-cell mass is regulated by a balance of b-cell replication and apoptosis, as well as development of new islets from exocrine pancreatic ducts (neogenesis) (9, 10). Disruption of any of the pathways of b-cell formation or increased rates of b-cell death would result in decreased b-cell mass and thus reduced capacity to produce insulin. There is controversy whether b-cell mass is decreased in type 2 diabetes mellitus (8, 11 -17). These discrepancies are in part due to the paucity of available data in humans. Furthermore, it is controversial whether b-cell apoptosis is truly increased in type 2 diabetes.