Zhaoyun Zhang

High glucose inhibits glucose-6-phosphate dehydrogenase, leading to increased oxidative stress and β-cell apoptosis

Patients with type 2 diabetes lose β cells, but the underlying mechanisms are incompletely understood. Glucose‐6‐phosphate dehydrogenase (G6PD) is the principal source of the major intracellular reduc‐tant, NADPH, which is required by many enzymes, including enzymes of the antioxidant pathway. Previous work from our laboratory has shown that high glucose impairs G6PD activity in endothelial and kidney cells, which leads to decreased cell survival. Pancreatic β cells are highly sensitive to increased ROS. This study aimed to determine whether G6PD and NADPH play central roles in β‐cell survival. Human and mouse islets, MIN6 cell line, and G6PD deficient mice were studied. High glucose inhibited G6PD expression and activity. Inhibition of G6PD with siRNA led to increased ROS and apoptosis, decreased proliferation, and impaired insulin secretion. High glucose decreased insulin secretion, which was improved by overexpressing G6PD. G6PD‐deficient mice had smaller islets and impaired glucose tolerance compared with control mice, which suggests that G6PD deficiency per se leads to β‐cell dysfunction and death. G6PD plays an important role in β‐cell function and survival. High‐glucose‐mediated decrease in G6PD activity may provide a mechanistic explanation for the gradual loss of β cells in patients with diabetes.—Zhang, Z., Liew, C. W., Handy, D. E., Zhang, Y., Leopold, J. A., Hu, J., Guo, L., Kulkarni, R. N., Loscalzo, J., Stanton, R. C. High glucose inhibits glucose‐6‐phosphate dehydrogenase, leading to increased oxidative stress and β‐cell apoptosis. FASEB J. 24, 1497–1505 (2010). www.fasebj.org

Recurrent gain-of-function USP8 mutations in Cushing's disease

Cushings disease, also known as adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (PAs) that cause excess cortisol production, accounts for up to 85% of corticotrophin-dependent Cushings syndrome cases. However, the genetic alterations in this disease are unclear. Here, we performed whole-exome sequencing of DNA derived from 12 ACTH-secreting PAs and matched blood samples, which revealed three types of somatic mutations in a candidate gene, USP8 (encoding ubiquitin-specific protease 8), exclusively in exon 14 in 8 of 12 ACTH-secreting PAs. We further evaluated somatic USP8 mutations in additional 258 PAs by Sanger sequencing. Targeted sequencing further identified a total of 17 types of USP8 variants in 67 of 108 ACTH-secreting PAs (62.04%). However, none of these mutations was detected in other types of PAs (n = 150). These mutations aggregate within the 14-3-3 binding motif of USP8 and disrupt the interaction between USP8 and 14-3-3 protein, resulting in an elevated capacity to protect EGFR from lysosomal degradation. Accordingly, PAs with mutated USP8 display a higher incidence of EGFR expression, elevated EGFR protein abundance and mRNA expression levels of POMC, which encodes the precursor of ACTH. PAs with mutated USP8 are significantly smaller in size and have higher ACTH production than wild-type PAs. In surgically resected primary USP8-mutated tumor cells, USP8 knockdown or blocking EGFR effectively attenuates ACTH secretion. Taken together, somatic gain-of-function USP8 mutations are common and contribute to ACTH overproduction in Cushings disease. Inhibition of USP8 or EGFR is promising for treating USP8-mutated corticotrophin adenoma. Our study highlights the potentially functional mutated gene in Cushings disease and provides insights into the therapeutics of this disease.

Metabolic effects of bariatric surgery in type 2 diabetic patients with body mass index < 35 kg/m2

Aim: The aim of this meta‐analysis is to assess the metabolic effects of bariatric surgery in type 2 diabetes mellitus (T2DM) patients with body mass index (BMI) < 35 kg/m2.

Serum uric acid level and its association with metabolic syndrome and carotid atherosclerosis in patients with type 2 diabetes.

ObjectiveWe aimed to investigate whether elevated serum uric acid concentrations are associated with higher risk of metabolic syndrome (MetS) and carotid atherosclerosis in patients with type 2 diabetes.MethodsWe conducted a population-based cross-sectional survey in Shanghai, with a total of 395 men and 631 women age 41 to 92 years. The carotid artery intima-media thickness (IMT) and carotid atherosclerotic plaques (PLQ) were measured by B-mode ultrasound. MetS was defined according to the updated National Cholesterol Education Program Adult Treatment Panel III criteria for Asian Americans.ResultsUric acid levels were negatively associated with duration of diabetes, fasting plasma glucose, glycohemoglobin, eGFR, HDL-cholesterol (all P < 0.001) and positively with BMI, CRP, waist circumference, triglycerides, systolic blood pressure, ACR, HOMA-IR and IMT (all P < 0.05). In the highest quartile of uric acid levels, the risks were substantially higher for MetS [odds ratio 3.97, (95% confidence interval 2.58-6.13)] (P < 0.001 for trend) and PLQ [odds ratio 2.71 (95% confidence interval 1.62-4.47)] (p = 0.013 for trend) compared with that in the lowest quartile of uric acid levels after multiple adjustment. These associations remained significant after further adjustment for potential confounders.ConclusionsSerum uric acid level is associated with MetS and is an independent risk factor for carotid atherosclerosis in patients with type 2 diabetes.

Glucose-6-phosphate dehydrogenase-deficient mice have increased renal oxidative stress and increased albuminuria

Glucose‐6‐phosphate dehydrogenase (G6PD) is the rate‐limiting enzyme of the pentose phosphate pathway and the principal source of NADPH, a major cellular reductant, and is central to cell survival. Our previous work showed that diabetes and increased aldosterone are acquired forms of G6PD deficiency, leading to decreased G6PD activity and NADPH levels and damage to kidney tissue and endothelial cells. In this study, G6PD‐deficient mice were studied to test the hypothesis that decreased G6PD activity per se can cause changes similar to those seen in the acquired conditions of G6PD deficiency. Results show that as compared with control mice, G6PD‐deficient mice had increased oxidative stress, as manifested by decreased NADPH levels and decreased GSH levels, and increased markers of lipid peroxidation. G6PD‐deficient mice had increased protein kinase C activity, increased nuclear factor‐κΒ activity, and increased urinary albumin levels, all of which is similar to changes seen in diabetic mice. Changes persisted as the mice aged, as old G6PD‐deficient mice (17–20 mo) had higher urine albumin levels and also had evidence for increased apoptosis in the renal cortex. These results show that decreased G6PD activity per se is sufficient to cause changes similar to those seen in diabetic mice.—Xu, Y., Zhang, Z., Hu, J., Stillman, I. E., Leopold, J. A., Handy, D. E., Loscalzo, J., Stanton, R. C. Glucose‐6‐phosphate dehydrogenase‐deficient mice have increased renal oxidative stress and increased albuminuria. FASEB J. 24, 609–616 (2010). www.fasebj.org

High prevalence of chronic kidney disease in population-based patients diagnosed with type 2 diabetes in downtown Shanghai

OBJECTIVE This study aimed to evaluate the prevalence of chronic kidney disease (CKD) and the risk factors associated with CKD among Chinese patients diagnosed with type 2 diabetes aged over 30 in downtown Shanghai and to assess the relationship between CKD and diabetic retinopathy (DR). METHODS We investigated 1039 Chinese patients diagnosed with type 2 diabetes aged over 30 by randomized cluster sampling in downtown Shanghai, and 1009 patients in this study were analyzed based on data integrity. Body measurements including height, weight, waist circumference and hip circumference, resting blood pressure, fasting blood measures, and urinary albumin-to-creatinine ratio (ACR), as well as the digitally stored fundus images, were investigated. Glomerular filtration rate (GFR) was estimated using the Cockcroft-Gault equation. The prevalence of CKD was calculated, and the risk factors associated with CKD were evaluated using stepwise logistic regression. The relationship between CKD and DR was evaluated using Spearman correlation and the chi-square test. RESULTS The following were the results found in this study: (a) The prevalence rate of CKD (Stages 1-5) was 63.9% in Chinese patients diagnosed with type 2 diabetes, 8.8% in those with CKD Stage 1, 22.3% in those with CKD Stage 2, and 32.8% in those with CKD Stages 3-5 (GFR<60 ml/min/1.73 m(2)). The prevalence of CKD increased with age. (b) CKD patients were older and had higher duration of diabetes, systolic blood pressure, urea nitrogen, uric acid, creatinine, and ACR of the first urine than those without CKD. (c) Male patients had a higher percentage of CKD Stages 3-5, and female patients had a higher percentage of CKD Stages 1-2. (d) CKD was significantly associated with duration of diabetes, older age, systolic blood pressure, and serum urea nitrogen based on logistic regression analysis. (e) Of the patients without CKD, 15.6% had DR, and of those with CKD, 27.6% had DR. The decrease in GFR was significantly correlated with DR after controlling for sex, age, and albuminuria staging. CONCLUSION The high prevalence of CKD observed in Chinese patients diagnosed with type 2 diabetes aged over 30 in downtown Shanghai was similar to that in Western patients, and the cause of CKD is likely to be any of the following: type 2 diabetes, IgA nephropathy, hypertension, or any combination of these. The screening program for GFR in type 2 diabetic patients should be performed even on those with normoalbuminuria. The decrease in GFR might predict the occurrence of DR among patients diagnosed with type 2 diabetes.

Hyperglycemia Induced by Glucocorticoids in Nondiabetic Patients: A Meta-Analysis

Background/Aims: Glucocorticoids are associated with a number of side effects including the development of new-onset hyperglycemia or diabetes. The diagnosis and treatment of glucocorticoid-induced hyperglycemia are surprisingly undervalued by many health-care professionals, probably due to the lack of quality studies that assess specific reasons for and prevention of hyperglycemia. The aim of this meta-analysis was to evaluate the long-term incidence of glucocorticoid-induced hyperglycemia and diabetes in nondiabetic patients who received glucocorticoid treatment. Methods: We searched Medline, Embase, and the Cochrane Library (Central) until January 2014 for studies in which subjects received systematic glucocorticoid treatment and which evaluated whether subjects developed hyperglycemia or were diagnosed with diabetes following treatment. The primary outcome for this analysis was the incidence of hyperglycemia and the secondary outcome was the frequency of diabetes. Results: We identified 13 studies that met our inclusion criteria; 12 of the studies were retrospective or observational in design. We found that the rate at which patients developed glucocorticoid-induced hyperglycemia or diabetes was 32.3% (p = 0.003) and 18.6% (p = 0.002), respectively. Conclusions: Our meta-analysis indicated that glucocorticoid-induced hyperglycemia occurs fairly frequently and points to the need for the design of prospective, randomized, controlled studies to further investigate and better understand this medical problem.

Lipocalin-2, glucose metabolism and chronic low-grade systemic inflammation in Chinese people

BackgroundLipocalin-2 is a novel adipokine with connection to insulin resistance. In this study, we aimed to investigate the association of serum lipocalin-2 with glucose metabolism and other metabolic phenotype in a large-scale Chinese population.MethodsWe evaluated serum lipocalin-2 in a cross-sectional sample of 2519 Chinese aged from 50 to 82 year in a Shanghai downtown district by ELISA. Glucose, insulin, lipid profile, inflammatory markers, and adipokines were also measured.ResultsSerum lipocalin-2 was significantly higher in subjects with isolated impaired fasting glucose, isolated impaired glucose tolerance, combined impaired fasting glucose/impaired glucose tolerance and newly-diagnosed type 2 diabetes than in those with normal glucose regulation. Lipocalin-2 elevation was clearly associated with a higher risk for impaired glucose regulation (OR 1.30 for each 10 ng/ml increase in serum lipocalin-2, 95% CI 1.23-1.62, p = 0.009) after adjustment of age, gender, smoking, alcohol drinking, family history of diabetes, serum CRP, serum adiponectin, serum CXCL5, HOMA-IR, BMI, and waist/hip ratio. The OR for participants with impaired glucose regulation and type 2 diabetes was 1.31 (95% CI 1.21-1.69, p < 0.001).ConclusionsOur findings suggest that elevated serum lipocalin-2 is closely and independently associated with impaired glucose regulation and type 2 diabetes.

Determination of Peripheral Neuropathy Prevalence and Associated Factors in Chinese Subjects with Diabetes and Pre-Diabetes – ShangHai Diabetic neuRopathy Epidemiology and Molecular Genetics Study (SH-DREAMS)

Objective This study determined the prevalence and factors associated with peripheral neuropathy (PN) in subjects with diabetes mellitus, impaired glucose regulation (IGR), and normal glucose tolerance (NGT) in a community-based Chinese population. Research Design and Methods A total of 2035 subjects in Shanghai were classified as having NGT, IGR, or diabetes. All subjects underwent complete foot examination. PN was assessed according to the neuropathy symptom and neuropathy disability scores. Binary logistic regression was performed to analyze the contributions of factors to PN. Results The prevalence of PN was 8.4%, 2.8%, and 1.5% in diabetes mellitus, IGR, and NGT subjects, respectively (P<0.05 for diabetes vs. NGT, and IGR). The subjects with known diabetes had the highest frequency of PN (13.1%). Among the subjects without diabetes, those with PN were older, had a higher waist circumference and 2-h postprandial plasma glucose levels, and were more likely to be hypertensive. Among the IGR subjects, other than age, the 2-h postprandial plasma glucose level was an independent factor significantly associated with PN. Meanwhile, among the subjects with diabetes, PN was associated with fasting plasma glucose, duration of diabetes, and decreased estimated glomerular filtration rate. Conclusions The prevalence of PN is slightly higher in individuals with IGR than that in individuals with NGT, but small fibre damage in IGR as the earliest nerve fibre deficit may be underestimated in our study. As an independent risk factor, postprandial plasma glucose level may be an important target for strategies to prevent or improve PN in IGR subjects.

High prevalence of diabetic neuropathy in population-based patients diagnosed with type 2 diabetes in the Shanghai downtown

AIMS To determine the prevalence of diabetic peripheral neuropathy (DPN) and risk factors associated with DPN in type 2 diabetic patients. METHODS 435 diabetic patients were evaluated on complete foot examination. Body mass measurements, resting blood pressure, fasting blood measures, urinary albumin-to-creatinine ratio (ACR) and the digitally stored fundus images were investigated. RESULTS (1) The prevalence of DPN was 61.8% among the Chinese patients diagnosed with type 2 diabetes aged over 30 in the Shanghai downtown, 59.1% with vibration perception threshold > or =25 V and 13.8% with inability to feel the monofilament. (2) DPN was significantly associated with age (beta: 0.068, S.E.: 0.013, OR: 1.070, CI: 1.043-1.098, P<0.001) and HbA1c (beta: 0.224, S.E.: 0.081, OR: 1.251, CI: 1.067-1.466, P=0.006) by a logistic regression analysis. (3) The percentage of diabetic retinopathy (DR) in the DPN group (26.5%) was significantly higher than that in the non-DPN group (15.2%). (4) The percentage of macroalbuminuria in the DPN group (9.0%) was significantly higher than that in the non-DPN group (1.8%). CONCLUSIONS The prevalence of DPN observed in the Chinese patients diagnosed with type 2 diabetes aged over 30 in the Shanghai downtown reached up to 61.8% though the observations in our study might be representative of the diabetic patients of the Shanghai downtown.