Diabetic β-Cells Can Achieve Self-Protection against Oxidative Stress through an Adaptive Up-Regulation of Their Antioxidant Defenses

Background Oxidative stress (OS), through excessive and/or chronic reactive oxygen species (ROS), is a mediator of diabetes-related damages in various tissues including pancreatic β-cells. Here, we have evaluated islet OS status and β-cell response to ROS using the GK/Par rat as a model of type 2 diabetes. Methodology/Principal Findings Localization of OS markers was performed on whole pancreases. Using islets isolated from 7-day-old or 2.5-month-old male GK/Par and Wistar control rats, 1) gene expression was analyzed by qRT-PCR; 2) insulin secretion rate was measured; 3) ROS accumulation and mitochondrial polarization were assessed by fluorescence methods; 4) antioxidant contents were quantified by HPLC. After diabetes onset, OS markers targeted mostly peri-islet vascular and inflammatory areas, and not islet cells. GK/Par islets revealed in fact protected against OS, because they maintained basal ROS accumulation similar or even lower than Wistar islets. Remarkably, GK/Par insulin secretion also exhibited strong resistance to the toxic effect of exogenous H2O2 or endogenous ROS exposure. Such adaptation was associated to both high glutathione content and overexpression (mRNA and/or protein levels) of a large set of genes encoding antioxidant proteins as well as UCP2. Finally, we showed that such a phenotype was not innate but spontaneously acquired after diabetes onset, as the result of an adaptive response to the diabetic environment. Conclusions The GK/Par model illustrates the effectiveness of adaptive response to OS by beta-cells to achieve self-tolerance. It remains to be determined to what extend such islet antioxidant defenses upregulation might contribute to GK/Par beta-cell secretory dysfunction

Lithium treatment mitigates the diabetogenic effects of chronic cortico-therapy

Background and purpose: Glucocorticoids (GCs) are the main treatment for autoimmune and inflammatory disorders and are also used as immunosuppressive therapy for patients with organ transplantation. However, these treatments have several side effects, including metabolic disorders. Indeed, cortico-therapy may induce insulin resistance, glucose intolerance, disrupted insulin and glucagon secretion, excessive gluconeogenesis, leading to diabetes in susceptible individuals. Recently, lithium has been shown to alleviate deleterious effects of GCs in various diseased conditions. Experimental approach: In this study, using two rat models of GC-induced metabolic disorders, we investigated the effects of Lithium Chloride (LiCl) in the mitigation of deleterious effects of GCs. Rats were treated either with corticosterone or dexamethasone, and with or without LiCl. Animals were then assessed for glucose tolerance, insulin sensitivity, in vivo and ex vivo glucose-induced insulin secretion and hepatic gluconeogenesis. Key results: We showed that in rats chronically treated with corticosterone, lithium treatment markedly reduced insulin resistance. In addition, in rats treated with dexamethasone, lithium administration improved glucose tolerance, associated with enhanced insulin secretion in vivo. Moreover, liver gluconeogenesis was reduced upon LiCl treatment. The improvement of insulin secretion in vivo appeared to be due to an indirect regulation of β cell function, since the ex vivo assessment of insulin secretion and β cell mass in islets from animals treated with LiCl revealed no difference compared to untreated animals. Conclusion and Implications: Collectively, our data provide evidences for the beneficial effects of lithium to mitigate the adverse metabolic effects of chronic cortico-therapy

The Novel Oral Drug Subetta Exerts an Antidiabetic Effect in the Diabetic Goto-Kakizaki Rat: Comparison with Rosiglitazone

The aim of the present study was to evaluate the potential antidiabetic effects of two-component drug Subetta and its components (release-active dilutions of antibodies to β-subunit insulin receptor (RAD of Abs to β-InsR) and to endothelial nitric oxide synthase (RAD of Abs to eNOS)) in Goto-Kakizaki (Paris colony) (GK/Par) diabetic rats. Subetta was administered orally for 28 days once daily (5 mL/kg) and compared to its two components (2.5 mL/kg), Rosiglitazone (5 mg/kg), and vehicle (5 mL water/kg). At day 28, fasting plasma glucose levels were significantly decreased only in Subetta and Rosiglitazone groups as compared to vehicle (P<0.01): 147±4 mg/dL and 145±4 mg/dL and 165±4 mg/dL, respectively. The data of glucose tolerance test showed that Subetta and RAD of Abs to β-InsR (similar to Rosiglitazone) prevented significantly (P<0.01) the age-related spontaneous deterioration of glucose tolerance as seen in the control group. Subetta and RAD of Abs to β-InsR did not significantly modify the glucose-induced insulin secretion. Chronic administration of Subetta and RAD of Abs to β-InsR improves glucose control, to an extent similar to that of Rosiglitazone. We hypothesize that Subetta and RAD of Abs to β-InsR mostly act via an insulin-sensitizing effect upon target tissues

Type 2 Diabetes Mellitus and Alzheimer’s Disease: Shared Molecular Mechanisms and Potential Common Therapeutic Targets

The global prevalence of diabetes mellitus and Alzheimer’s disease is increasing alarmingly with the aging of the population. Numerous epidemiological data suggest that there is a strong association between type 2 diabetes and an increased risk of dementia. These diseases are both degenerative and progressive and share common risk factors. The amyloid cascade plays a key role in the pathophysiology of Alzheimer’s disease. The accumulation of amyloid beta peptides gradually leads to the hyperphosphorylation of tau proteins, which then form neurofibrillary tangles, resulting in neurodegeneration and cerebral atrophy. In Alzheimer’s disease, apart from these processes, the alteration of glucose metabolism and insulin signaling in the brain seems to induce early neuronal loss and the impairment of synaptic plasticity, years before the clinical manifestation of the disease. The large amount of evidence on the existence of insulin resistance in the brain during Alzheimer’s disease has led to the description of this disease as “type 3 diabetes”. Available animal models have been valuable in the understanding of the relationships between type 2 diabetes and Alzheimer’s disease, but to date, the mechanistical links are poorly understood. In this non-exhaustive review, we describe the main molecular mechanisms that may link these two diseases, with an emphasis on impaired insulin and IGF-1 signaling. We also focus on GSK3β and DYRK1A, markers of Alzheimer’s disease, which are also closely associated with pancreatic β-cell dysfunction and type 2 diabetes, and thus may represent common therapeutic targets for both diseases

Ceramide synthase 4 and de novo production of ceramides with specific N-acyl chain lengths are involved in gluco-lipotoxicity-induced apoptosis of INS-1 β-cells.

International audiencePancreatic β-cell apoptosis induced by palmitate requires high glucose concentrations. Ceramides have been suggested to be important mediators of gluco-lipotoxicity-induced β-cell apoptosis. In INS-1 β-cells, 0.4 mM palmitate with 5 mM glucose increased the levels of dihydrosphingosine and dihydroceramides, two lipid intermediates in the de novo biosynthesis of ceramides, without inducing apoptosis. Increasing glucose concentrations to 30 mM amplified palmitate-induced accumulation of dihydrosphingosine and the formation of (dihydro)-ceramides. Of note, gluco-lipotoxicity specifically induced the formation of 18:0, 22:0 and 24:1 (dihydro)-ceramide molecular species, which was associated with the up-regulation of ceramide synthase 4 (CerS4) levels. Fumonisin-B1, a ceramide synthase inhibitor, partially blocked apoptosis induced by gluco-lipotoxicity. In contrast, apoptosis was potentiated in the presence of D,L-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol, an inhibitor of glucosyl-ceramide synthase. Moreover, over-expression of CerS4 amplified ceramide production and apoptosis induced by palmitate with 30 mM glucose whereas down-regulation of CerS4 by siRNA reduced apoptosis. CerS4 also potentiates ceramide accumulation and apoptosis induced by another saturated fatty acid, stearate. Collectively, our results suggest that gluco-lipotoxicity induced β-cell apoptosis through a dual mechanism involving the de novo ceramide biosynthesis and the formation of ceramides with specific N-acyl chain lengths rather than an overall increase of ceramide content

Restitution of defective glucose-stimulated insulin secretion in diabetic GK rat by acetylcholine uncovers paradoxical stimulatory effect of β-cell muscarinic receptor activation on cAMP production

Because acetylcholine (ACh) is a recognized potentiator of glucose-stimulated insulin release in the normal beta-cell, we have studied ACh's effect on islets of the Goto-Kakizaki (GK) rat, a spontaneous model of type 2 diabetes. We first verified that ACh was able to restore the insulin secretory glucose competence of the GK beta-cell. Then, we demonstrated that in GK islets 1) ACh elicited a first-phase insulin release at low glucose, whereas it had no effect in Wistar; 2) total phospholipase C activity, ACh-induced inositol phosphate production, and intracellular free calcium concentration ([Ca2+]i) elevation were normal; 3) ACh triggered insulin release, even in the presence of thapsigargin, which induced a reduction of the ACh-induced [Ca2+]i response (suggesting that ACh produces amplification signals that augment the efficacy of elevated [Ca2+]i on GK exocytosis); 4) inhibition of protein kinase C did not affect [Ca2+]i nor the insulin release responses to ACh; and 5) inhibition of cAMP-dependent protein kinases (PKAs), adenylyl cyclases, or cAMP generation, while not affecting the [Ca2+]i response, significantly lowered the insulinotropic response to ACh (at low and high glucose). In conclusion, ACh acts mainly through activation of the cAMP/PKA pathway to potently enhance Ca2+-stimulated insulin release in the GK beta-cell and, in doing so, normalizes its defective glucose responsiveness

The Goto-Kakizaki rat is a spontaneous prototypical rodent model of polycystic ovary syndrome

International audiencePolycystic ovary syndrome (PCOS) is characterized by an oligo-anovulation, hyperandrogenism and polycystic ovarian morphology combined with major metabolic disturbances. However, despite the high prevalence and the human and economic consequences of this syndrome, its etiology remains unknown. In this study, we show that female Goto-Kakizaki (GK) rats, a type 2 diabetes mellitus model, encapsulate naturally all the reproductive and metabolic hallmarks of lean women with PCOS at puberty and in adulthood. The analysis of their gestation and of their fetuses demonstrates that this PCOS-like phenotype is developmentally programmed. GK rats also develop features of ovarian hyperstimulation syndrome. Lastly, a comparison between GK rats and a cohort of women with PCOS reveals a similar reproductive signature. Thus, this spontaneous rodent model of PCOS represents an original tool for the identification of the mechanisms involved in its pathogenesis and for the development of novel strategies for its treatment