Search

Overstimulation of pancreatic β-cells can lead to dysfunction and death, prior to the clinical manifestations of type 2 diabetes (T2D). The excessive consumption of carbohydrates induces metabolic alterations that can affect the functions of the β-cells and cause their death. We analyzed the role of p53 in pancreatic β cell death in carbohydrate-supplemented Sprague Dawley rats. For four months, the animals received drinking water containing either 40% sucrose or 40% fructose. The glucose tolerance test was performed at week 15. Apoptosis was assessed with the TUNEL assay (TdT-mediated dUTP-nick end-labeling). Bax, p53, and insulin were assessed by Western blotting, immunofluorescence, and real-time quantitative PCR. Insulin, triacylglycerol, and serum glucose and fatty acids in pancreatic tissue were measured. Carbohydrate consumption promotes apoptosis and mobilization of p53 from the cytosol to rat pancreatic β-cell mitochondria before blood glucose rises. An increase in p53, miR-34a, and Bax mRNA was also detected (P < 0.001) in the sucrose group. As well as hypertriglyceridemia, hyperinsulinemia, glucose intolerance, insulin resistance, visceral fat accumulation, and increased pancreatic fatty acids in the sucrose group. Carbohydrate consumption increases p53 and its mobilization into β-cell mitochondria and coincides with the increased rate of apoptosis, which occurs before serum glucose levels rise. [ABSTRACT FROM AUTHOR]

Pdia4 has been characterized as a key protein that positively regulates β-cell failure and diabetes via ROS regulation. Here, we investigated the function and mechanism of PS1, a Pdia4 inhibitor, in β-cells and diabetes. We found that PS1 had an IC50 of 4 μM for Pdia4. Furthermore, PS1 alone and in combination with metformin significantly reversed diabetes in db/db mice, 6 to 7 mice per group, as evidenced by blood glucose, glycosylated hemoglobin A1c (HbA1c), glucose tolerance test, diabetic incidence, survival and longevity (P < 0.05 or less). Accordingly, PS1 reduced cell death and dysfunction in the pancreatic β-islets of db/db mice as exemplified by serum insulin, serum c-peptide, reactive oxygen species (ROS), islet atrophy, and homeostatic model assessment (HOMA) indices (P < 0.05 or less). Moreover, PS1 decreased cell death in the β-islets of db/db mice. Mechanistic studies showed that PS1 significantly increased cell survival and insulin secretion in Min6 cells in response to high glucose (P < 0.05 or less). This increase could be attributed to a reduction in ROS production and the activity of electron transport chain complex 1 (ETC C1) and Nox in Min6 cells by PS1. Further, we found that PS1 inhibited the enzymatic activity of Pdia4 and mitigated the interaction between Pdia4 and Ndufs3 or p22 in Min6 cells (P < 0.01 or less). Taken together, this work demonstrates that PS1 negatively regulated β-cell pathogenesis and diabetes via reduction of ROS production involving the Pdia4/Ndufs3 and Pdia4/p22 cascades. [ABSTRACT FROM AUTHOR]

Type I diabetes mellitus is an autoimmune disease characterized by the destruction of β-cells, leading to severe insulin deficiency. Environmental factors and genetic predisposition are implicated in β-cell destruction, which is the final step in a cascade of complex events. Possible triggers of β-cell destruction are activation of Fas, activation of perforin, increased generation of reactive oxygen species, increased production of inflammatory cytokines, and endoplasmic reticulum (ER) stress. In this study, we examined whether Gryllus bimaculatus (GB) extract could prevent palmitate-induced β-cell apoptosis. Exposure to GB extract prevented palmitate-induced death of MIN6 cells, a mouse pancreatic β-cell line. Palmitate increased total ceramide levels with the elevation of ceramide synthase (CerS)1, CerS4, and CerS6 expressions. Treatment with GB extract decreased the levels and expressions of ceramides related to insulin resistance. CerS4 and CerS6 overexpression, but not CerS1 overexpression, increased palmitate-induced MIN6 cell death by increasing ceramide synthesis. Oppositely, inhibition of ceramide synthesis by fumonisin B1 treatment partially recovered palmitate-induced MIN6 cell death. Furthermore, GB extract reduced ER stress (phosphorylation of PERK and eIF2α), NF-κB–iNOS signaling, and the phosphorylation of MAP kinase (JNK, p38). GB extract reduced pro-apoptotic Bax protein expression but increased anti-apoptotic Bcl2 expression. In addition, CerS4 and CerS6 overexpression aggravated impairment of insulin secretion by palmitate, but GB extract recovered it. In conclusion, GB could be a functional food that improves palmitate-induced β-cell death and insulin secretion. [ABSTRACT FROM AUTHOR]

A significantly high percentage of hospitalized COVID-19 patients with diabetes mellitus (DM) had severe conditions and were admitted to ICU. In this review, we have delineated the plausible molecular mechanisms that could explain why there are increased clinical complications in patients with DM that become critically ill when infected with SARS-CoV2. RNA viruses have been classically implicated in manifestation of new onset diabetes. SARS-CoV2 infection through cytokine storm leads to elevated levels of pro-inflammatory cytokines creating an imbalance in the functioning of T helper cells affecting multiple organs. Inflammation and Th1/Th2 cell imbalance along with Th17 have been associated with DM, which can exacerbate SARS-CoV2 infection severity. ACE-2-Ang-(1–7)-Mas axis positively modulates β-cell and cardiac tissue function and survival. However, ACE-2 receptors dock SARS-CoV2, which internalize and deplete ACE-2 and activate Renin-angiotensin system (RAS) pathway. This induces inflammation promoting insulin resistance that has positive effect on RAS pathway, causes β-cell dysfunction, promotes inflammation and increases the risk of cardiovascular complications. Further, hyperglycemic state could upregulate ACE-2 receptors for viral infection thereby increasing the severity of the diabetic condition. SARS-CoV2 infection in diabetic patients with heart conditions are linked to worse outcomes. SARS-CoV2 can directly affect cardiac tissue or inflammatory response during diabetic condition and worsen the underlying heart conditions. [ABSTRACT FROM AUTHOR]

As physiological pathways of intercellular communication produced by all cells, cytokines are involved in the pathogenesis of inflammatory insulitis as well as pivotal mediators of immune homeostasis. Proinflammatory cytokines including interleukins, interferons, transforming growth factor-β, tumor necrosis factor-α, and nitric oxide promote destructive insulitis in type 1 diabetes through amplification of the autoimmune reaction, direct toxicity to β-cells, and sensitization of islets to apoptosis. The concept that neutralization of cytokines may be of therapeutic benefit has been tested in few clinical studies, which fell short of inducing sustained remission or achieving disease arrest. Therapeutic failure is explained by the redundant activities of individual cytokines and their combinations, which are rather dispensable in the process of destructive insulitis because other cytolytic pathways efficiently compensate their deficiency. Proinflammatory cytokines are less redundant in regulation of the inflammatory reaction, displaying protective effects through restriction of effector cell activity, reinforcement of suppressor cell function, and participation in islet recovery from injury. Our analysis suggests that the role of cytokines in immune homeostasis overrides their contribution to β-cell death and may be used as potent immunomodulatory agents for therapeutic purposes rather than neutralized. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is a multi-factorial, organ-specific autoimmune disease in genetically susceptible individuals, which is characterized by a selective and progressive loss of insulin-producing β-cells. Cells mediating innate as well as adaptive immunity infiltrate pancreatic islets, thereby generating an aberrant inflammatory process called insulitis that can be mirrored by a pathologic autoantibody production and autoreactive T-cells. In tight cooperation with infiltrating innate immune cells, which secrete high levels of pro-inflammatory cytokines like IL-1β, TNFα, and INFγ effector T-cells trigger the fatal destruction process of β-cells. There is ongoing discussion on the contribution of inflammation in T1D pathogenesis, ranging from a bystander reaction of autoimmunity to a dysregulation of immune responses that initiate inflammatory processes and thereby actively promoting β-cell death. Here, we review recent advances in anti-inflammatory interventions in T1D animal models and preclinical studies and discuss their mode of action as well as their capacity to interfere with T1D development. [ABSTRACT FROM AUTHOR]