Pancreatic α Cells are Resistant to Metabolic Stress-induced Apoptosis in Type 2 Diabetes.
Ontology highlight
ABSTRACT:
SUBMITTER: Marroqui L
PROVIDER: S-EPMC4485913 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:The derangement of endoplasmic reticulum (ER) homeostasis triggers ?-cell apoptosis, leading to diabetes. Glucokinase upregulates insulin receptor substrate 2 (IRS-2) expression in ?-cells, but the role of glucokinase and IRS-2 in ER stress has been unclear. In this study, we investigated the impact of glucokinase activation by glucokinase activator (GKA) on ER stress in ?-cells. GKA administration improved ?-cell apoptosis in Akita mice, a model of ER stress-mediated diabetes. GKA increased the expression of IRS-2 in ?-cells, even under ER stress. Both glucokinase-deficient Akita mice and IRS-2-deficient Akita mice exhibited an increase in ?-cell apoptosis, compared with Akita mice. ?-cell-specific IRS-2-overexpressing (?IRS-2-Tg) Akita mice showed less ?-cell apoptosis than Akita mice. IRS-2-deficient islets were vulnerable, but ?IRS-2-Tg islets were resistant to ER stress-induced apoptosis. Meanwhile, GKA regulated the expressions of C/EBP homologous protein (CHOP) and other ER stress-related genes in an IRS-2-independent fashion in islets. GKA suppressed the expressions of CHOP and Bcl2-associated X protein (Bax) and protected against ?-cell apoptosis under ER stress in an ERK1/2-dependent, IRS-2-independent manner. Taken together, GKA ameliorated ER stress-mediated apoptosis by harmonizing IRS-2 upregulation and the IRS-2-independent control of apoptosis in ?-cells.
| S-EPMC3781485 | biostudies-literature
Project description:C-X-C Motif Chemokine Ligand 10 (CXCL10) is a pro-inflammatory chemokine specifically recognized by the ligand receptor CXCR3 which is mostly expressed in T-lymphocytes. Although CXCL10 expression and secretion have been widely associated to pancreatic islets both in non-obese diabetic (NOD) mice and in human type 1 diabetic (T1D) donors, the specific expression pattern among pancreatic endocrine cell subtypes has not been clarified yet. Therefore, the purpose of this study was to shed light on the pancreatic islet expression of CXCL10 in NOD, in C57Bl/6J and in NOD-SCID mice as well as in human T1D pancreata from new-onset T1D patients (DiViD study) compared to non-diabetic multiorgan donors from the INNODIA European Network for Pancreatic Organ Donors with Diabetes (EUnPOD). CXCL10 was expressed in pancreatic islets of normoglycaemic and new-onset diabetic NOD mice but not in C57Bl/6J and NOD-SCID mice. CXCL10 expression was increased in pancreatic islets of new-onset diabetic NOD mice compared to normoglycaemic NOD mice. In NOD mice, CXCL10 colocalized both with insulin and glucagon. Interestingly, CXCL10-glucagon colocalization rate was significantly increased in diabetic vs. normoglycaemic NOD mouse islets, indicating an increased expression of CXCL10 also in alpha-cells. CXCL10 was expressed in pancreatic islets of T1D patients but not in non-diabetic donors. The analysis of the expression pattern of CXCL10 in human T1D pancreata from DiViD study, revealed an increased colocalization rate with glucagon compared to insulin. Of note, CXCL10 was also expressed in alpha-cells residing in insulin-deficient islets (IDI), suggesting that CXCL10 expression in alpha cells is not driven by residual beta-cells and therefore may represent an independent phenomenon. In conclusion, we show that in T1D CXCL10 is expressed by alpha-cells both in NOD mice and in T1D patients, thus pointing to an additional novel role for alpha-cells in T1D pathogenesis and progression.
| S-EPMC7523508 | biostudies-literature
Project description:To determine the role of glucagon action in diet-induced and genetic type 2 diabetes (T2D), we studied high-fat-diet-induced obese (DIO) and leptin receptor-defective (LepR(-/-)) rodents with and without glucagon receptors (GcgRs). DIO and LepR(-/-),GcgR(+/+) mice both developed hyperinsulinemia, increased liver sterol response element binding protein 1c, and obesity. DIO GcgR(+/+) mice developed mild T2D, whereas LepR(-/-),GcgR(+/+) mice developed severe T2D. High-fat-fed (HFF) glucagon receptor-null mice did not develop hyperinsulinemia, increased liver sterol response element binding protein 1c mRNA, or obesity. Insulin treatment of HFF GcgR(-/-) to simulate HFF-induced hyperinsulinemia caused obesity and mild T2D. LepR(-/-),GcgR(-/-) did not develop hyperinsulinemia or hyperglycemia. Adenoviral delivery of GcgR to GcgR(-/-),LepR(-/-) mice caused the severe hyperinsulinemia and hyperglycemia of LepR(-/-) mice to appear. Spontaneous disappearance of the GcgR transgene abolished the hyperinsulinemia and hyperglycemia. In conclusion, T2D hyperglycemia requires unsuppressible hyperglucagonemia from insulin-resistant α cells and is prevented by glucagon suppression or blockade.
| S-EPMC4246985 | biostudies-literature
Project description:Type 1 diabetes (T1D) results from dysfunction of pancreatic islets β cells. Recent studies supported that endoplasmic reticulum (ER) stress takes an important role in pancreatic β cell excessive loss, resulting in T1D. Here, we aimed to review the relationship between ER stress and T1D. Additionally, we also reviewed the potential mechanisms underlying ER stress mediated T1D. Studies have shown that severe ER stress is directly involved in the pancreatic β cells destruction and pathogenesis of T1D. ER stress plays a key part in pancreatic β cells and T1D, which will help in developing new effective therapeutics for T1D.
| S-EPMC7028193 | biostudies-literature
Project description:Background and purposeApproaches to prevent selective and progressive loss of insulin-producing beta cells in Type 1 diabetes mellitus (T1DM) will help to manage this prevalent and devastating disease. Curcumin (CUR), a natural anti-inflammatory substance, suppresses diabetes-associated inflammation and cell death. However, very high doses need to be used because of poor oral bioavailability, making it difficult to translate the anti-inflammatory actions to clinical situations.Experimental approachWe have prepared biodegradable nanosystems encapsulating curcumin (nCUR), resulting in at least nine-fold improvement in oral bioavailability. Here, we tested the ability of nCUR to prevent streptozotocin (STZ)-induced inflammation and apoptosis in pancreatic islets and beta cells, in rats.Key resultsNon-fasted rats pretreated with 10 or 50 mg·kg-1 nCUR 6 h prior to STZ challenge had up to 37% reduction in the glucose levels, while plain CUR (50 mg·kg-1 ) results in 12% reduction. This treatment with nCUR was accompanied by decreased islet or beta cell death, as shown by TUNEL assay and H&E staining. Both CUR and nCUR significantly decreased levels of inflammatory cytokines in pancreatic tissue homogenates that correlated well with minimal histiocytic infiltration. Pre-treatment with nCUR, but not CUR, decreased 8-oxo-2'-deoxyguanosine, a sensitive biomarker of ROS-induced DNA damage, in pancreas. In normal rodents, daily dosing for 28 days, with nCUR (25-100 mg·kg-1 ) did not cause any deleterious health issues by the carrier.Conclusions and implicationsTogether, these data indicate a potentially translatable dose of nCUR that is safe and efficacious in improving beta cell function, which could prevent T1DM.
| S-EPMC5466524 | biostudies-literature
Project description:ObjectiveThe pathogenesis of type 1 diabetes has a strong genetic component. Genome-wide association scans recently identified novel susceptibility genes including the phosphatases PTPN22 and PTPN2. We hypothesized that PTPN2 plays a direct role in beta-cell demise and assessed PTPN2 expression in human islets and rat primary and clonal beta-cells, besides evaluating its role in cytokine-induced signaling and beta-cell apoptosis.Research design and methodsPTPN2 mRNA and protein expression was evaluated by real-time PCR and Western blot. Small interfering (si)RNAs were used to inhibit the expression of PTPN2 and downstream STAT1 in beta-cells, allowing the assessment of cell death after cytokine treatment.ResultsPTPN2 mRNA and protein are expressed in human islets and rat beta-cells and upregulated by cytokines. Transfection with PTPN2 siRNAs inhibited basal- and cytokine-induced PTPN2 expression in rat beta-cells and dispersed human islets cells. Decreased PTPN2 expression exacerbated interleukin (IL)-1beta + interferon (IFN)-gamma-induced beta-cell apoptosis and turned IFN-gamma alone into a proapoptotic signal. Inhibition of PTPN2 amplified IFN-gamma-induced STAT1 phosphorylation, whereas double knockdown of both PTPN2 and STAT1 protected beta-cells against cytokine-induced apoptosis, suggesting that STAT1 hyperactivation is responsible for the aggravation of cytokine-induced beta-cell death in PTPN2-deficient cells.ConclusionsWe identified a functional role for the type 1 diabetes candidate gene PTPN2 in modulating IFN-gamma signal transduction at the beta-cell level. PTPN2 regulates cytokine-induced apoptosis and may thereby contribute to the pathogenesis of type 1 diabetes.
| S-EPMC2682688 | biostudies-literature
Project description:Current research indicates that beta cell loss in type 2 diabetes may be attributed to beta cell dedifferentiation rather than apoptosis; however, the mechanisms by which this occurs remain poorly understood. Our previous study demonstrated that elevation of microRNA-24 (miR-24) in a diabetic setting caused beta cell dysfunction and replicative deficiency. In this study, we focused on the role of miR-24 in beta cell apoptosis and dedifferentiation under endoplasmic reticulum (ER) stress conditions. We found that miR-24 overabundance protected beta cells from thapsigargin-induced apoptosis at the cost of accelerating the impairment of glucose-stimulated insulin secretion (GSIS) and enhancing the presence of dedifferentiation markers. Ingenuity® Pathway Analysis (IPA) revealed that elevation of miR-24 had an inhibitory effect on XBP1 and ATF4, which are downstream effectors of two key branches of ER stress, by inhibiting its direct target, Ire1α. Notably, elevated miR-24 initiated another pathway that targeted Mafa and decreased GSIS function in surviving beta cells, thus guiding their dedifferentiation under ER stress conditions. Our results demonstrated that the elevated miR-24, to the utmost extent, preserves beta cell mass by inhibiting apoptosis and inducing dedifferentiation. This study not only provides a novel mechanism by which miR-24 dominates beta cell turnover under persistent metabolic stress but also offers a therapeutic consideration for treating diabetes by inducing dedifferentiated beta cells to re-differentiation.
| S-EPMC6821228 | biostudies-literature
Project description:Aims/hypothesisType 2 diabetes is a bi-hormonal disease characterised by relative hypoinsulinaemia and hyperglucagonaemia with elevated blood glucose levels. Besides pancreatic beta cell defects, a low number of beta cells (low beta cell mass) may contribute to the insufficient secretion of insulin. In this study our aim was to determine whether the alpha cell mass is also altered.MethodsUsing a point counting method, we measured the ratio of alpha to beta cell areas in pancreas samples obtained at autopsy from 50 type 2 diabetic subjects, whose beta cell mass had previously been found to be 36% lower than that of 52 non-diabetic subjects.ResultsThe topography of alpha and beta cells was similar in both groups: many alpha cells were localised in the centre of the islets and the ratio of alpha/beta cell areas increased with islet size. The average ratio was significantly higher in type 2 diabetic subjects (0.72) than in non-diabetic subjects (0.42), with, however, a large overlap between the two groups. In contrast, the alpha cell mass was virtually identical in type 2 diabetic subjects (366 mg) and non-diabetic subjects (342 mg), and was not influenced by sex, BMI or type of diabetes treatment.ConclusionsThe higher proportion of alpha to beta cells in the islets of some type 2 diabetic subjects is due to a decrease in beta cell number rather than an increase in alpha cell number. This imbalance may contribute to alterations in the normal inhibitory influence exerted by beta cells on alpha cells, and lead to the relative hyperglucagonaemia observed in type 2 diabetes.
| S-EPMC3110273 | biostudies-literature
Project description:Pancreatic beta cell failure is the hallmark of type 1 diabetes (T1D). Recent studies have suggested that pathogen recognizing receptors (PRRs) are involved in the survival, proliferation and function of pancreatic beta cells. So far, little is known about the role of alpha-protein kinase 1 (ALPK1), a newly identified cytosolic PRR specific for ADP-β-D-manno-heptose (ADP-heptose), in beta cell survival. In current study we aimed to fill the knowledge gap by investigating the role of Alpk1 in the apoptosis of MIN6 cells, a murine pancreatic beta cell line. We found that the expression of Alpk1 was significantly elevated in MIN6 cells exposed to pro-inflammatory cytokines, but not to streptozotocin, low-dose or high-dose glucose. Activation of Alpk1 by ADP heptose alone was insufficient to induce beta cell apoptosis. However, it significantly exacerbated cytokine-induced apoptosis in MIN6 cells. Mechanistic investigations showed that Alpk1 activation was potent to further induce the expression of tumor necrosis factor (TNF)-α and Fas after cytokine stimulation, possibly due to enhanced activation of the TIFA/TAK1/NF-κB signaling axis. Treatment of GLP-1 receptor agonist decreased the expression of TNF-α and Fas and improved the survival of beta cells exposed to pro-inflammatory cytokines and ADP heptose. In summary, our data suggest that Alpk1 sensitizes beta cells to cytokine-induced apoptosis by potentiating TNF-α signaling pathway, which may provide novel insight into beta cell failure and T1D development.
| S-EPMC8490819 | biostudies-literature
Project description:Excessive nitric oxide (NO) production in cytokine-activated beta cells has been implicated in beta cell disruption in type 1 diabetes. beta cells are very vulnerable to NO-induced apoptosis. However, the mechanism underlying this phenomenon is unclear. Low concentrations of NO that lead to apoptosis apparently do not cause severe DNA damage in mouse MIN6 beta cells. CHOP, a C/EBP homologous protein that is induced by endoplasmic reticulum (ER) stress and plays a role in growth arrest and cell death, was induced by a NO donor, S-nitroso-N-acetyl-D,L-penicillamine (SNAP). SNAP increased cytosolic Ca(2+), and only agents depleting ER Ca(2+) induced CHOP expression and led to apoptosis, suggesting that NO depletes ER Ca(2+). Overexpression of calreticulin increased the Ca(2+) content of ER and afforded protection to cells against NO-mediated apoptosis. Furthermore, pancreatic islets from CHOP knockout mice showed resistance to NO. We conclude that NO depletes ER Ca(2+), causes ER stress, and leads to apoptosis. Thus, ER Ca(2+) stores are a new target of NO, and the ER stress pathway is a major mechanism of NO-mediated beta cell apoptosis.
| S-EPMC58562 | biostudies-literature