Concomitant Hyperglycemia Research Articles

Hemodynamics and Arterial Stiffness in Response to Oral Glucose Loading in Individuals with Type II Diabetes and Controlled Hypertension.

Type 2 diabetes (T2D), the fastest growing pandemic, is typically accompanied by vascular complications. A central hallmark of both T2D and vascular disease is insulin resistance which causes impaired glucose transport and vasoconstriction concomitantly. Those with cardiometabolic disease display greater variation in central hemodynamics and arterial elasticity, both potent predictors of cardiovascular morbidity and mortality, which may be exacerbated by concomitant hyperglycemia and hyperinsulinemia during glucose testing. Thus, elucidating central and arterial responses to glucose testing in those with T2D may identify acute vascular pathophysiologies triggered by oral glucose loading. This study compared hemodynamics and arterial stiffness to an oral glucose challenge (OGC: 50g glucose) between individuals with and without T2D. 21 healthy (48 ± 10 years) and 20 participants with clinically diagnosed T2D and controlled hypertension (52 ± 8 years) were tested. Hemodynamics and arterial compliance were assessed at baseline, and 10, 20, 30, 40, 50, and 60 min post-OGC. Heart rate increased between 20 and 60 post-OGC in both groups (p < 0.05). Central systolic blood pressure (SBP) decreased in the T2D group between 10 and 50 min post-OGC while central diastolic blood pressure (DBP) decreased in both groups from 20 to 60 post-OGC. Central SBP decreased in T2D between 10 and 50 min post-OGC and central DBP decreased in both groups between 20 and 60 min post-OGC. Brachial SBP decreased between 10 and 50 min in healthy participants, whereas both groups displayed decreases in brachial DBP between 20 and 60 min post-OGC. Arterial stiffness was unaffected. An OGC alters central and peripheral blood pressure in healthy and T2D participants similarly with no changes in arterial stiffness.

Acute kidney injury with partial Fanconi syndrome in a patient with leptospirosis: a case report

BackgroundLeptospirosis is an underdiagnosed bacterial infection with nonspecific symptoms, hence, a diagnostic challenge. Identifying a case of leptospirosis in Switzerland is uncommon. Although kidney complications are frequent in severe forms, including tubular dysfunction, observing this complication is rare in our country. We report the case of a patient with leptospirosis and kidney dysfunction, which was notable for proximal tubulopathy. This case report describes the diagnosis and management of this patient’s tubular dysfunction.Case presentationA 34-year-old Caucasian male known for alcohol and drug abuse presented to our emergency department suffering from severe pain in the lower limbs, jaundice, and fever with flu-like symptoms. Physical examination was not contributory. Blood tests showed cytopenia, elevated inflammatory markers, acute kidney injury, and altered liver function tests with predominant cholestasis. Urinalysis showed proteinuria and significant glycosuria without concomitant hyperglycemia. Leptospirosis was suspected and confirmed by both positive serum polymerase chain reaction and elevated immunoglobulin M for Leptospira interrogans. The patient was treated with intravenous amoxicillin–clavulanate and doxycycline for 7 days. After antibiotic treatment, symptoms disappeared, and kidney dysfunction completely resolved.ConclusionOur case focuses on the description of leptospirosis-related acute kidney injury with proximal tubular dysfunction, which is a rare finding in Switzerland.

High concentration of sugars is genotoxic to folate-deficient cells

Patients with type 2 diabetes mellitus (T2DM) are associated with an elevated, but poorly understood baseline of genomic instability (GIN). Expert panels are still debating on whether hyperglycemia is the key element in conferring this high GIN. Since high blood glucose and low blood folate are prevalent in T2DM, we hypothesized that high glucose may work with low folate to induce GIN. Using NCM460, CCD841 and L02 cell lines as in vitro cell models, we investigated the genotoxic effects of high sugars (HS; 1–2% glucose, fructose, galactose or sucrose) alone or in combination with folate deficiency (23 nM, FD) over a course of 7 days by the cytokinesis block micronucleus assay. We found that HS is nongenotoxic to NCM460, CCD841 and L02 cells. However, the combination of HS and FD induced significantly higher levels of micronuclei, nucleoplasmic bridges and nuclear buds. Our in vitro work demonstrates that HS is non-genotoxic under folate repletive condition, but is genotoxic under FD condition. These results provide preclinal proof of concept that concomitant hyperglycemia and low folate may explain, at least in part, the high baseline of GIN in T2DM patients, suggesting that folate levels should be kept under control in order to limit the risk of GIN and carcinogenesis in T2DM.

Study of cytokine profile in men with hypertension.

Gender differences in the risk factors' influence on the development of cardiovascular diseases determine the study of the pathogenetic causes of these features. Inflammatory is one of the mechanisms for the participation of risk factors in the development of hypertension. The aim of the study was to investigate the relationship between inflammatory biomarkers with hypertension and cardiovascular risk factors in men. The study included 60 men with hypertension who were divided into groups depending on the risk of cardiovascular events: 30 men with low risk and 30 men with high risk. 86 hypertensive patients with risk factors such as obesity, impaired glucose metabolism, impaired lipid metabolism also were examined. Biochemical parameters and a wide range of cytokines: IL-4, IL - 8, IL-10, IL-12, IL-17, IL-18, TGF-β, TNF-α, IFN-γ were estimated. The obtained results were compared with echocardiographic (EchoCG), ambulatory blood pressure monitoring (ABPM), duplex scanning of the carotid arteries. A direct correlation between the risk factors and target organs' damage - left ventricular hypertrophy, increased intima-media complex thickness, was revealed. The dependence of cytokine profile from risk of cardiovascular events in men was also revealed. We studied the contribution of individual risk factors in men in the development of hypertension and the severity of inflammation. More significant changes in the cytokine profile observed in patients with concomitant hyperglycemia, obesity and dyslipidemia. A correlation between cytokine profile and duration of hypertension also revealed. Correlation analysis revealed the relationship between ABPM parameters and levels of interleukins, HS-CRP, and fibrinogen. Biomarkers of inflammation associated with the severity of visceral obesity, with a BMI. Analysis of results also showed the relationship between hyperinsulinemia or insulin resistance and inflammatory biomarkers. The relationship of inflammation with lipid metabolism in hypertensive men was more significant than with the other studied risk factors.

Management of Glycemia in Acute Febrile Illness.

With increasing the prevalence of diabetes and prediabetes across the globe, a large number of patients with acute febrile illness (AFI) are likely to have concomitant diabetes or stress hyperglycemia. Management of associated hyperglycemia in patients with AFI is of utmost importance for early recovery and to prevent complications. There is no published literature, detailing the strategies and targets for glycemic control in AFI specifically; however, guidelines do exist for the management of hyperglycemia in hospitalized or outpatients in general. This review attempts to provide pragmatic and practical suggestions to facilitate effective and safe management of hyperglycemia in patients with AFI.

Hyperglycemia exacerbates antiretroviral drug combination induced blood-brain barrier endothelial toxicity

In this study, we sought to investigate how concomitant hyperglycemia influences the impact of combination antiretroviral therapy on blood-brain barrier (BBB) endothelial function. Immortalized human brain microvascular endothelial cell line (hCMEC/D3) was exposed to azidothymidine (AZT; a nucleoside reverse transcriptase inhibitor) and/or indinavir (IND; protease inhibitor) in normal glycemic (5.5mM) or hyperglycemic (HG; 25mM) media containing D-glucose for 24–72h. Cellular reactive oxygen species (ROS) and mitochondria-specific superoxide levels were assayed in addition to membrane potential to determine the extent of mitochondrial dysfunction. Nrf2 expression was analyzed by immunofluorescence. Our results indicated a significant increase in BBB endothelial toxicity (decreased ATP) by HG and AZT+IND with progression of time (24–72h). Concurrent HG and antiviral drug combination synergistically elevated BBB endothelial ROS induced by either condition alone. Further, HG and AZT+IND mutually interact to elicit a pronounced increase in mitochondrial superoxide levels post 24h (vs. either condition alone or controls). In addition, HG and AZT+IND complemented each other to induce potential loss of mitochondrial membrane potential. While HG or AZT+IND alone for 24h increased Nrf2 nuclear distribution, co-exposure conditions induced a potential loss of Nrf2 expression/nuclear translocation in BBB endothelium. In summary, our data strongly suggest that antiretroviral drug combination potentially interacts with concomitant HG and triggers exacerbated mitochondrial dysfunction and BBB endothelial toxicity, possibly through dysregulation of Nrf2 signaling. Thus, this study warrants the critical need for safety evaluation and monitoring of neurovascular complications of HAART regimens in HIV-infected diabetic patient cohort.

Sugar and Chromosome Stability: Clastogenic Effects of Sugars in Vitamin B6-Deficient Cells

Pyridoxal 5′-phosphate (PLP), the active form of vitamin B6, has been implicated in preventing human pathologies, such as diabetes and cancer. However, the mechanisms underlying the beneficial effects of PLP are still unclear. Using Drosophila as a model system, we show that PLP deficiency, caused either by mutations in the pyridoxal kinase-coding gene (dPdxk) or by vitamin B6 antagonists, results in chromosome aberrations (CABs). The CAB frequency in PLP-depleted cells was strongly enhanced by sucrose, glucose or fructose treatments, and dPdxk mutant cells consistently displayed higher glucose contents than their wild type counterparts, an effect that is at least in part a consequence of an acquired insulin resistance. Together, our results indicate that a high intracellular level of glucose has a dramatic clastogenic effect if combined with PLP deficiency. This is likely due to an elevated level of Advanced Glycation End-products (AGE) formation. Treatment of dPdxk mutant cells with α-lipoic acid (ALA) lowered both AGE formation and CAB frequency, suggesting a possible AGE-CAB cause-effect relationship. The clastogenic effect of glucose in PLP-depleted cells is evolutionarily conserved. RNAi-mediated silencing of PDXK in human cells or treatments with PLP inhibitors resulted in chromosome breakage, which was potentiated by glucose and reduced by ALA. These results suggest that patients with concomitant hyperglycemia and vitamin B6 deficiency may suffer chromosome damage. This might impact cancer risk, as CABs are a well-known tumorigenic factor.

Streptozotocin‐Induced Diabetes Partially Attenuates the Effects of a High‐Fat Diet on Liver and Brain Fatty Acid Composition in Mice

The current study addresses the effects of a high-fat diet on liver and brain fatty acid compositions and the interaction of that diet with diabetes in a type 1 mouse model. Adult, male, normal and streptozotocin-induced diabetic C57BL/6 mice were fed standard (14%kcal from fat) or high-fat (54%kcal from fat, hydrogenated vegetable shortening and corn oil) diets for 8weeks. Liver and whole brain total phospholipid fatty acid compositions were then determined by TLC/GC. In the liver of non-diabetic mice, the high-fat diet increased the percentages of 18:1n-9, 20:4n-6, and 22:5n-6 and decreased 18:2n-6 and 22:6n-3. Diabetes increased 16:0 in liver, and decreased 18:1n-7 and 20:4n-6. The effects of the high-fat diet on liver phospholipids in diabetic mice were similar to those in non-diabetic mice, or were of smaller magnitude. In the brain, the high-fat diet increased 18:0 and 20:4n-6 of non-diabetic, but not diabetic mice. Brain 22:5n-6 acid was increased by the high-fat diet in both non-diabetic and diabetic mice, but this increase was smaller in diabetic mice. Diabetes alone did not alter the percentage of any individual fatty acid in brain. This indicates that the effects of a high-fat diet on liver and brain phospholipid fatty acid compositions are partially attenuated by concomitant hyperglycemia with hypoinsulinemia.

Rapid progression and unusual premortal diagnosis of mucormycosis in patients with hematologic malignancies: analysis of eight patients

Mucormycosis is a rare but emerging group of life-threatening opportunistic mycoses. We described experience of eight patients who developed mucormycosis. These patients had developed hematologic malignancies, and none achieved complete remission. Six of the eight patients presented with neutropenia, five received corticosteroid, and four had concomitant hyperglycemia. The most frequent physical finding was fever, and five patients complained of facial pain, headache, or chest pain. Four patients presented with concomitant bacterial infection, pulmonary aspergillosis, or intestinal candidiasis. Premortal diagnosis of mucormycosis was made in only one patient. Postmortem biopsy or autopsy was the diagnostic tool for the other patients. Although patients who were treated with amphotericin B survived longer than those treated with micafungin or voriconazole, all patients died due to the progression of mucormycosis. Estimated median survival was 23 days. Premortal diagnosis was rarely achieved as biopsy of infected tissues was the only diagnostic tool, and four patients who revealed dual infection were diagnosed with aspergillosis or bacterial infections. In patients with a high risk of mucormycosis presenting with pain and uncontrollable fever, mucormycosis should be included in the differential diagnosis. High dosages of liposomal amphotericin B should be given and surgical debridement should be performed promptly in cases highly suggestive of mucormycosis.

Serum thyroid hormone, insulin, glucose, triglycerides and protein concentrations in normal horses: Association with topical dexamethasone usage

The aim of this study was to determine if topical application of dexamethasone affected the serum concentrations of thyroid hormones (triiodothyronine T(3) and thyroxine T(4)), glucose, triglycerides, total protein and insulin in normal horses. Ten horses were treated twice daily for 10 days with 50 g dexamethasone using an ointment formulation. Thyroid hormones and insulin were assayed using standard radioimmunoassay methods, while glucose, triglycerides and total protein were determined using a standard enzymatic method and the Biuret reaction, respectively. An increase in serum glucose and triglyceride concentrations was accompanied by 2-6-fold increases in serum insulin concentrations, but there was no change in serum total protein concentration. Insulin secretion increased with concomitant hyperglycemia and hypertriglyceridemia. A non-significant decline in T(4) secretion was noted. Serum T(3) and T(4) concentrations declined continuously below baseline values from 48 h. Glucose and insulin levels returned to baseline values 3 days after treatment withdrawal, whereas triglycerides reverted to baseline by 7 days. In contrast, baseline values of serum T(3) and T(4) were not reached by 20 days following drug withdrawal. The results indicated that topical administration of dexamethasone affected thyroid function and physiological metabolic functions, which may have implications for potential doping cases in racing horses.

Diabetes‐induced hyperglycemia is associated with inhibition of insulin pathway without NF‐κB‐p65 activation in skeletal muscle.

Obesity‐induced inflammation is associated with the onset of diabetes. Whether obesity‐related increase in adipose tissue or hyperglycemia is the initiator of this inflammation is still unknown. Nuclear‐Factor kB (NF‐κB) is a critical transcription factor in the inflammatory process but its role in diabetes onset is unclear. We hypothesized that hyperglycemia is an early modulator of key proteins in the NF‐κB cascade. 10 Streptozotocin‐(STZ)‐treated rats were compared to10 control rats. Using total, cytosolic and nuclear protein extracts from hindlimb muscles: soleus (SOL), extensor digitorum longus (EDL), gastrocnemius (GM), and liver tissue, we assessed key proteins of NF‐κB and insulin pathway. STZ treatment decreased insulin to 3.9 ± 1.2 μU/ml and induced a concomitant hyperglycemia (296.5 ± 15.6mg/dL). SOL, EDL and GM mass decreased and liver mass increased in STZ‐treated animals. p65 expression in GM, and liver increased in diabetic rats, however, there was no IκB degradation or IKK phosphorylation. Muscle p65 remained bound to IκB and did not translocate or bind to DNA. Although insulin receptor (IR) and substrate‐1 (IRS‐1) expression were similar, STZ treatment abrogated their phosphorylation. Despite upstream inactivation of insulin pathway, STZ treatment did not acutely activate the NF‐κB cascade. Therefore, it is unlikely that hyperglycemia initiates obesity‐induced inflammation.

Thrombolysis in Acute Ischaemic Stroke Pathway

Thrombolysis of appropriate and selected patients presenting with an acute ischaemic stroke within 3 h of onset with recombinant Tissue Plasminogen Activator (alteplase, r-TPA) can be implemented safely, reduce long-term disability, and is recommended by the National Institute of Health and Clinical Excellence and the Department of Health's National Stroke Strategy. We have developed an integrated and comprehensive pathway in order to achieve the above aims, which also provide guidelines for nursing in the peri-acute period and management of complications arising from the ischaemic stroke itself, from thrombolysis or from concomitant hyperglycaemia.

PANIC-ATTAC: A Mouse Model for Inducible and Reversible β-Cell Ablation

OBJECTIVE—Islet transplantations have been performed clinically, but their practical applications are limited. An extensive effort has been made toward the identification of pancreatic β-cell stem cells that has yielded many insights to date, yet targeted reconstitution of β-cell mass remains elusive. Here, we present a mouse model for inducible and reversible ablation of pancreatic β-cells named the PANIC-ATTAC (pancreatic islet β-cell apoptosis through targeted activation of caspase 8) mouse.RESEARCH DESIGN AND METHODS—We efficiently induce β-cell death through apoptosis and concomitant hyperglycemia by administration of a chemical dimerizer to the transgenic mice. In contrast to animals administered streptozotocin, the diabetes phenotype and β-cell loss are fully reversible in the PANIC-ATTAC mice, and we find significant β-cell recovery with normalization of glucose levels after 2 months.RESULTS—The rate of recovery can be enhanced by various pharmacological interventions with agents acting on the glucagon-like peptide 1 axis and agonists of peroxisome proliferator–activated receptor-γ. During recovery, we find an increased population of GLUT2+/insulin− cells in the islets of PANIC-ATTAC mice, which may represent a novel pool of potential β-cell precursors.CONCLUSIONS—The PANIC-ATTAC mouse may be used as an animal model of inducible and reversible β-cell ablation and therefore has applications in many areas of diabetes research that include identification of β-cell precursors, evaluation of glucotoxicity effects in diabetes, and examination of pharmacological interventions.

Hyponatraemia in acute heart failure is a marker of increased mortality but not when associated with hyperglycaemia

Previous studies suggest that hyponatraemia is a marker of neurohormonal activation and increased mortality in patients with acute heart failure (AHF). Although diabetes is a common co-morbidity in heart failure, no prior study has considered the impact of serum glucose on this relationship. Over four consecutive months we prospectively registered all patients admitted due to AHF. Sodium and glucose levels were determined immediately upon admission. Patients were followed through admission and for the next 6 months. Of 342 patients enrolled, complete data were available for 331 patients. Hyponatraemia (sodium <135 mmol/L) was detected in 22% of patients. However, 47% of patients with hyponatraemia had concomitant hyperglycaemia (glucose level >11 mmol/L). Hyponatraemia was associated with increased 6-month mortality (21 vs. 8%, p=0.002). This association was restricted to patients who had hyponatraemia without concomitant hyperglycaemia. The 6-month mortality of patients with and without hyponatraemia was 11% versus 10% (p=0.87) when hyperglycaemia was present versus 29% and 7% (p<0.001) when hyperglycaemia was absent. In this preliminary study, hyperglycaemia-associated hyponatraemia was present in a significant proportion of patients admitted with AHF. In patients with hyperglycaemia, hyponatraemia had no prognostic significance, whereas in patients without hyperglycaemia, hyponatraemia remained a powerful predictor of mortality. These results need confirmation in a larger study.

Cardiovascular effects of acute hyperglycaemia: pathophysiological underpinnings

High admission blood glucose levels after acute myocardial infarction are common and are associated with an increased risk of death in subjects with and without diabetes. In this review, the possible toxic effects of acute hyperglycaemia are discussed as a possible explanation for the worse prognosis in subjects with myocardial infarction and concomitant hyperglycaemia. In particular, evidence supporting the hypothesis that acute hyperglycaemia may favour the appearance of cardiovascular disease through the generation of oxidative stress is presented.

Differential early mitogen‐activated protein kinase activation in hyperglycemic ischemic brain injury in the rat

Hyperglycemia aggravates brain injury induced by focal ischemia-reperfusion. The mitogen-activated protein kinase (MAPK) members extracellular-signal regulated kinase (Erk) and c-Jun N-terminal kinase (JNK) have been proposed as mediators of ischemic brain injury, and Erk is strongly activated by combined hyperglycemia and transient global ischemia. It is unclear whether similar MAPK activation appears in focal brain ischemia with concomitant hyperglycemia. Hyperglycemia was induced in rats by an intraperitoneal bolus of glucose (2 g kg(-1)). The rats were then subjected to 90 min of transient middle cerebral artery occlusion (MCAO). Erk and JNK activation were investigated with immunofluorescence and Western blot along with infarct size measurement based on tetrazolium staining and neurological score. The hyperglycemic rats showed increased tissue damage and impaired neurological performance after 1 day compared with controls. The hyperglycemia was generally moderate (< 15 mM). Erk activation was increased after 30 min of reperfusion in the ischemic cortex of the hyperglycemic rats, while JNK activation was present on the contralateral side. Phospho-Erk immunofluorescence revealed marked neuronal activation of Erk in the ischemic cortex of hyperglycemic rats compared with controls. Besides confirming the detrimental effects of hyperglycemia on focal ischemia-reperfusion, this study shows that hyperglycemia strongly activates the pathogenic mediator Erk in the ischemic brain in the early phase of reperfusion. JNK activation at this stage is present in the nonischemic hemisphere. The functional relevance of these findings needs further investigation.

The role of regulatory T cell defects in type I diabetes and the potential of these cells for therapy.

Type I diabetes is increasing in incidence in developed countries [1]. Diabetes arises from a breakdown of tolerance to islet antigens, resulting in T cell-driven destruction of the islet cells and concomitant hyperglycemia. In this review, we explore whether this loss of tolerance results in part from a defect in the action of regulatory T cells. We draw on both human data and that obtained from NOD mice, the murine model of autoimmune diabetes. Although insulin-based therapies have been highly successful in treating diabetes, the complications of long-term hyperglycemia are still major causes of morbidity and mortality. Accordingly, we also discuss whether treatment with regulatory T cells is a viable method for restoring long-term tolerance to self-antigens in recently diagnosed or pre-diabetic individuals. Regulatory T cell therapy offers many potential advantages, including a specific and lasting dampening of inflammation. However, some significant hurdles would have to be overcome before it could become an established treatment.

Acute hyperglycaemia: a ‘new’ risk factor during myocardial infarction

High admission blood glucose levels after acute myocardial infarction are common and are associated with an increased risk of death in subjects with and without diabetes. In this review, the possible toxic action of acute hyperglycaemia is discussed in order to explain the worse prognosis in subjects with myocardial infarction and concomitant hyperglycaemia. The possible usefulness of intensive insulin treatment is also discussed.

No effects of acute hyperglycaemia and hyperinsulinaemia on skin microcirculation and endothelial markers in Type II diabetes mellitus

Background: Increased microvascular permeability is a hallmark of microangiopathy in Type I diabetes mellitus and is associated with endothelial dysfunction and haemodynamic alterations. Type II diabetes mellitus is characterized by insulin resistance and hyperinsulinaemia. The purpose of this study was to determine whether acute hyperinsulinaemia, under both normoglycaemic and hyperglycaemic conditions, increases skin capillary permeability through its effect on skin haemodynamics, capillary recruitment or circulating markers of endothelial dysfunction in Type II diabetes. Methods: Nine Type II diabetic patients without microalbuminuria, (pre‐) proliferative retinopathy or clinical neuropathy underwent three glucose clamps of 210 min., in random order, on separate days. A “standard” clamp (insulin‐infusion rate 30 mU kg−1 h−1, glucose‐target 5.0 mmol/L) was compared with a hyperinsulinaemic (insulin‐infusion rate 150 mU kg−1 h−1, glucose‐target 5.0 mmol/L) and a hyperinsulinaemic, hyperglycaemic (insulin‐infusion rate 150 mU kg−1 h−1, glucose‐target 12.0 mmol/L) clamp. Skin capillary permeability and density were measured using large‐window sodium fluorescein videodensitometry, and skin blood flow by laser Doppler flowmetry. Endothelial dysfunction was estimated from increases in soluble intercellular adhesion molecule‐1 (sICAM‐1) and von Willebrand factor antigen (vWF). Results: No differences were found in skin capillary permeability, skin haemodynamics and capillary density at the end of the three glucose clamp periods. sICAM‐1 and vWF did not increase as compared to the standard glucose clamp. sICAM‐1 (r=−0.76, p<0.05) and vWF (r=−0.71, p<0.05) correlated negatively with insulin sensitivity, but not with skin microcirculatory parameters. Conclusions: Acute hyperinsulinaemia, both with and without concomitant hyperglycaemia, does not increase skin microvascular permeability, haemodynamics or parameters of endothelial dysfunction in Type II diabetic patients. Furthermore, these data suggest that the coexistence of hyperinsulinaemia and endothelial dysfunction in Type II diabetes does not indicate a causal relationship, but may rather indicate decreased insulin sensitivity as a common underlying cause.

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.