Beta-cell Failure In Type Research Articles

Microbial phenolic metabolites improve glucose-stimulated insulin secretion and protect pancreatic beta cells against tert-butyl hydroperoxide-induced toxicity via ERKs and PKC pathways

Oxidative stress is accepted as one of the causes of beta cell failure in type 2 diabetes. Therefore, identification of natural antioxidant agents that preserve beta cell mass and function is considered an interesting strategy to prevent or treat diabetes. Recent evidences indicated that colonic metabolites derived from flavonoids could possess beneficial effects on various tissues. The aim of this work was to establish the potential anti-diabetic properties of the microbial-derived flavonoid metabolites 3,4-dihydroxyphenylacetic acid (DHPAA), 2,3-dihydroxybenzoic acid (DHBA) and 3-hydroxyphenylpropionic acid (HPPA). To this end, we tested their ability to influence beta cell function and to protect against tert-butyl hydroperoxide-induced beta cell toxicity. DHPAA and HPPA were able to potentiate glucose-stimulated insulin secretion (GSIS) in a beta cell line INS-1E and in rat pancreatic islets. Moreover, pre-treatment of cells with both compounds protected against beta cell dysfunction and death induced by the pro-oxidant. Finally, experiments with pharmacological inhibitors indicate that these effects were mediated by the activation of protein kinase C and the extracellular regulated kinases pathways. Altogether, these findings strongly suggest that the microbial-derived flavonoid metabolites DHPAA and HPPA may have anti-diabetic potential by promoting survival and function of pancreatic beta cells.

Is there a role for the adaptive immune system in pancreatic beta cell failure in type 2 diabetes?

Pancreatic beta cell failure dictates the clinical onset of type 2 diabetes, with insulin secretion insufficient to overcome peripheral tissue insulin resistance. Over the past 5-10 years, a convincing case has emerged supporting the contribution of islet inflammation to this beta cell failure. IL-1 is central to this insult, impairing insulin secretion in preclinical and clinical studies. Further, islet-infiltrating macrophages are a major source of IL-1 and other cytokines in response to elevated levels of nutrients (glucose, saturated fatty acids), endocannabinoids and islet amyloid polypeptide (IAPP). In this issue of Diabetologia, Butcher et al have further characterised immune cell subsets present in islets from individuals with type 2 diabetes (DOI: 10.1007/s00125-013-3116-5). Increased numbers of CD45(+) leucocytes were found in these islets compared with islets from healthy controls, with an elevated proportion of CD20(+) B cells within the CD45(+) population. Their data also suggest that absolute numbers of CD3(+) T cells and CD11b(+)CD11c(+) myeloid cells may be increased in islets from individuals with type 2 diabetes. While many aspects of islet inflammation await further exploration, the study from Butcher and colleagues suggests a role for immune cell-mediated inflammation early in disease pathogenesis, and supports the concept that targeting the immune system may slow continued beta cell demise in type 2 diabetes.

Are we overestimating the loss of beta cells in type 2 diabetes?

Previous work has demonstrated that beta cell amount (whether measured as beta cell mass, beta cell volume or insulin-positive area) is decreased in type 2 diabetes; however, recent findings suggest that mechanisms other than death may contribute to beta cell failure in this disease. To better characterise beta cell mass and function in type 2 diabetes, we performed morphological, ultra-structural and functional studies using histological samples and isolated islets. Pancreases from ten non-diabetic (ND) and ten matched type 2 diabetic organ donors were studied by insulin, glucagon and chromogranin A immunocytochemistry and electron microscopy (EM). Glucose-stimulated insulin secretion was assessed using isolated islets and studies were performed using independent ND islet preparations after 24 h exposure to 22.2 mmol/l glucose. Immunocytochemistry showed that the fractional islet insulin-positive area was lower in type 2 diabetic islets (54.9 ± 6.3% vs 72.1 ± 8.7%, p < 0.01), whereas glucagon (23.3 ± 5.4% vs 20.2 ± 5.3%) and chromogranin A (86.4 ± 6.1% vs 89.0 ± 5.5%) staining was similar between the two groups. EM showed that the proportion of beta cells in type 2 diabetic islets was only marginally decreased; marked beta cell degranulation was found in diabetic beta cells; these findings were all reproduced after exposing isolated ND islets to high glucose. Glucose-stimulated insulin secretion was 40–50% lower from type 2 diabetic islets (p < 0.01), which again was mimicked by culturing non-diabetic islets in high glucose. These results suggest that, at least in subgroups of type 2 diabetic patients, the loss of beta cells as assessed so far might be overestimated, possibly due to changes in beta cell phenotype other than death, also contributing to beta cell failure in type 2 diabetes.

Antioxidant treatment may protect pancreatic beta cells through the attenuation of islet fibrosis in an animal model of type 2 diabetes

Islet fibrosis could be important in the progression of pancreatic beta cell failure in type 2 diabetes. It is known that oxidative stress is involved in the pancreatic fibrosis through the activation of pancreatic stellate cells. However, no study has investigated the in vivo effects of antioxidants on islet fibrogenesis in type 2 diabetes. In this study, antioxidants (taurine or tempol) were administered in drinking water to Otsuka Long-Evans Tokushima Fatty rats, an animal model of type 2 diabetes, for 16weeks. An intraperitoneal glucose tolerance test revealed that the blood glucose levels after the glucose injection were decreased by the antioxidants. The insulin secretion after the glucose injection, which was markedly reduced in the rats, was also restored by the antioxidants. Beta cell mass and pancreatic insulin content were greater in the rats treated with the antioxidants than in the untreated rats. Beta cell apoptosis was attenuated in the rats by the antioxidants. Finally, islet fibrosis and the activation of pancreatic stellate cells were markedly diminished in the rats by the antioxidants. Our data suggest that antioxidants may protect beta cells through the attenuation of both islet fibrosis and beta cell apoptosis in type 2 diabetes.

Distinct gene expression profiles characterize cellular responses to palmitate and oleate

Obese individuals are both insulin resistant and have high levels of circulating free fatty acids (FFAs). In cell culture, saturated but not unsaturated fatty acids induce endoplasmic reticulum (ER) stress. We hypothesized that chronic exposure to low dose fatty acids would significantly attenuate the acute stress response to a saturated fatty acid challenge and that unsaturated fatty acids (oleate) would be more protective than saturated fatty acids (palmitate). The ER stress response to palmitate was reduced after low dose fatty acid exposure in human hepatoma cells. Palmitate and oleate gave distinctive transcript responses, both acutely and after chronic low dose exposure. Differentially regulated pathways included lipid, cholesterol, fatty acid, and triglyceride metabolism, and IkappaB kinase and nuclear factor kappaB kinase inflammatory cascades. Oleate reduced palmitate-induced changes significantly more than low dose palmitate and completely blocked palmitate-induced phosphoinositide 3 kinase inhibitor (PIK3IP1) as well as induction of GADD45A and B. These changes are predicted to alter the PI3 kinase pathway and the pro-apoptotic p38 MAPK pathway. We recapitulated the oleate response by small interfering RNA-mediated block of PIK3IP1 stimulation with palmitate and significantly protected cells from palmitate-mediated ER stress. We show that transcriptional responses to oleate and palmitate are distinct, broad, and often discordant. We identified several potential candidates that may direct the transcriptional networks and demonstrate that PIK3IP1 partially accounts for the protective effects of oleate.

Human Catalase Gene is Regulated by Peroxisome Proliferator Activated Receptor-gamma through a Response Element Distinct from That of Mouse

Oxidative stress has been implicated as a causal role in atherosclerosis, microvascular complications of diabetes as well as in beta cell failure in type 2 diabetes. PPARgamma agonists not only improve insulin sensitivity but also eliminate oxidative stress. In mouse, catalase, a major antioxidant enzyme, is directly regulated by PPARgamma through two PPARgamma binding elements in its promoter. This study examined the regulatory mechanisms of catalase expression in human. Expression of catalase was significantly upregulated in human primary adipocytes upon treatment with a PPARgamma agonist. However, the mouse PPARgamma response elements are not functionally conserved in human catalase promoter. In luciferase reporter assay containing human catalase promoter, PPARgamma /RXRalpha, in combination of a PPARgamma agonist significantly transactivated 19 kb of promoter and this was mediated via a novel PPARgamma response element (PPRE) at -12 kb from transcription initiation site of human catalase gene. Electrophoretic mobility shift assay showed direct binding of PPARgamma to this PPRE. Together, our results indicate that PPARgamma regulates the expression of catalase gene in human through a PPRE distinct from that of mouse, and could explain, at least in part, the observed inhibitory effects of PPARgamma on oxidative stress in human.

Genetic and biochemical pathways of β‐cell failure in type 2 diabetes

We review mechanisms of beta-cell failure in type 2 diabetes. A wealth of information indicates that it is caused by impaired insulin secretion and decreased beta-cell mass. Interestingly, there appears to be a link between these two mechanisms. The earliest reaction to peripheral insulin resistance is an increase in insulin production, owing primarily to increased secretion, and to a lesser extent to decreased clearance. Experimental animal models indicate that hyperinsulinaemia promotes an increase in beta-cell mass, largely via increased beta-cell replication. In contrast, following the onset of overt diabetes, there is a slowly progressive loss of beta-cell function and mass, both in animal models and in diabetic humans. It is of great interest that most diabetes-associated genes identified in genome-wide association studies appear to be enriched in the beta-cell and to have the potential to regulate mass and/or function. Here, we review evidence derived from experimental animal models to unravel the mechanisms underlying beta-cell dysfunction. We focus primarily on signalling pathways, as opposed to nutrient sensing, and specifically on the notion that insulin and growth factor signalling via Foxo1 in pancreatic beta-cells links insulin secretion with cellular proliferation and survival.

NAPDH oxidase mediates glucolipotoxicity-induced beta cell dysfunction – Clinical implications

An impairment of glucose-stimulated insulin secretion--reflecting decreased glucokinase expression--and a moderate decrease in beta cell mass attributable to increased apoptosis, constitute the key features of beta cell failure in type 2 diabetes. Oxidative stress, provoked by prolonged exposure to excessive levels of glucose and/or fatty acids (glucolipotoxicity), appears to be a key mediator of these defects. Oxidant-provoked JNK activation induces nuclear export of the PDX-1 transcription factor, required for expression of glucokinase and other beta cell proteins. Conversely, increases in cAMP induced by incretin hormones promote the nuclear importation of PDX-1, counteracting the diabetogenic impact of oxidant stress; this may explain the utility of measures that slow dietary carbohydrate absorption for diabetes prevention. The ability of oxidative stress to boost apoptosis in beta cells is poorly understood, but may also entail JNK activation. Recent work establishes a phagocyte-type NADPH oxidase as the chief source of glucotoxicity-mediated oxidative stress in beta cells. Since bilirubin is now known to function physiologically as an inhibitor of NADPH oxidase, and phycocyanobilin (PCB) derived from spirulina likewise can inhibit this enzyme complex, supplemental PCB may have utility in the prevention and control of diabetes, and Gilbert syndrome, associated with chronically elevated free bilirubin, may be associated with decreased diabetes risk.

Inhibition of dipeptidyl peptidase 4 by BI-1356, a new drug for the treatment of beta-cell failure in type 2 diabetes

BI 1356, a xanthine-based DPP-4 inhibitor, has reached Phase III trials. The compound efficiently inhibits dipeptidyl peptidase 4 (DPP-4) in vitro and in vivo. In vivo GLP-1 levels increase to levels at or above the levels of other DPP-4 inhibitors. Preclinical trials suggest a once-daily administration of 5 mg to be efficient, long-lasting and without known side effects.

Glucose Amplifies Fatty Acid-Induced Endoplasmic Reticulum Stress in Pancreatic β-Cells via Activation of mTORC1

BackgroundPalmitate is a potent inducer of endoplasmic reticulum (ER) stress in β-cells. In type 2 diabetes, glucose amplifies fatty-acid toxicity for pancreatic β-cells, leading to β-cell dysfunction and death. Why glucose exacerbates β-cell lipotoxicity is largely unknown. Glucose stimulates mTORC1, an important nutrient sensor involved in the regulation of cellular stress. Our study tested the hypothesis that glucose augments lipotoxicity by stimulating mTORC1 leading to increased β-cell ER stress.Principal FindingsWe found that glucose amplifies palmitate-induced ER stress by increasing IRE1α protein levels and activating the JNK pathway, leading to increased β-cell apoptosis. Moreover, glucose increased mTORC1 activity and its inhibition by rapamycin decreased β-cell apoptosis under conditions of glucolipotoxicity. Inhibition of mTORC1 by rapamycin did not affect proinsulin and total protein synthesis in β-cells incubated at high glucose with palmitate. However, it decreased IRE1α expression and signaling and inhibited JNK pathway activation. In TSC2-deficient mouse embryonic fibroblasts, in which mTORC1 is constitutively active, mTORC1 regulated the stimulation of JNK by ER stressors, but not in response to anisomycin, which activates JNK independent of ER stress. Finally, we found that JNK inhibition decreased β-cell apoptosis under conditions of glucolipotoxicity.Conclusions/SignificanceCollectively, our findings suggest that mTORC1 mediates glucose amplification of lipotoxicity, acting through activation of ER stress and JNK. Thus, mTORC1 is an important transducer of ER stress in β-cell glucolipotoxicity. Moreover, in stressed β-cells mTORC1 inhibition decreases IRE1α protein expression and JNK activity without affecting ER protein load, suggesting that mTORC1 regulates the β-cell stress response to glucose and fatty acids by modulating the synthesis and activity of specific proteins involved in the execution of the ER stress response. This novel paradigm may have important implications for understanding β-cell failure in type 2 diabetes.

The right stuff: β-cell channels, cycles, and sensors

THE VAST MAJORITY of the 200 million or so individuals with diabetes worldwide suffer from type 2 diabetes, with relative insulin deficiency arising from the failure of -cells to compensate for the prevailing insulin resistance. Indeed, it is the combination of impaired -cell function and decreased -cell mass that underlies the progression from insulin resistance with normal glucose tolerance toward clinically manifested diabetes (11). Understanding the mechanism and regulation of insulin secretion in fine molecular detail may lead to the identification of new drug targets for type 2 diabetes. This is the focus of the three review articles in this issue of the American Journal of Physiology - Endocrinology and Metabolism. Written by acknowledged leaders in the field, they are not intended to be all embracing but rather to update us on today’s understanding of the molecules and events underlying three specific facets of the regulation of insulin secretion by glucose. As we learn more about neuroendocrine cells in general and the -cell in particular, the more obvious it becomes that characterizing the “right stuff” that underlies their exquisitely well-differentiated state will be one of the great challenges of contemporary cell biology. Forty years after publication of the method for isolating pancreatic islets that allowed for the in vitro study of -cells and insulin secretion (12), we are still discovering major new molecular players as we continue to unravel the mysteries of this enigmatic cell. At the same time, genomewide association studies are providing insight into the genetic basis of type 2 diabetes, placing the spotlight squarely on the -cell (6). It has been known for many years that glucose stimulussecretion coupling depends on metabolism of the sugar. Historically, the resulting rise in the ATP/ADP ratio was considered the major if not the only metabolic signal, closing ATPsensitive K (KATP) channels, triggering a cascade of electrophysiological events, increasing cytosolic Ca 2 , and ultimately stimulating exocytosis. But this is by no means the whole story. The (often lonesome) work of pioneers such as Jean-Claude Henquin indicated the profound effect of other metabolic messengers that amplify the glucose signal once cytosolic Ca 2 is elevated, acting largely independently of the KATP channel pathway (8). Identifying these other messengers remains a work in progress as is apparent from the review by Jensen et al. (10). Lydia Aguilar-Bryan has contributed greatly to our understanding of KATP channel structure and function (4), along with Europeans including Frances Ashcroft, who deserves special mention for her original and sustained body of work from 1984 (3) to this day (2). Nobody contests the importance of the canonical KATP pathway, and obviously not Hiriart and Aguilar-Bryan (9). However, given the great attention paid to this channel in earlier reviews, it is legitimate of them to have reviewed in greater detail some of the other major players in the ionic events underlying glucose sensing in the -cell. The scholarly approach taken there (9) is to break down the cascade of electrophysiological events arising from a glucose stimulus with a detailed evaluation of the possible involvement of specific channels in each of these events. A particularly important caveat that is mentioned on several occasions, here, in the other two reviews, and previously by Aguilar-Bryan (1), is the great difference between -cells from different species and primary and transformed -cells from the same species. These differences are all too often overlooked with cavalier and misleading extrapolation from transformed rodent to primary human -cells (that are only rarely used for direct study).

Importance of Aggregated Islet Amyloid Polypeptide for the Progressive Beta-Cell Failure in Type 2 Diabetes and in Transplanted Human Islets

Importance of Aggregated Islet Amyloid Polypeptide for the Progressive Beta-Cell Failure in Type 2 Diabetes and in Transplanted Human Islets

The Role for Endoplasmic Reticulum Stress in Diabetes Mellitus

Accumulating evidence suggests that endoplasmic reticulum (ER) stress plays a role in the pathogenesis of diabetes, contributing to pancreatic beta-cell loss and insulin resistance. Components of the unfolded protein response (UPR) play a dual role in beta-cells, acting as beneficial regulators under physiological conditions or as triggers of beta-cell dysfunction and apoptosis under situations of chronic stress. Novel findings suggest that "what makes a beta-cell a beta-cell", i.e., its enormous capacity to synthesize and secrete insulin, is also its Achilles heel, rendering it vulnerable to chronic high glucose and fatty acid exposure, agents that contribute to beta-cell failure in type 2 diabetes. In this review, we address the transition from physiology to pathology, namely how and why the physiological UPR evolves to a proapoptotic ER stress response and which defenses are triggered by beta-cells against these challenges. ER stress may also link obesity and insulin resistance in type 2 diabetes. High fat feeding and obesity induce ER stress in liver, which suppresses insulin signaling via c-Jun N-terminal kinase activation. In vitro data suggest that ER stress may also contribute to cytokine-induced beta-cell death. Thus, the cytokines IL-1beta and interferon-gamma, putative mediators of beta-cell loss in type 1 diabetes, induce severe ER stress through, respectively, NO-mediated depletion of ER calcium and inhibition of ER chaperones, thus hampering beta-cell defenses and amplifying the proapoptotic pathways. A better understanding of the pathways regulating ER stress in beta-cells may be instrumental for the design of novel therapies to prevent beta-cell loss in diabetes.

Diabetes mellitus as a prothrombotic condition

Diabetes mellitus (DM) is characterized by fasting hyperglycaemia and a high risk of atherothrombotic disorders affecting the coronary, cerebral and peripheral arterial trees. The risk of myocardial infarction (MI) is 3-5 fold higher in Type 2 DM and a DM subject with no history of MI has the same risk as a non-DM subject with a past history of MI. In total around 70% of deaths are vascular with poorer outcomes to both acute events and cardiological interventions. It was proposed that clustering of vascular risk factors (hyperinsulinaemia, dysglycaemia, dyslipidaemia and hypertension) around insulin resistance (IR) accounted for the increase in risk with Type 2 DM. The importance of this became apparent with the recognition that risk clustering occurs in normoglycaemic and impaired glucose tolerance (IGT) subjects with IR, in total around 25% of the population in addition to long-standing Type 1 subjects with renal disease. Evidence indicates that thrombotic risk clustering also occurs in association with IR, suppression of fibrinolysis due to elevated concentrations of the fibrinolytic inhibitor, plasminogen activator inhibitor-1 (PAI-1) is invariable with IR and there is evidence that this is regulated by the effects of triglyceride on the PAI-1 gene promoter. Other studies indicated that prothrombotic risk (coagulation factors VII, XII and fibrinogen) also associates with the IR syndrome. The development of endothelial cell dysfunction with suppression of nitric oxide and prostacyclin synthesis, combined with platelet resistance to the anti-aggregatory effects of these hormones leads to loss of control over platelet activation. In addition, hyperglycaemia and glycation have marked effects on fibrin structure function, generating a clot which has a denser structure, resistant to fibrinolysis. The combination of increased circulating coagulation zymogens, inhibition of fibrinolysis, changes in fibrin structure/function and alterations in platelet reactivity creates a thrombotic risk clustering which underpins the development of cardiovascular disease.

Prevention of hepatic steatosis and hepatic insulin resistance in mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase 1 knockout mice

In order to investigate the role of mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase 1 (mtGPAT1) in the pathogenesis of hepatic steatosis and hepatic insulin resistance, we examined whole-body insulin action in awake mtGPAT1 knockout (mtGPAT1(-/-)) and wild-type (wt) mice after regular control diet or three weeks of high-fat feeding. In contrast to high-fat-fed wt mice, mtGPAT1(-/-) mice displayed markedly lower hepatic triacylglycerol and diacylglycerol concentrations and were protected from hepatic insulin resistance possibly due to a lower diacylglycerol-mediated PKC activation. Hepatic acyl-CoA has previously been implicated in the pathogenesis of insulin resistance. Surprisingly, compared to wt mice, mtGPAT1(-/-) mice exhibited increased hepatic insulin sensitivity despite an almost 2-fold elevation in hepatic acyl-CoA content. These data suggest that mtGPAT1 might serve as a novel target for treatment of hepatic steatosis and hepatic insulin resistance and that long chain acyl-CoA's do not mediate fat-induced hepatic insulin resistance in this model.

Progressive beta cell failure in type 2 diabetes mellitus of youth*1

The pathophysiology of type 2 diabetes mellitus (T2DM) involves insulin resistance and insulin deficiency. We report the progression in insulin sensitivity and secretion over a 6-year period in an adolescent with T2DM. This report further demonstrates that the earliest abnormality in youth T2DM is insulin resistance followed by progressive β-cell failure.

Progressive beta cell failure in type 2 diabetes mellitus of youth

The pathophysiology of type 2 diabetes mellitus (T2DM) involves insulin resistance and insulin deficiency. We report the progression in insulin sensitivity and secretion over a 6-year period in an adolescent with T2DM. This report further demonstrates that the earliest abnormality in youth T2DM is insulin resistance followed by progressive β-cell failure.

Overexpression of Repressive cAMP Response Element Modulators in High Glucose and Fatty Acid-treated Rat Islets: A COMMON MECHANISM FOR GLUCOSE TOXICITY AND LIPOTOXICITY?

The hyperlipidemia and hyperglycemia of the diabetic state accelerate beta-cell dysfunction, yet the mechanisms are not fully defined. We used rat islet-specific oligonucleotide arrays (Metabolex Rat Islet Genechips) to identify genes that are coordinately regulated by high glucose and free fatty acids (FFA). Exposure of rat islets to FFA (125 microM for 2 days) or glucose (27 mM for 4 days) reduced glucose-stimulated insulin secretion by 70 +/- 5 and 40 +/- 4%, respectively, relative to control-cultured islets. These treatments also substantially reduced the insulin content of the islets. Islet Genechips analysis revealed that the mRNA levels of cAMP response element modulator (CREM)-17X and inducible cAMP early repressor were significantly increased in both 27 mM glucose- and FFA-treated islets. Removing FFA or high glucose from the culture medium restored glucose-stimulated insulin secretion and the mRNA levels of the two CREM repressors to normal. Northern blot analysis revealed a 5-fold increase in the abundance of CREM-17X mRNA and a concomitant 50% reduction in the insulin mRNA in FFA-treated islets. Transient transfection of the insulin-secreting beta HC9 cells with CREM-17X suppressed rat insulin promoter activity by nearly 50%. Overexpression of CREM-17X in intact islets via adenovirus infection decreased islet insulin mRNA levels and insulin content and resulted in a significant decrease in glucose- or KCl-induced insulin secretion. Taken together, these data suggest that up-regulation of CREM repressors by either FFA or high glucose exacerbates beta-cell failure in type 2 diabetes by suppressing insulin gene transcription.

The pathogenesis of type 2 diabetes--new aspects and clinical consequences

Type 2 diabetes mellitus manifests itself in individuals who lose the ability to produce sufficient quantities of insulin to maintain normoglycemia in the face of insulin resistance. The ability to secrete adequate amounts of insulin depends on beta-cell function and mass. The endocrine pancreas has a remarkable capacity to adapt to conditions of increased insulin demand and only a minority of individuals fail to adapt and become diabetic with time. Secondary events that further reduce the function of beta-cells in type 2 diabetes mellitus are the so-called beta-cell gluco- and lipotoxicity: chronic stimulation of islets by high glucose and free fatty acid levels results in the reduction of insulin secretion. Part of these effects are reversible once these metabolites are normalized and the beta-cell re-exposed to a physiologic environment. The essential role of the beta-cell failure in type 2 diabetes is reminiscent to the pathophysiology of type 1 diabetes. The possible link between both diseases and the therapeutic implications are discussed.

Minireview: Secondary beta-cell failure in type 2 diabetes--a convergence of glucotoxicity and lipotoxicity.

Chronic hyperglycemia and hyperlipidemia can exert deleterious effects on beta-cell function, respectively referred to as glucotoxicity and lipotoxicity. Over time, both contribute to the progressive deterioration of glucose homeostasis characteristic of type 2 diabetes. The mechanisms of glucotoxicity involve several transcription factors and are, at least in part, mediated by generation of chronic oxidative stress. Lipotoxicity is probably mediated by accumulation of a cytosolic signal derived from the fatty acid esterification pathway. Our view that hyperglycemia is a prerequisite for lipotoxicity is supported by several recent studies performed in our laboratories. First, prolonged in vitro exposure of isolated islets to fatty acids decreases insulin gene expression in the presence of high glucose concentrations only, and glucose is rate-limiting for the incorporation of fatty acids into neutral lipids. Second, normalization of blood glucose in Zucker diabetic fatty rats prevents accumulation of triglycerides and impairment of insulin gene expression in islets, whereas normalization of plasma lipid levels is without effect. Third, high-fat feeding in Goto-Kakizaki rats significantly impairs glucose-induced insulin secretion in vitro, whereas a similar diet has no effect in normoglycemic animals. We propose that chronic hyperglycemia, independent of hyperlipidemia, is toxic for beta-cell function, whereas chronic hyperlipidemia is deleterious only in the context of concomitant hyperglycemia.