A reevaluation of the role of the unfolded protein response in islet dysfunction: maladaptation or a failure to adapt?

Endoplasmic reticulum (ER) stress caused by perturbations in ER homeostasis activates an adaptive response termed the unfolded protein response (UPR) whose function is to resolve ER stress. If unsuccessful, the UPR initiates a proapoptotic program to eliminate the malfunctioning cells from the organism. It is the activation of this proapoptotic UPR in pancreatic β-cells that has been implicated in the onset of type 2 diabetes and thus, in this context, is considered a maladaptive response. However, there is growing evidence that β-cell death in type 2 diabetes may not be caused by a maladaptive UPR but by the inhibition of the adaptive UPR. In this review, we discuss the evidence for a role of the UPR in β-cell dysfunction and death in the development of type 2 diabetes and ask the following question: Is β-cell dysfunction the result of a maladaptive UPR or a failure of the UPR to adequately adapt? The answer to this question is critically important in defining potential therapeutic strategies for the treatment and prevention of type 2 diabetes. In addition, we discuss the potential role of the adaptive UPR in staving off type 2 diabetes by enhancing β-cell mass and function in response to insulin resistance

Glucose-Induced O2 Consumption Activates Hypoxia Inducible Factors 1 and 2 in Rat Insulin-Secreting Pancreatic Beta-Cells

Glucose increases the expression of glycolytic enzymes and other hypoxia-response genes in pancreatic beta-cells. Here, we tested whether this effect results from the activation of Hypoxia-Inducible-factors (HIF) 1 and 2 in a hypoxia-dependent manner

Mice Deficient in GEM GTPase Show Abnormal Glucose Homeostasis Due to Defects in Beta-Cell Calcium Handling

Glucose-stimulated insulin secretion from beta-cells is a tightly regulated process that requires calcium flux to trigger exocytosis of insulin-containing vesicles. Regulation of calcium handling in beta-cells remains incompletely understood. Gem, a member of the RGK (Rad/Gem/Kir) family regulates calcium channel handling in other cell types, and Gem over-expression inhibits insulin release in insulin-secreting Min6 cells. The aim of this study was to explore the role of Gem in insulin secretion. We hypothesised that Gem may regulate insulin secretion and thus affect glucose tolerance in vivo

Differing Endoplasmic Reticulum Stress Response to Excess Lipogenesis versus Lipid Oversupply in Relation to Hepatic Steatosis and Insulin Resistance

Mitochondrial dysfunction and endoplasmic reticulum (ER) stress have been implicated in hepatic steatosis and insulin resistance. The present study investigated their roles in the development of hepatic steatosis and insulin resistance during de novo lipogenesis (DNL) compared to extrahepatic lipid oversupply. Male C57BL/6J mice were fed either a high fructose (HFru) or high fat (HFat) diet to induce DNL or lipid oversupply in/to the liver. Both HFru and HFat feeding increased hepatic triglyceride within 3 days (by 3.5 and 2.4 fold) and the steatosis remained persistent from 1 week onwards (p<0.01 vs Con). Glucose intolerance (iAUC increased by ∼60%) and blunted insulin-stimulated hepatic Akt and GSK3β phosphorylation (∼40–60%) were found in both feeding conditions (p<0.01 vs Con, assessed after 1 week). No impairment of mitochondrial function was found (oxidation capacity, expression of PGC1α, CPT1, respiratory complexes, enzymatic activity of citrate synthase & β-HAD). As expected, DNL was increased (∼60%) in HFru-fed mice and decreased (32%) in HFat-fed mice (all p<0.05). Interestingly, associated with the upregulated lipogenic enzymes (ACC, FAS and SCD1), two (PERK/eIF2α and IRE1/XBP1) of three ER stress pathways were significantly activated in HFru-fed mice. However, no significant ER stress was observed in HFat-fed mice during the development of hepatic steatosis. Our findings indicate that HFru and HFat diets can result in hepatic steatosis and insulin resistance without obvious mitochondrial defects via different lipid metabolic pathways. The fact that ER stress is apparent only with HFru feeding suggests that ER stress is involved in DNL per se rather than resulting from hepatic steatosis or insulin resistance

Emerging Roles of Metallothioneins in Beta Cell Pathophysiology: Beyond and above Metal Homeostasis and Antioxidant Response

Metallothioneins (MTs) are low molecular weight, cysteine-rich, metal-binding proteins whose precise biological roles have not been fully characterized. Existing evidence implicated MTs in heavy metal detoxification, metal ion homeostasis and antioxidant defense. MTs were thus categorized as protective effectors that contribute to cellular homeostasis and survival. This view has, however, been challenged by emerging evidence in different medical fields revealing novel pathophysiological roles of MTs, including inflammatory bowel disease, neurodegenerative disorders, carcinogenesis and diabetes. In the present focused review, we discuss the evidence for the role of MTs in pancreatic beta-cell biology and insulin secretion. We highlight the pattern of specific isoforms of MT gene expression in rodents and human beta-cells. We then discuss the mechanisms involved in the regulation of MTs in islets under physiological and pathological conditions, particularly type 2 diabetes, and analyze the evidence revealing adaptive and negative roles of MTs in beta-cells and the potential mechanisms involved. Finally, we underscore the unsettled questions in the field and propose some future research directions

Loss-of-function of the long non-coding RNA A830019P07Rik in mice does not affect insulin expression and secretion.

Long non-coding RNAs (lncRNAs) contribute to diverse cellular functions and the dysregulation of their expression or function can contribute to diseases, including diabetes. The contributions of lncRNAs to β-cell development, function and survival has been extensively studied in vitro. However, very little is currently known on the in vivo roles of lncRNAs in the regulation of glucose and insulin homeostasis. Here we investigated the impact of loss-of-function in mice of the lncRNA A830019P07Rik, hereafter P07Rik, which was previously reported to be associated with reduced plasma insulin levels. Compared with wild-type littermates, male and female P07Rik mutant mice did not show any defect in glycaemia and plasma insulin levels in both fed and fasted state. Furthermore, P07Rik mutant mice displayed similar glucose and insulin levels in response to an intra-peritoneal glucose tolerance test. Ex vivo, islets from mutant P07Rik released similar amount of insulin in response to increased glucose concentration as wildtype littermates. In contrast with previous reports, our characterization of P07Rik mouse mutants revealed that loss of function of this lncRNA does not affect glucose and insulin homeostasis in mice

Mechanisms of β-cell dedifferentiation in diabetes: recent findings and future research directions

Like all the cells of an organism, pancreatic β-cells originate from embryonic stem cells through a complex cellular process termed differentiation. Differentiation involves the coordinated and tightly controlled activation/repression of specific effectors and gene clusters in a time-dependent fashion thereby giving rise to particular morphological and functional cellular features. Interestingly, cellular differentiation is not a unidirectional process. Indeed, growing evidence suggests that under certain conditions, mature β-cells can lose, to various degrees, their differentiated phenotype and cellular identity and regress to a less differentiated or a precursor-like state. This concept is termed dedifferentiation and has been proposed, besides cell death, as a contributing factor to the loss of functional β-cell mass in diabetes. β-cell dedifferentiation involves: 1) the downregulation of β-cell-enriched genes, including key transcription factors, insulin, glucose metabolism genes, protein processing and secretory pathway genes, 2) the concomitant upregulation of genes suppressed or expressed at very low levels in normal β-cells; the β-cell forbidden genes, and 3) the likely upregulation of progenitor cell genes. These alterations lead to phenotypic reconfiguration of β-cells and ultimately defective insulin secretion. While the major role of glucotoxicity in β-cell dedifferentiation is well established, the precise mechanisms involved are still under investigation. This review highlights the identified molecular mechanisms implicated in β-cell dedifferentiation including oxidative stress, endoplasmic reticulum (ER) stress, inflammation and hypoxia. It discusses the role of FoxO1, MYC and inhibitor of differentiation proteins and underscores the emerging role of non-coding RNAs. Finally, it proposes a novel hypothesis of β-cell dedifferentiation as a potential adaptive mechanism to escape cell death under stress conditions