Fusheng Fang

MiR-199a is overexpressed in plasma of type 2 diabetes patients which contributes to type 2 diabetes by targeting GLUT4

Abstract Decreased GLUT4 expression and impaired GLUT4 cell membrane translocation are involved in type 2 diabetes mellitus (T2DM) pathogenesis so the factors impacting GLUT4 expression may be associated with T2DM. In this study, we identified four miRNAs: miR-31, miR-93, miR-146a, and miR-199a which suppress GLUT4 expression in HEK293T cells. Subsequently, we determined expression of these four miRNAs in plasma samples of T2DM patients, T2DM susceptible individuals, and healthy controls and found miR-199a was overexpressed in patients’ plasma compared with healthy control. Because the miR-199a binding site in GLUT4 3′UTR is highly conserved among vertebrates, we detected the glucose uptake in rat L6 myoblast cells through gain- and loss-of-function of miR-199a. We found that miR-199a can repress glucose uptake in L6 cells, which was rescued by GLUT4 overexpression. These results indicate that T2DM patients may have a high level miR-199a that reduce GLUT4 expression and contribute to the insulin resistance. Hence, miR-199a may be a novel biomarker for risk estimation and classification in T2DM patients.

Hepatotoxicity induced by zoledronic acid in an aged woman with primary osteoporosis.

Zoledronic acid, a bisphosphonate, has been approved for treatment and prevention of osteoporosis. This case describes a 73-year-old woman with primary osteoporosis who developed transient hepatotoxicity after zoledronic acid (ZOL) treatment. Three days after ZOL infusion, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyltransferase (GGT) were increased by 9.9, 8.1, and 3.7 times, respectively, compared with pretreatment values. Liver protective agents were administered. The aminotransferase returned within normal ranges 12 days post-infusion. Currently, the relationship of ZOL and liver damage is not quite clear, which cannot be explained by its pharmacokinetics. The aim of this case report is to increase the clinicians awareness of the possible adverse effect on the liver, and ZOL should be cautiously administered in patients with liver disease.

Assessment of Insulin Resistance in Subjects with Normal Glucose Tolerance, Hyperinsulinemia with Normal Blood Glucose Tolerance, Impaired Glucose Tolerance, and Newly Diagnosed Type 2 Diabetes (Prediabetes Insulin Resistance Research)

Aim. To evaluate the differences in insulin resistance (IR) among subjects with normal glucose tolerance (NGT), hyperinsulinemia with NGT (HINS), impaired glucose tolerance (IGT), and newly diagnosed type 2 diabetes mellitus (T2DM). Methods. 5 NGT, 25 HINS, 25 IGT, and 25 T2DM subjects participated in this research. The hyperinsulinemic-euglycemic clamp technique (HECT) was performed in all of them to evaluate IR levels. The relative factors influencing IR were evaluated. The simple insulin sensitivity indices were calculated, and the correlation between each index and the M value was analyzed. Results. The M values of NGT, HINS, IGT, and T2DM groups were 11.88 ± 2.93 mg·kg−1·min−1, 6.23 ± 1.73 mg·kg−1·min−1, 6.37 ± 2.12 mg·kg−1·min−1, and 6.19 ± 1.89 mg·kg−1·min−1, respectively. M values in HINS, IGT, and T2DM groups were lower than those in the NGT group (P = 0.005); however, the differences among the HINS, IGT, and T2DM groups were not statistically significant (P = 0.835). The independent factors influencing the M value were waistline and fasting insulin level (FINS). The simple insulin sensitivity indices, especially Matsuda and Gutt index, were significantly associated with the M value (P < 0.01). Conclusion. IR existed in the HINS, IGT, and T2DM groups, and IR levels were consistent in the three groups. The independent factors influencing IR were waistline and FINS.

Comparison of repaglinide and metformin monotherapy as an initial therapy in Chinese patients with newly diagnosed type 2 diabetes mellitus

BACKGROUND We aimed to compare the effect of repaglinide and metformin monotherapy as an initial therapy in Chinese patients with newly diagnosed type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS In this 15-week, open-labelled, parallel-controlled, randomised study, 60 Chinese drug-naive patients with newly diagnosed T2DM were randomised (2:1) to receive repaglinide or metformin monotherapy. Primary endpoint was change in HbA1c from baseline to the end of the trial. Secondary endpoints included changes in glycaemic variability, insulin sensitivity and β-cell function. RESULTS Patients in both repaglinide and metformin groups achieved significant reductions in HbA1c (-1.8 ± 1.5 vs -1.6 ± 1.5%), FPG (fasting blood glucose) (-1.7 ± 1.7 vs -2.1 ± 1.7  mmol/l) and 2-h PPG (post-prandial glucose) (-3.8 ± 3.1 vs -3.8 ± 3.6  mmol/l), with no statistical differences between the groups. Glycaemic variability, glucose infusion rate and β-cell function were all significantly improved from baseline in the two groups (all P<0.05), without any statistical differences in the improvement between the groups. CONCLUSIONS Repaglinide and metformin achieved comparable efficacy in improving glycaemic control, reducing glycaemic variability, enhancing insulin sensitivity and ameliorating β-cell function. Therefore, repaglinide is an optional agent for initial therapy in Chinese patients with newly diagnosed T2DM.

The DPP-4 inhibitor MK0626 and exercise protect islet function in early pre-diabetic kkay mice

Dipeptidyl peptidase-4 (DPP-4) inhibitor and exercise have proven to be effective treatments for diabetes. However, the effects of these interventions in compensatory hyperinsulinemia prediabetic period are unknown. The purpose of this study was to determine if these interventions have protective effects on β-cell function and preventive effects on the onset of diabetes in prediabetic kkay mice. After 2 weeks of high-fat diet feeding, we treated 7-week-old mice with a normal diet, high-fat diet, exercise training, or the DPP-4 inhibitor for 8 weeks. C57BL/6J mice served as a normal control. Kkay mice without intervention developed diabetes at week 15, but no diabetic mice were observed in the DPP-4I or exercise groups as well as the normal control group. The DPP-4I and exercise groups showed improved body weight, blood glucose level, glucose tolerance, insulin sensitivity, islet area, and islet morphology. In addition, the proportion of Ki67-positive β-cells in the treatment groups was obviously higher than that in the untreated groups. MafA (V-maf musculoaponeurotic fibrosarcoma oncogene homolog A) expression in the treated groups increased markedly. However PDX-1 (pancreatic and duodenal homeobox-1) expression did not differ significantly among the groups. The results show that exercise and DPP-4I treatment conducted during the hyperinsulinemic prediabetic stage contribute to the maintenance of β-cell function and morphology, enhance β-cell proliferation, extend the compensatory insulin hypersecretion period, and delay disease onset. The expression of PDX-1 was not altered significantly during the early stages of diabetes. However, the reduced expression of the insulin transcription factor MafA may play an important role in the development of prediabetes.

Fasting glucose level is associated with nocturnal hypoglycemia in elderly male patients with type 2 diabetes

Abstract Background: Nocturnal hypoglycemia was a common and serious problem among patients with type 2 diabetes (T2DM), especially in the elderly. This study investigated whether fasting glucose was an indicator of nocturnal hypoglycemia in elderly male patients with T2DM. Methods: A total of 291 elderly male type 2 diabetic patients who received continuous glucose monitoring (CGM) between January 2007 and January 2011 were enrolled in the study. The association of fasting glucose and nocturnal hypoglycemia based on CGM data was analyzed, comparing with bedtime glucose. Results: Based on CGM data, patients with nocturnal hypoglycemia had significantly lower fasting glucose (5.88 ± 1.29 versus 6.92 ± 1.32 mmol/L) and bedtime glucose (7.33 ± 1.70 versus 8.01 ± 1.95 mmol/L) than patients without nocturnal hypoglycemia (both p < 0.01). Compared with the highest quartile, the lowest quartile of fasting glucose had a significantly increased risk of nocturnal hypoglycemia after the multiple adjustments (pfor trend < 0.001). However, this association did not appear in bedtime glucose. When the prediction of nocturnal hypoglycemia either by fasting glucose or bedtime glucose using the area under receiver operating characteristic (ROC) curve, fasting glucose but not bedtime glucose, was an indicator of nocturnal hypoglycemia, with an area under the ROC curve (AUC) of 0.714 (95% CI: 0.653 ∼ 0.774, p < 0.001). On the ROC curve, the Youden index was maximal when fasting glucose was 6.1 mmol/L. Conclusions: Fasting glucose may be a convenient and clinically useful indicator of nocturnal hypoglycemia in elderly male patients with T2DM. Risk of nocturnal hypoglycemia significantly increased when fasting glucose was less than 6.1 mmol/L.

Effects of body mass index and weight change on mortality in older men with impaired glucose regulation

Objectives: To assess the effect of baseline body mass index (BMI) status and weight change on mortality in older men with impaired glucose regulation (IGR). Methods: Eight hundred eighty‐five men with IGR aged 60 to 90 were included. Baseline and endpoint weight were measured. All‐cause and cardiovascular mortality were observed during a median follow‐up period of 10 years. Multivariate Cox regressions were used to estimate associations between BMI, weight change and mortality. Results: Relative to normal weight, overweight was associated with lower all‐cause mortality (hazard ratios, HRs [95% confidence interval, 95% CI]: 0.57 [0.41, 0.78]) and cardiovascular mortality (0.52 [0.29, 0.93]), whereas obesity did not significantly decrease or increase the mortality risk. Furthermore, compared to weight stability, all types of weight change led to increased mortality risk, except small weight gain. Specifically, after adjustment for covariates and the initial weight, the HRs (95% CI) of large weight loss were 1.64 (1.15, 2.34) for all‐cause mortality and 1.85 (1.10, 3.14) for cardiovascular mortality, and the HRs (95% CI) of large weight gain were 1.55 (1.01, 2.40) for all‐cause mortality and 2.11 (1.04, 4.30) for cardiovascular mortality. Similar associations were observed when weight change was redefined in sensitivity analyses. Conclusions: Both BMI at baseline and weight change have independent U‐shaped associations with all‐cause and cardiovascular mortality among older men with IGR. The present study suggests that older men with IGR may ensure their best survival by being overweight at baseline or by maintaining their weight regardless of their baseline weight status. HighlightsEffects of obesity and weight loss on death remain controversial in the elderly.Body mass index had a U‐shaped association with mortality in older men with IGR.Weight change had a U‐shaped association with mortality in older men with IGR.Older men with IGR may benefit from being overweight or maintaining their weight.

The cutoffs and performance of glycated hemoglobin for diagnosing diabetes and prediabetes in a young and middle-aged population and in an elderly population

The aims were to compare the appropriate cutoffs of glycated hemoglobin (HbA1c) in a population of varying ages and to evaluate the performance of HbA1c for diagnosing diabetes and prediabetes. A total of 1064 participants in the young and middle-aged group and 1671 in the elderly group were included and underwent HbA1c testing and an oral glucose tolerance test (OGTT). Sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were calculated to evaluate the optimal HbA1c cutoffs. Kappa coefficients were used to test for agreement between HbA1c categorization and OGTT-based diagnoses. The optimal HbA1c cutoffs for diagnosing diabetes were 5.7% (39 mmol/mol) in the young and middle-aged group with a sensitivity of 66.7%, specificity of 86.7%, and AUC of 0.821 (95% CI: 0.686, 0.955) and 5.9% (41 mmol/mol) in the elderly group with a sensitivity of 80.4%, specificity of 73.3%, and AUC of 0.831 (0.801, 0.861). The optimal cutoffs for diagnosing prediabetes were 5.6% (38 mmol/mol) and 5.7% (39 mmol/mol) in the young and middle-aged group and in the elderly group, respectively. Agreement between the OGTT-based diagnosis of diabetes or prediabetes and the optimal HbA1c cutoff was low (all kappa coefficients <0.4). The combination of HbA1c and fasting plasma glucose increased diagnostic sensitivities or specificities. In conclusion, age-specific HbA1c cutoffs for diagnosing diabetes or prediabetes were appropriate. Furthermore, the performance of HbA1c for diagnosing diabetes and prediabetes was poor. HbA1c should be used in combination with traditional glucose criteria when detecting and diagnosing diabetes or prediabetes.