Reduced peripheral blood mtDNA content is associated with impaired glucose-stimulated islet ß cell function in a Chinese population with different degrees of glucose tolerance.

AIMS: Our aim is to explore the associations between mitochondrial DNA (mtDNA) content and basal plasma glucose, plasma glucose after oral glucose administration and oxidative stress in a Chinese population with different levels of glucose tolerance. We also aimed to investigate the effect of mtDNA content on basal and oral glucose-stimulated insulin secretion. METHODS: Five hundred and fifty-six Chinese subjects underwent a 75-g, 2-h oral glucose tolerance test. Subjects with diabetes (n = 159), pre-diabetes (n = 197) and normal glucose tolerance (n = 200) were screened. Blood lipid profile was assessed, and levels of the oxidative stress indicators superoxide dismutase, glutathione reductase (GR) and 8-oxo-2'-deoxyguanosine (8-oxo-dG) were measured. Levels of HbA1c , plasma glucose, insulin and C-peptide were also determined. Measurements were taken at 0, 30, 60 and 120 min after 75 g oral glucose tolerance test. Peripheral blood mtDNA content was assessed using a real-time polymerase chain reaction assay. Insulin sensitivity was evaluated by homeostatic model assessment of insulin resistance and Matsuda index (ISIM ). Basal insulin secretion index (HOMA-ß), early phase disposition index (DI30 ) and total phase disposition index (DI120 ) indicate insulin levels at different phases of insulin secretion. RESULTS: Peripheral blood mtDNA content was positively associated with DI30 and DI120 and was negatively associated with plasma glucose measured 30, 60 and 120 min after oral glucose administration. However, there was no correlation between mtDNA content and basal insulin secretion (HOMA-ß), serum lipid or oxidative stress indicators (8-oxo-dG, superoxide dismutase, GR). HbA1c was negatively associated with GR (r = -0.136, p = 0.001). Multiple linear regression analysis showed that reduced peripheral blood mtDNA content increased the risk of impaired glucose-stimulated ß cell function (DI30 : ß = 0.104, p = 0.019; DI120 : ß = 0.116, p = 0.009). CONCLUSIONS: Decreased peripheral blood mtDNA content was more closely associated with glucose-stimulated insulin secretion than with basal secretion. Reduction in glucose-stimulated insulin secretion causes postprandial hyperglycaemia. The oxidative stress was probably largely influenced by hyperglycaemia; it was probably that the decreased mt DNA content led to hyperglycaemia, which caused elevated oxidative stress. © 2016 The Authors. Diabetes/Metabolism Research and Reviews Published by John Wiley & Sons Ltd.

Clinical Characteristics of 261 Cases of Hospitalized Patients with Type 1 Diabetes Mellitus.

Objective To retrospectively analyze the clinical characteristics of 261 cases of hospitalized patients with type 1 diabetes mellitus (T1DM) in Peking Union Medical College Hospital (PUMCH).Methods Clinical data of 261 cases of hospitalized patients diagnosed with T1DM in the Department of Endocrinology at PUMCH from January 2007 to December 2014 were analyzed retrospectively. All patients were divided into the T1DM antibodies positive group (n=180) and negative group (n=81) according to the results of immunohistochemistry, in which 123 newly diagnosed T1DM patients were divided into the adult onset group (>18 years, n=58) and non-adult onset group (≤18 years, n=65) according to the onset age of T1DM, respectively. The clinical characteristics from different groups were compared.Results In 261 patients, the average age was 26.6±15.4 years, the average disease duration was 49 (1-480) months, the positive rate of antibodies to glutamic acid decarboxylase antibody was 58.8% (153/260). The level of 2-hour postprandial C peptide and the positive rate of T1DM antibodies in the non-adult onset group were higher than those in the adult onset group (0.98 vs. 0.52 ng/ml, P=0.002 and 80.4% vs. 62.5%, P=0.048). The age of onset in the T1DM antibodies positive group was smaller than that in the T1DM antibodies negative group (19.7±11.4 vs. 24.7±15.6 years, P=0.04), while the incidence of ketosis in the T1DM antibodies positive group was higher than that in the T1DM antibodies negative group (48.3% vs. 34.2%, P=0.035). With the progress of the disease, the fasting C peptide level of the T1DM antibodies positive group decreased more rapidly. Compared with the single time hospitalized patients, multiple hospitalized patients had a lower incidence of diabetic retinopathy (8.2% vs. 22.4%, P=0.032), a lower hemoglobin A1c level (8.04%±2.10% vs. 9.56%±2.64%, P<0.001) and fasting blood glucose level (8.7±3.1 vs. 10.9±4.2 mmol/L, P<0.001).Conclusions Compared with the non-adult onset T1DM patients, the islet function of adult onset patients was even worse. In the T1DM antibodies positive patients, the islet ß cell function decreased more rapidly, so the antibodies could not only clarify the diagnosis of T1DM and also predict prognosis of the islet ß cell function. In the management of T1DM patients, regular hospital revisits contributed to get better glycemic control and reduced the occurrence of diabetic complications.

Analysis of association among clinical features and shorter leukocyte telomere length in mitochondrial diabetes with m.3243A>G mitochondrial DNA mutation.

BACKGROUND: Mitochondrial diabetes is a kind of rare diabetes caused by monogenic mutation in mitochondria. The study aimed to summarize the clinical phenotype profiles in mitochondrial diabetes with m.3243 A>G mitochondrial DNA mutation and to investigate the mechanism in this kind of diabetes by analyzing the relationship among clinical phenotypes and peripheral leukocyte DNA telomere length. METHODS: Fifteen patients with maternally inherited diabetes in five families were confirmed as carrying the m.3243 A>G mitochondrial DNA mutation. One hundred patients with type 2 diabetes and one hundred healthy control subjects were recruited to participate in the study. Sanger sequencing was used to detect the m.3243 A>G mitochondrial DNA mutation. The peak height G/A ratio in the sequence diagram was calculated. Real-time polymerase chain reaction (PCR) was used to measure telomere length. RESULTS: The patients with mitochondrial diabetes all had definite maternally inherited history, normal BMI (19.5 ± 2.36 kg/m(2)), early onset of diabetes (35.0 ± 14.6 years) and deafness. The peak height G/A ratio correlated significantly and negatively with the age at onset of diabetes (≦ 25 years, 61.6 ± 20.17%; 25-45 years, 16.59 ± 8.64%; >45 years, 6.37 ± 0.59%; p = 0.000). Telomere length was significantly shorter among patients with mitochondrial diabetes and type 2 diabetes than in the control group (1.28 ± 0.54 vs. 1.14 ± 0.43 vs. 1.63 ± 0.61; p = 0.000). However, there was no significant difference between patients with mitochondrial diabetes and those with type 2 diabetes. There was no correlation between telomere length and the peak height G/A ratio. CONCLUSION: Deafness with definite maternal inheritance and normal BMI, associated with elevated blood lactic acid and encephalomyopathy, for the most part, suggest the diagnosis of mitochondrial diabetes . The peak height G/A ratio could reflect the spectrum of age at onset of the disease. Telomere length was shorter in patients with mitochondrial diabetes and those with type 2 diabetes, which suggests that the shorter telomere length is likely involved in the pathogenesis of diabetes but is not specific for this kind of diabetes.

[A comparative study of the effects of needle free (INJEX30) versus insulin pen injection on insulin absorption in diabetic patients].

OBJECTIVE: To evaluate the effect of the needle free injection system (INJEX30) and insulin pen on insulin absorption and glycemic control in diabetic patients. METHODS: A total of 30 diabetic patients on insulin therapy without obvious complications were enrolled in the study with average BMI of 25.24 kg/m(2). A comparison study was carried out in those subjects with the INJEX30 and insulin pen at 1(st) day and 5(th) day. After an overnight fasting of 8-10 h, a standard mixed meal (50 g bread, 50 g egg and 250 ml milk) was given to each patient. Blood samples at 0, 20, 40, 60 min of the standard mixed meal were collected to test plasma glucose, serum insulin and C peptide. RESULTS: No difference was shown in fasting plasma glucose, serum insulin and C peptide between the patients with the two injection methods. The area under the curve (AUC) of plasma glucose and serum C peptide was significantly lower after the INJEX30 injection than that after insulin pen injection [plasma glucose AUC (542 ± 172)min·mmol·L(-1) vs (601 ± 199) min·mmol·L(-1), P < 0.01; C peptide AUC (70 ± 53) min·µg· L(-1) vs (80 ± 58) min·µg·L(-1), P < 0.01]. The AUC of serum insulin was significantly higher after the INJEX30 injection than that after insulin pen injection [serum insulin AUC (5621 ± 3790) min·mIU·L(-1) vs (4285 ± 3376) min·mIU· L(-1), P < 0.01]. No difference was found in the AUC of serum insulin between the two injection methods in the patients with BMI below 25.24 kg/m(2), while the AUC of serum insulin was significantly higher after the INJEX30 injection than the insulin pen injection in the patients with BMI above 25.24 kg/m(2) [serum insulin AUC (6453 ± 4099) min·mIU· L(-1) vs (4879 ± 3701) min·mIU·L(-1), P < 0.01]. CONCLUSION: The INJEX30 improves the serum insulin level which may lead to a beneficial effect on the glycemic control. Such effect is more obvious in the overweight patients.

Deoxyribonucleic acid telomere length shortening can predict the incidence of non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus.

AIMS/INTRODUCTION: To investigate the effect of telomere shortening and other predictive factors of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes mellitus patients in a 6-year prospective cohort study. MATERIALS AND METHODS: A total of 70 type 2 diabetes mellitus (mean age 57.8 ± 6.7 years) patients without NAFLD were included in the study, and 64 of them were successfully followed up 6 years later, excluding four cases with significant alcohol consumption. NAFLD was diagnosed by the hepatorenal ratio obtained by a quantitative ultrasound method using NIH image analysis software. The 39 individuals that developed NAFLD were allocated to group A, and the 21 individuals that did not develop NAFLD were allocated to group B. Fluorescent real-time quantitative polymerase chain reaction was used to measure telomere length. RESULTS: There was no significant difference between the two groups in baseline telomere length; however, at the end of the 6th year, telomere length had become shorter in group A compared with group B. There were significant differences between these two groups in baseline body mass index, waistline, systolic blood pressure, glycated hemoglobin and fasting C-peptide level. In addition, the estimated indices of baseline insulin resistance increased in group A. Fasting insulin level, body mass index, systolic blood pressure at baseline and the shortening of telomere length were independent risk factors of NAFLD in type 2 diabetes mellitus patients. CONCLUSIONS: Telomere length became shorter in type 2 diabetes mellitus patients who developed NAFLD over the course of 6 years. Type 2 diabetes mellitus patients who developed NAFLD had more serious insulin resistance compared with those who did not develop NAFLD a long time ago.

Expression profiling analysis: Uncoupling protein 2 deficiency improves hepatic glucose, lipid profiles and insulin sensitivity in high-fat diet-fed mice by modulating expression of genes in peroxisome proliferator-activated receptor signaling pathway.

AIMS/INTRODUCTION: Uncoupling protein 2 (UCP2), which was an important mitochondrial inner membrane protein associated with glucose and lipid metabolism, widely expresses in all kinds of tissues including hepatocytes. The present study aimed to explore the impact of UCP2 deficiency on glucose and lipid metabolism, insulin sensitivity and its effect on the liver-associated signaling pathway by expression profiling analysis. MATERIALS AND METHODS: Four-week-old male UCP2-/- mice and UCP2+/+ mice were randomly assigned to four groups: UCP2-/- on a high-fat diet, UCP2-/- on a normal chow diet, UCP2+/+ on a high-fat diet and UCP2+/+ on a normal chow diet. The differentially expressed genes in the four groups on the 16th week were identified by Affymetrix gene array. RESULTS: The results of intraperitoneal glucose tolerance test and insulin tolerance showed that blood glucose and ß-cell function were improved in the UCP2-/- group on high-fat diet. Enhanced insulin sensitivity was observed in the UCP2-/- group. The differentially expressed genes were mapped to 23 pathways (P < 0.05). We concentrated on the 'peroxisome proliferator-activated receptor (PPAR) signaling pathway' (P = 3.19 × 10(-11)), because it is closely associated with the regulation of glucose and lipid profiles. In the PPAR signaling pathway, seven genes (PPARγ, Dbi, Acsl3, Lpl, Me1, Scd1, Fads2) in the UCP2-/- mice were significantly upregulated. CONCLUSIONS: The present study used gene arrays to show that activity of the PPAR signaling pathway involved in the improvement of glucose and lipid metabolism in the liver of UCP2-deficient mice on a long-term high-fat diet. The upregulation of genes in the PPAR signaling pathway could explain our finding that UCP2 deficiency ameliorated insulin sensitivity. The manipulation of UCP2 protein expression could represent a new strategy for the prevention and treatment of diabetes.

Rationale and Design of RNAFH Study: Effect of Rosuvastatin (10 mg/d) on Nonalcoholic Fatty Liver in Metabolic Syndrome Patients without Overt Diabetes Evaluated by 1H-Magnetic Resonance Spectroscopy.

Objective. The RNAFH study (effect of rosuvastatin on nonalcoholic fatty liver disease in metabolic syndrome patients without overt diabetes evaluated by 1H-MRS) is a prospective randomized, single-center, open-label trail designed to assess the effect of rosuvastatin on the intrahepatocellular lipid (IHCL) level of nonalcoholic fatty liver disease (NAFLD). Methods. 40 NAFLD patients meeting inclusion and exclusion criteria with metabolic syndrome (MS) but without overt diabetes mellitus will be included. Patients will be randomized to 52-week treatment with either rosuvastatin (10 mg/d) or blank control. The primary end point is IHCL evaluated by 1H-MRS, which was considered to be the most accurate noninvasive method for the evaluation of NAFLD. Secondary end points include homeostasis model assessment of insulin resistance (HOMA-IR) index on behalf of insulin resistance level and lipid parameters. Safety indicators will be monitored such as liver function, renal function, muscle stability, and glucose metabolism. The aims of the present study are noteworthy in respect that (1) IHCL is a quantitative indicator for evaluating the degree of fatty liver disease and 1H-MRS is a noninvasive technique to provide this specific index precisely, (2) meanwhile the HOMA-IR index and lipid parameters will be monitored, and (3) the safety of rosuvastatin treatment for 52 weeks will be evaluated including glucose metabolism, muscle stability, liver function, and renal function.