Yuxiu Li

Heteroplasmy level of the mitochondrial tRNaLeu(UUR) A3243G mutation in a Chinese family is positively associated with earlier age-of-onset and increasing severity of diabetes.

OBJECTIVEnTo investigate the mutations of mitochondrial genome in a pedigree with suspected maternally inherited diabetes and deafness and to explore the correlations between the mutations and clinical features.nnnMETHODSnGenomic DNA was isolated from blood leucocytes of each member of the pedigree. The mitochondrial genome was amplified with 24-pair primers that could cover the entire mitochondrial DNA. Direct sequencing of PCR products was used to identify any mitochondrial DNA mutations.nnnRESULTSnFamily members on the maternal side all harbored the tRNALeu(UUR) A3243G mutation. The paternal side family members did not have the mutation. The age-of-onset of diabetes of the 4 maternal side family members was 15, 41, 44, and 65 years old, and their corresponding heteroplasmy level of the mutation was 34.5%, 14.9%, 14.6%, and 5.9%, respectively. The age-of-onset of diabetes and heteroplasmy level of A3243G mutation were negatively correlated with a correlation coefficient of -0.980 (P = 0.02). Meanwhile, patient with high heteroplasmy level of A3243G mutation had relatively low severity of disease. Moreover, 6 reported polymorphisms and 2 new variants were found.nnnCONCLUSIONSnThe main cause of diabetes in this pedigree is the tRNALeu(UUR) A3243G mutation. However, other gene variants may contribute to its pathogenicity. The heteroplasmy level of the tRNALeu(UUR) A3243G mutation is positively associated with earlier age-of-onset and increasing severity of diabetes.

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

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.

The triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio as a predictor of insulin resistance but not of β cell function in a Chinese population with different glucose tolerance status

BackgroundTriglyceride/high-density lipoprotein-cholesterol (TG/HDL-C) ratio was a surrogate marker of IR; however, the relationship of TG/HDL-C with IR might vary by ethnicity. This study aims to investigate whether lipid ratios-TG/HDL-C, cholesterol/high-density lipoprotein-cholesterol (TC/HDL-C) ratio, low-density lipoprotein-cholesterol/high-density lipoprotein-cholesterol (LDL-C/HDL-C)) could be potential clinical markers of insulin resistance (IR) and β cell function and further to explore the optimal cut-offs in a Chinese population with different levels of glucose tolerance.MethodsFour hundred seventy-nine subjects without a history of diabetes underwent a 75xa0g 2xa0h Oral Glucose Tolerance Test (OGTT). New-onset diabetes (nu2009=u2009101), pre-diabetes (nu2009=u2009186), and normal glucose tolerance (nu2009=u2009192) were screened. IR was defined by HOMA-IRu2009>u20092.69. Based on indices (HOMA-β, early-phase disposition index [DI30], (ΔIns30/ΔGlu30)/HOMA-IR and total-phase index [DI120]) that indicated different phases of insulin secretion, the subjects were divided into two groups, and the lower group was defined as having inadequate β cell compensation. Logistic regression models and accurate estimates of the areas under receiver operating characteristic curves (AUROC) were obtained.ResultsIn all of the subjects, TG/HDL, TC/HDL-C, LDL-C/HDL-C, and TG were significantly associated with IR. The AUROCs of TG/HDL-C and TG were 0.71 (95xa0% CI: 0.66–0.75) and 0.71 (95xa0% CI: 0.65–0.75), respectively. The optimal cut-offs of TG/HDL-C and TG for IR diagnosis were 1.11 and 1.33xa0mmol/L, respectively. The AUROCs of TC/HDL-C and LDL-C/HDL-C were 0.66 and 0.65, respectively, but they were not acceptable for IR diagnosis. TG/HDL-C,LDL-C/HDL-C and TG were significantly associated with HOMA-β, but AUROCs were less than 0.50; therefore, the lipid ratios could not be predictors of basal β cell dysfunction. None of the lipid ratios was associated with early-phase insulin secretion. Only TG/HDL-C and TG were significantly correlated with total-phase insulin secretion, but they also were not acceptable predictors of total-phase insulin secretion (0.60u2009<u2009AUROCu2009<u20090.70).ConclusionsIn a Chinese population with different levels of glucose tolerance, TG/HDL-C and TG could be the predictors of IR. The lipid ratios could not be reliable makers of β cell function in the population.

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

BackgroundMitochondrial diabetes is a kind of rare diabetes caused by monogenic mutation in mitochondia. The study aimed to summarize the clinical phenotype profiles in mitochondrial diabetes withm.3243A>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.MethodsFifteen patients with maternally inherited diabetes in five families were confirmed as carrying the m.3243A>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.3243A>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.ResultsThe patients with mitochondrial diabetes all had definite maternally inherited history, normal BMI (19.5u2009±u20092.36xa0kg/m2), early onset of diabetes (35.0u2009±u200914.6xa0years) and deafness. The peak height G/A ratio correlated significantly and negatively with the age at onset of diabetes (≦25xa0years, 61.6u2009±u200920.17xa0%; 25–45 years, 16.59u2009±u20098.64xa0%; >45xa0years, 6.37u2009±u20090.59xa0%; pu2009=u20090.000). Telomere length was significantly shorter among patients with mitochondrial diabetes and type 2 diabetes than in the control group (1.28u2009±u20090.54 vs. 1.14u2009±u20090.43 vs. 1.63u2009±u20090.61; pu2009=u20090.000). 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.ConclusionDeafness 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.

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

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.

Using continuous glucose monitoring to measure glucose variation of patients with type 2 diabetes: switching from premixed human insulin 70/30 to insulin lispro mix 75/25 or lispro mix 50/50 for 8 weeks

Aim: To compare the impact of premixed human insulin 70/30 and two different premixed insulin analogues (insulin lispro mix 75/25 and 50/50) on glucose variation of the patients with type 2 diabetes (T2D). Methods: A total of 19 T2D patients who were treated with premixed human insulin 70/30 (PHI70/30) more than 90 days. All patients were divided into two groups receiving either insulin lispro mix 75/25 (LM25) or 50/50 (LM50) for 8 weeks. They were then crossed over to the other arm and continued to receive either LM50 or LM25 for 8 weeks. Continuous glucose monitoring (CGM) was performed on all patients for 72 hours in every stage to examine the differences in variability of interstitial glucose. All patients received questionnaire survey regarding subjective feeling of insulin therapy. Results: No significant difference was found in HbA1c, mean interstitial glucose (MIG) and mean amplitude of glycemic excursion (MAGE) in whole day among three regimens. However, in the subgroup with baseline MIG≥10.0mmol/L (n=6), MIG in whole day in LM25 regimen was significantly lower than that in PHI70/30 regimen (9.4±1.5 vs. 12.2±2.0mmol/L, P=0.024). The largest amplitude of glycemic excursion (LAGE) and MAGE in LM50 regimen were lower than those in LM25 regimen in the period of 22pm-6am (6.9±3.1 vs. 9.8±2.8mmol/L, P=0.034; 2.2±1.9 vs. 4.0±3.0mmol/L, P=0.043; respectively). Conclusions: Premixed Insulin analogue may provide better glycemic control compared to human premixed insulin in the patients with higher glucose level. The T2D patients with adequate glycemic control or greater risk of hypoglycemia at night were suitable to LM50.

Successful treatment of Type B insulin resistance with mixed connective tissue disease by pulse glucocorticoids and cyclophosphamide

Type B insulin resistance syndrome is a very rare condition caused by autoantibodies against the insulin receptor. We report the successful treatment of a patient with refractory type B insulin resistance with pulse glucocorticoids and cyclophosphamide. The medical record of a patient with type B insulin resistance was reviewed. A 36‐year‐old Chinese woman presented with menopause, weight loss and refractory hyperglycemia for 3 months, which could not be controlled by up to 972 of insulin units per day. Mixed connective tissue disease was diagnosed with high titers of antinuclear antibody, ribonucleoprotein antibody and interstitial lung disease. Type B insulin resistance was diagnosed with positive immunoprecipitation assay of anti‐insulin‐receptor antibodies in serum. We started one cycle of pulse methylprednisolone (1,000 mg/day for 3 days) then tapered to prednisone 1 mg/kg/day, and cyclophosphamide 0.4 g/week was added on. Three weeks after pulse glucocorticoid therapy, fasting glucose returned to 4.4 mmol/L. Fasting insulin decreased from 647.27 to 12.95 uIU/mL 6 weeks later. The patient had gained 15 kg during 20 months of uneventful following up, and glycated hemoglobin decreased from 10.1 to 5.1%.In this patient with type B insulin resistance, a combination of pulse glucocorticoids and cyclophosphamide was successful in inducing a complete remission. Close cooperation between endocrinologists and rheumatologists will ensure an individualized regimen for this rare condition.

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

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.

Uncoupling Protein 2 and Peroxisome Proliferator-Activated Receptor γ Gene Polymorphisms in Association with Diabetes Susceptibility in Chinese Han Population with Variant Glucose Tolerance

Objective To investigate the association of polymorphisms in uncoupling protein 2 (UCP2) and peroxisome proliferator-activated receptor (PPARγ) with glucolipid metabolism in Chinese Han population. Methods Five hundred eighty-nine subjects were divided into normal glucose tolerance (NGT) group (n = 198) and abnormal glucose tolerance group (n = 358). HbA1c, blood lipid profile, plasma glucose, and insulin were determined. Insulin sensitivity (HOMA-IR and Matsuda index (ISIM)) and insulin secretion indexes (HOMA-β, early and total phase disposition index) were evaluated. Eight potential functional SNPs in UCP2 and 7 in PPARγ were selected. SNPs were genotyped on Sequenom MassARRAY platform. Results The GG genotype of rs2920502 in PPARγ was associated with decreased risk of impaired glucose tolerance (G allele: OR: 0.818, 95%CI: 0.526–0.969, P = 0.042; GG: OR: 0.715, 95%CI: 0.527–0.97, P = 0.031). The TT genotype of rs3856806 in PPARγ was associated with increased risk of impaired glucose tolerance (T allele: OR: 1.46, 95%CI: 1.055–2.017, P = 0.022; TT: OR: 1.58, 95%CI: 1.104–2.761, P = 0.032). The GG genotype of rs2920502 in PPARγ had better blood glucose and increased insulin secretion and had lower HOMA-IR than GC/CC genotypes. Conclusion It probably could prevent insulin resistance in early stage by classifying the genotype of rs649446 and rs7109266 in UCP2. The GG genotype of rs2920502 in PPARγ had a decreased risk for diabetes. The TT genotype of rs3856806 in PPARγ had an increased risk for 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 (10u2009mg/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.