Disorders Of Glucose Homeostasis Research Articles

Might β3-adrenergic receptor agonists be useful in disorders of glucose homeostasis?

Brown and beige adipose tissues contain thermogenic fat cells that can be activated by β3-adrenergic receptor agonists. In rodents, such drugs both diminish obesity and improve glucose homeostasis. In this issue of the JCI, O'Mara et al. and Finlin and Memetimin et al. report that chronic administration of the approved β3 agonist mirabegron to human subjects was without effect on body weight or fat mass, but improved several measures of glucose homeostasis. Though the mechanisms mediating these metabolic effects are uncertain, the data suggest that β3 agonists could have therapeutic utility in disorders of glucose homeostasis.

Impact of Disturbed Glucose Homeostasis Regulated by AMPK in Endometrium on Embryo Implantation in Diabetes Mice.

The incidence of diabetes in women of childbearing age has been increasing recently and implantation failure and early abortion are important reasons for infertility in diabetic women. Glycogen synthesis and decomposition are the cores of glucose homeostasis in endometrium and AMPK is activated when cellular energy consumption increases. Embryo implantation is a complex process required huge energy. Yet the changes of glucose metabolism in endometrium and its impact on embryo implantation in diabetic women are still unclear. In this research, we established diabetic pregnancy mice model by intraperitoneal injecting streptozotocin on pregnant day 1. We first tested the changes of endometrial glucose homeostasis and embryo implantation. Next, we demonstrated abnormal activation of AMPK in the endometrium of diabetic mice and its affecting endometrial glucose homeostasis. Finally, we compared the endometrial glucose homeostasis and embryo implantation outcome in diabetic pregnant mice treated with insulin or insulin combined with metformin. The results indicated that there was disturbed glucose homeostasis associated with excessive activation of AMPK in endometrium of diabetic pregnant mice. AMPK inhibitor improved the over-activation of AMPK pathway in the endometrium, meanwhile, partially corrected the abnormal glycogen metabolism and improved the implantation. Insulin improved the disorder of endometrial glucose homeostasis and implantation of diabetic mice. Our research explores the causes of high abortion and infertility rate in diabetic women which is to provide a therapeutic reference for patients with diabetes complicated with infertility and early abortion.

Mineralocorticoids, glucose homeostasis and type 2 diabetes mellitus: The Henan Rural Cohort study

AimsWe aimed to evaluate the associations of mineralocorticoids with type 2 diabetes mellitus (T2DM) and glucose homeostasis among rural Chinese adults. MethodsA total of 2713 participants were selected from the Henan Rural Cohort study. Serum mineralocorticoids were measured by liquid chromatography-tandem mass spectrometry. Logistic regression and restricted cubic splines were employed to evaluate the associations of mineralocorticoids with pre-diabetes and T2DM. Linear regression was implemented to assess the associations of aldosterone and 11-deoxycorticosterone with different markers of glucose homeostasis by different diabetes status. ResultsElevated aldosterone and 11-deoxycorticosterone were associated with an increased prevalence of pre-diabetes and T2DM (P < 0.05), with a nonlinear dose-response trend, but the association between 11-deoxycorticosterone and T2DM was no statistical significance after adjustment. A 100% increase in ln-aldosterone was associated with a 0.029 mg/dl higher fasting plasma glucose (FPG) and a 1.2% higher HOMA2-IR among those with normal glucose tolerance (NGT), and related to a 0.034 mg/dl lower FPG, a 1.1% higher HbA1c and a 1.3% higher HOMA2-β among individuals with pre-diabetes. A 100% increment in ln-11-deoxycorticosterone was associated with a 16% increase in HbA1c and a 5.6% decrease in HOMA2-β in participants with T2DM. ConclusionsHigher aldosterone and 11-deoxycorticosterone are associated with T2DM risk and glucose homeostasis disorder among different diabetes status.

A novel individualized drug repositioning approach for predicting personalized candidate drugs for type 1 diabetes mellitus.

The existence of high cost-consuming and high rate of drug failures suggests the promotion of drug repositioning in drug discovery. Existing drug repositioning techniques mainly focus on discovering candidate drugs for a kind of disease, and are not suitable for predicting candidate drugs for an individual sample. Type 1 diabetes mellitus (T1DM) is a disorder of glucose homeostasis caused by autoimmune destruction of the pancreatic β-cell. Here, we present a novel single sample drug repositioning approach for predicting personalized candidate drugs for T1DM. Our method is based on the observation of drug-disease associations by measuring the similarities of individualized pathway aberrance induced by disease and various drugs using a Kolmogorov-Smirnov weighted Enrichment Score algorithm. Using this method, we predicted several underlying candidate drugs for T1DM. Some of them have been reported for the treatment of diabetes mellitus, and some with a current indication to treat other diseases might be repurposed to treat T1DM. This study conducts drug discovery via detecting the functional connections among disease and drug action, on a personalized or customized basis. Our framework provides a rational way for systematic personalized drug discovery of complex diseases and contributes to the future application of custom therapeutic decisions.

Retinol binding protein 4 mediates MEHP-induced glucometabolic abnormalities in HepG2 cells

Epidemiological and experimental data have implicated the role of di(2-ethylhexyl) phthalate (DEHP) and its metabolite mono(2-ethylhexyl) phthalate (MEHP) in the pathogenesis of metabolic syndrome, including the impairment of hepatic glucose metabolism. To elucidate the underlying mechanism by which DEHP or MEHP perturbs hepatic glucose homeostasis, we compared the effect of DEHP (0–200 μM) and MEHP (0–200 μM) on glucose metabolism in HepG2 cells. In this study, we found that MEHP can induce more severe impairments in glucose homeostasis than DEHP can; these include increased hepatic gluconeogenesis via receptor substrate-1/protein kinase B/fork-head box protein O1 (IRS-1/AKT/FOXO1)-mediated phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6PC) up-regulation, as well as decreased hepatic glycogen synthesis via glucokinase (GCK) inhibition and IRS-1/AKT/glycogen synthase kinase-3β (GSK-3β)-mediated glycogen synthase (GYS) inactivation. Additionally, our results demonstrated that retinol binding protein 4 (RBP4), an insulin resistance-inducing factor, plays a critical role in the MEHP-induced disorder of glucose homeostasis and the dysfunction of insulin signaling transduction, whereas the deletion of RBP4 by the clustered regularly interspaced short palindromic repeats-Cas9 (CRISPR/Cas9) significantly reversed these toxic effects. Although these should be interpreted with caution in view of limited in vivo evidence, the present study provides the first in vitro evidence for potential involvements of RBP4 in disturbance of glucose homeostasis in the MEHP-treated HepG2 cells.

Association study of apelin-APJ system genetic polymorphisms with incident metabolic syndrome in a Chinese population: a case-control study

Objectives: Apelin-APJ system has been implicated in the regulation of metabolic homeostasis. This study aimed to explore the genetic predisposition of the apelin-APJ system to metabolic syndrome. Materials And Methods: 1005 subjects were enrolled, including 448 metabolic syndrome patients and 557 controls. Seven single nucleotide polymorphisms, including rs909656, rs5975126, and rs3115757 of the apelin gene and rs7119375, rs10501367, rs9943582 and rs11544374 of the APJ gene, were genotyped. Results: For males, apelin-36 were higher in metabolic syndrome subjects compared with controls (p < 0.05). Apelin-36 were significantly lower in those with TT genotype of rs10501367 than those with CC and CT genotypes (p < 0.05), and fasting plasma glucose were higher in T allele carriers of rs10501367 and A allele carriers of rs7119375 compared with non-carriers (both p < 0.05). A significant difference in genotype distribution between diabetes mellitus patients and controls existed for both rs10501367 and rs7119375 (both p < 0.05). However, the association between apelin-APJ system genetic polymorphisms and metabolic syndrome was nonsignificant. For females, apelin-36 were higher in metabolic syndrome subjects compared with controls (p < 0.05). The association between apelin-APJ system genetic polymorphisms and apelin-36, fasting plasma glucose and diabetes mellitus was nonsignificant. However, carrying A allele in rs7119375 was associated with lower metabolic syndrome risk compared with non-carriers of A allele (odds ratio: 0.646, 95% confidence interval: 0.420–0.994, p = 0.043). Conclusions: The current findings revealed a gender-specific association of apelin-APJ system genetic polymorphisms with metabolic syndrome and glucose homeostasis disorders in a Han Chinese population.

610-P: Sphingosine Kinase 1 Dissociates Glucocorticoid-Induced Insulin Resistance and Hepatic Dyslipidemia

It is well established that chronic and/or excess glucocorticoid (GC) exposure causes glucose and lipid homeostasis disorders. Previous studies have shown that chronic glucocorticoid exposure elevates hepatic ceramide production to inhibit insulin action and increase triglyceride accumulation in the liver. Glucocorticoid treatment not only increases the levels of hepatic ceramides, but also the levels of sphingosine-1-phosphate (S1P). This is because glucocorticoids not only promote the ceramide synthetic pathway, but also increase the expression of sphingosine kinase 1 (Sphk1). Ceramides can be converted to sphingosine, which is further converted to S1P through Sphk1. Here, we reduced the expression of Sphk1 in liver to evaluate its role in chronic glucocorticoid exposure-induced glucose and lipid disorders. We found that mice with reduced hepatic Sphk1 expression had improved glucose and pyruvate tolerance, while no significant difference in insulin tolerance was found upon glucocorticoid treatment. In contrast, glucocorticoid treatment-induced hepatic steatosis and hypertriglyceridemia were exacerbated in these mice with reduced hepatic Sphk1 expression. These results are surprising, as insulin resistance is frequently associated with the development of hepatic dyslipidemia. In this case, while Sphk1 is involved in the insulin resistance induced by glucocorticoids, it plays a negative role in chronic glucocorticoid treatment-induced hepatic dyslipidemia. Here, we will report our recent analysis on the mechanism underlying the role of Sphk1, ceramides, and S1P, in chronic glucocorticoid exposure-induced metabolic disorders. Disclosure R.A. Lee: None. A. Tsay: None. M. Chang: None. N. Yiv: None. J.H. Tan: None. J. Wang: None. Funding National Institutes of Health (R01DK113019)

Ion Transporters, Channelopathies, and Glucose Disorders.

Ion channels and transporters play essential roles in excitable cells including cardiac, skeletal and smooth muscle cells, neurons, and endocrine cells. In pancreatic beta-cells, for example, potassium KATP channels link the metabolic signals generated inside the cell to changes in the beta-cell membrane potential, and ultimately regulate insulin secretion. Mutations in the genes encoding some ion transporter and channel proteins lead to disorders of glucose homeostasis (hyperinsulinaemic hypoglycaemia and different forms of diabetes mellitus). Pancreatic KATP, Non-KATP, and some calcium channelopathies and MCT1 transporter defects can lead to various forms of hyperinsulinaemic hypoglycaemia (HH). Mutations in the genes encoding the pancreatic KATP channels can also lead to different types of diabetes (including neonatal diabetes mellitus (NDM) and Maturity Onset Diabetes of the Young, MODY), and defects in the solute carrier family 2 member 2 (SLC2A2) leads to diabetes mellitus as part of the Fanconi–Bickel syndrome. Variants or polymorphisms in some ion channel genes and transporters have been reported in association with type 2 diabetes mellitus.

Kisspeptin and Glucose Homeostasis.

Kisspeptin has well-established critical roles in the control of reproduction and fertility. Recently, evidence has emerged that suggests kisspeptin may have additional roles in the regulation of glucose homeostasis. Conflicting reports on the effects of kisspeptin on insulin secretion in animal models have been published, which cannot be fully accounted for by the different kisspeptin isoforms and range of kisspeptin doses used in these studies. Human studies have demonstrated associations between circulating kisspeptin levels and measures of insulin secretion and insulin resistance; and the only published interventional study has confirmed kisspeptin enhances glucose-stimulated insulin secretion in humans. Further studies are required to elucidate the mechanisms underlying the effects of kisspeptin on the pancreatic β-cell and to determine the therapeutic potential of kisspeptin receptor agonist in the treatment of disorders of glucose homeostasis.

Serum Total Adiponectin Level Is Associated with Incident Prediabetes in Japanese Workers

Emerging evidence suggests that adiponectin secreted into the serum by adipocytes may be involved in the development of type 2 diabetes. In addition, some cross-sectional studies have suggested that adiponectin may be related to PreD (prediabetes). Thus, it is reasonable to expect that adiponectin may play a role in PreD development. However, there are still few prospective cohort studies, which could successfully demonstrate a causative relationship between adiponectin and PreD. The aim of this study was to establish the significance of Adipo (serum total adiponectin level) as a biomarker for PreD in Japanese workers. To this end, we analyzed data in our prospective occupational-based cohort study, which has been conducted since 2008. A total of 551 workers without PreD aged 20-60 years were followed-up (mean follow-up period 4.2 years). The subjects were divided into four categories based on the quartiles of baseline Adipo for each sex (male: &amp;lt; 4.9, 4.9-6.6, 6.7-8.9 and &amp;gt; 8.9 µg/ml, female: &amp;lt; 8.2, 8.2-11.1, 11.2-13.9 and &amp;gt; 13.9 µg/ml). The age- and sex-adjusted incidence of PreD significantly increased with decreasing quartile of Adipo at baseline (P for trend &amp;lt;0.001). In multivariate analyses after adjusting for age, sex, BMI, smoking habit, alcohol intake, regular exercise, HDL cholesterol, triglycerides, family history of diabetes, and hypertension, the hazard ratio of PreD was 1.64 [95% confidence interval: 1.to 2.51, P=0.02] in the second quartile and 1.33 [95% confidence interval: 0.83 to 2.11, P=0.24] in the lowest quartile, when compared with the highest quartile. Furthermore, the risk of PreD was 5% higher (P=0.04) with a per 1 µg/ml decrement of Adipo in the multivariate-adjusted model. These results suggest that decreased Adipo is a risk factor for the incidence of PreD in Japanese workers, which could assign a new role to Adipo as a biomarker for the early stage of glucose homeostasis disorders, besides being a biomarker for the development of diabetes and cardiovascular events. Disclosure A. Hata: None. M. Miyoshi: None. T. Nakao: None. T. Ichihara: None. A. Tamura: None. T. Minagawa: None. Y. Kuwamura: None. M. Funaki: Research Support; Self; Otsuka Holdings Co., Ltd., The Knowledge Cluster from the Ministry of Education, Science, and Culture of Japan. Board Member; Self; Mechanogenic C.C..

Growth and Endocrine Function in Tunisian Thalassemia Major Patients.

β-thalassemia major (β–TM) is among the most common hereditary disorders imposing high expenses on health-care system worldwide. The patient’s survival is dependent on lifetime blood transfusion which leads to iron overload and its toxicity in various organs including endocrine glands. This article provides an overview of endocrine disorders in beta-TM patients. This single center investigation enrolled 28 β-TM patients (16 males, 12 females) regularly transfused with packed red cell since early years of life. For each patient were determined: age, sex, number of transfusions received, history of splenectomy and anthropometric parameters. All patients underwent an evaluation of hormonal status including growth, gonadal, thyroid, adrenal cortex, and parathyroid glands. Dual-energy X-ray absorptiometry was used to diagnose low bone mass. Assessment of iron overload status was performed by measuring the serum ferritin concentration and the results of magnetic resonance imaging T2*. Growth retardation was found in 16 of the 28 studied patients (57 %). Thirteen among them had delayed puberty. Spontaneous puberty was achieved in 16 cases. Growth hormone (GH) deficiency was found in 10 cases (35 %). Seventeen among the studied patients (60 %) developed disorders of glucose homeostasis. Subclinical hypothyroidism was found in six patients (21 %). Intensive chelation therapy had allowed the reversibility of this complication in five cases. Adrenal Insufficiency was observed in 9 cases (32%). Hypoparathyroidism has occurred in one case. Ten of the 28 studied patients had low bone mass (35%). Twenty-three of the 28 studied patients (82%) had at least one endocrine complication.

Association of sleep disturbances with obesity, insulin resistance and the metabolic syndrome

Insufficient sleep, which has become endemic in recent years, has been variably associated with increased risk of obesity, disorders of glucose and insulin homeostasis, and the metabolic syndrome; to a lesser degree, so has excessive sleep. This review summarizes recent epidemiological and pathophysiological evidence linking sleep disturbances (primarily abnormalities of sleep duration) with obesity, insulin resistance, type 2 diabetes and the metabolic syndrome in children and adults.

Co-exposure to endocrine disruptors: effect of bisphenol A and soy extract on glucose homeostasis and related metabolic disorders in male mice.

Bisphenol A (BPA) is a xenoestrogen, which is commonly used as a monomer of polycarbonate plastics food containers and epoxy resins. Little is known about the interaction effects between xeno- and phyto- estrogens on glucose homeostasis or other metabolic disorders. The aim of this study was to examine effects of individual or combined exposure to low doses of BPA and soy extract on glucose metabolism in mice with the goal to establish its potential mechanisms. Fifty-four male mice were randomly divided into six groups. Mice were treated with soy extract at 60 or 150 mg/kg by daily gavage with or without subcutaneously administration of BPA (100 μg/kg/day) for four weeks at the same time, while the control group received a vehicle. Serum levels of fasting glucose, insulin, adiponectin, testosterone, malondialdehyde (MDA), and total antioxidant capacity (TAC) were measured. Homeostatic model assessment-β cell function (HOMA-β) index was also determined. BPA exposure induced hyperglycemia and significantly reduced HOMA-β, serum levels of insulin, adiponectin, testosterone, and TAC and noticeably enhanced MDA in BPA group compared to control one. While treatment with soy extract in high dose (150 mg/kg) significantly decreased the levels of fasting blood glucose and MDA and notably improved the serum levels of insulin, HOMA-β, and TAC compared to BPA group. Soy extract may protect against some adverse effects of BPA. These findings represent the first report suggesting a potential effect between soy extract and BPA in low doses, however, further studies are needed to confirm these results.

Micronutrients in Nonalcoholic Fatty Liver Disease Pathogenesis.

Micronutrients include electrolytes, minerals, vitamins, and carotenoids, and are required in microgram or milligram quantities for cellular metabolism. The liver plays an important role in micronutrient metabolism and this metabolism often is altered in chronic liver diseases. Here, we review how the liver contributes to micronutrient metabolism; how impaired micronutrient metabolism may be involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), a systemic disorder of energy, glucose, and lipid homeostasis; and how insights gained from micronutrient biology have informed NAFLD therapeutics. Finally, we highlight some of the challenges and opportunities that remain with investigating the contribution of micronutrients to NAFLD pathology and suggest strategies to incorporate our understanding into the care of NAFLD patients.

Polycystic ovary syndrome (PCOS) and the accompanying disorders of glucose homeostasis among girls at the time of puberty.

Polycystic ovary syndrome (PCOS) usually arises during puberty and is marked by insulin resistance, hyperinsulinemia, and hyperandrogenism. The principle is that the diagnosis of PCOS must be based on the presence of at least two of the following three criteria: chronic anovulation, hyperandrogenism (clinical or biological), and polycystic ovaries. The diagnosis of PCOS in adolescents is particularly difficult due to developmental problems in this group. Many symptoms of PCOS, including acne, menstrual irregularities, and hyperinsulinemia, are common in normal puberty. Adolescents with PCOS are at an increased risk of developing health problems later on in life, such as diabetes, cardiovascular disease, and infertility. One should reckon with the frequent occurrence of the PCOS in type 1 diabetes, when the ovaries and the adrenals are exposed to excessive insulin concentrations. Ovarian hyperandrogenism is common in adolescent girls with type 1 diabetes. Methods of treatment for an adolescent with PCOS include diet and exercise. Metformin is commonly used in young girls and adolescents with PCOS as first-line monotherapy or in combination with anti-androgen medications.

Glucocorticoids and beta-cell function.

Glucocorticoids (GCs) play a pivotal role in carbohydrate metabolism. They counteract insulin by decreasing peripheral glucose uptake and stimulating hepatic gluconeogenesis, although they are best known for inducing insulin resistance (IR). Moreover, GCs may attenuate the incretin effect. Nevertheless, their direct impact on beta cells is not fully defined. This review aims to present the current understanding of this subject. Humans exposed to GC excess display IR, impaired glucose tolerance, and eventually develop diabetes. Although their insulin levels are elevated, they present lower insulin output in response to glucose than obese individuals. Rodent models demonstrate that GC-induced IR is accompanied by compensatory beta-cell hyperplasia. GC excess with high-fat diet leads to fasting hyperglycaemia and suppressed glucose-stimulated insulin secretion (GSIS) despite increased beta cell mass. The majority of in vitro studies confirm an inhibitory GC effect on insulin secretion. The mechanism remains ambiguous but might involve its direct influence upon expression of molecules essential for glucose sensing and metabolism, enhanced glucose cycling, down-regulated insulin gene transcription, hampered insulin exocytosis, amplified alpha-adrenergic signalling, and/or increased beta-cell apoptosis. There are also reports that suggest increased GSIS after beta cell exposure to GCs in vitro. Transgenic mice with enhanced corticosterone regeneration within their beta cells present augmented secretory capacity of their islets. To summarise, GCs exert a significant role in carbohydrate balance through various mechanisms, including direct impact on beta cell function. Observed discrepancies may arise from differences in study design. A thorough understanding of GC action will provide important clinical clues for disorders of glucose homeostasis.

Ketoacidosis With Canagliflozin Prescribed for Phosphoinositide 3-Kinase Inhibitor-Induced Hyperglycemia: A Case Report.

Context. Many phosphoinositide-3-kinase (PI3K) inhibitors are under trial for cancer treatment. We present a patient taking taselisib who developed ketoacidosis within 1 week of starting canagliflozin. Case Description. A 69-year-old female patient with no previous history of diabetes mellitus was enrolled in a clinical trial for taselisib therapy in stage IV breast cancer. Hyperglycemia treatment with metformin was insufficient and not tolerated. The addition of canagliflozin daily resulted in ketoacidosis and hospitalization within 1 week. Conclusions. This case report brings together 2 poorly understood and relatively understudied disorders of glucose homeostasis: hyperglycemia due to PI3K inhibition and euglycemic ketoacidosis due to dehydration/SGLT2 inhibition. It demonstrates the complexities of glucose management in the setting of PI3K inhibition. PI3K stimulation (via insulin) in this setting is counterintuitive; therefore, non–insulin-mediated therapies (eg, metformin, thiazolidinediones) might be favored over insulin-mediated therapies.

A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk.

To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.

Management of critically ill patients with diabetes.

Disorders of glucose homeostasis, such as stress-induced hypoglycemia and hyperglycemia, are common complications in patients in the intensive care unit. Patients with preexisting diabetes mellitus (DM) are more susceptible to hyperglycemia, as well as a higher risk from glucose overcorrection, that may results in severe hypoglycemia. In critically ill patients with DM, it is recommended to maintain a blood glucose range between 140-180 mg/dL. In neurological patients and surgical patients, tighter glycemic control (i.e., 110-140 mg/d) is recommended if hypoglycemia can be properly avoided. There is limited evidence that shows that critically ill diabetic patients with a glycosylated hemoglobin levels above 7% may benefit from looser glycemic control, in order to reduce the risk of hypoglycemia and significant glycemic variability.

Urea impairs β cell glycolysis and insulin secretion in chronic kidney disease.

Disorders of glucose homeostasis are common in chronic kidney disease (CKD) and are associated with increased mortality, but the mechanisms of impaired insulin secretion in this disease remain unclear. Here, we tested the hypothesis that defective insulin secretion in CKD is caused by a direct effect of urea on pancreatic β cells. In a murine model in which CKD is induced by 5/6 nephrectomy (CKD mice), we observed defects in glucose-stimulated insulin secretion in vivo and in isolated islets. Similarly, insulin secretion was impaired in normal mouse and human islets that were cultured with disease-relevant concentrations of urea and in islets from normal mice treated orally with urea for 3 weeks. In CKD mouse islets as well as urea-exposed normal islets, we observed an increase in oxidative stress and protein O-GlcNAcylation. Protein O-GlcNAcylation was also observed in pancreatic sections from CKD patients. Impairment of insulin secretion in both CKD mouse and urea-exposed islets was associated with reduced glucose utilization and activity of phosphofructokinase 1 (PFK-1), which could be reversed by inhibiting O-GlcNAcylation. Inhibition of O-GlcNAcylation also restored insulin secretion in both mouse models. These results suggest that insulin secretory defects associated with CKD arise from elevated circulating levels of urea that increase islet protein O-GlcNAcylation and impair glycolysis.