Intracellular Retention of Human Melanocortin-4 Receptor:A Molecular Mechanism Underlying Early-onset Obesity in F261S Pedigree of Chinese

Objective To investigate how F261S mutation identified from Chinese obese patients affects the function of melanocorfin 4 receptor (MC4R) and to analyze the obesity-related phenotypes in subjects carrying the F261S mutation. Methods F261S mutant of MC4R was generated by site-directed mutagenesis. Plasmids encoding wild-type or F261S mutant of MC4R were transfected into HEK293 and COS-7 cells to examine their functional characteristics. Signaling properties of F261S MC4R were assessed by measuring intracellular cAMP levels in response to α-MSH stimulation. Cell surface expression of F261S MC4R was compared with that of wild-type MC4R. Clinical examinations were performed in subjects carrying F261S mutation and in non-mutated controls. Results The a-MSH-stimulated reporter gene activity was significantly reduced in cells expressing F261S MC4R, with a maximal response equal to 57% of wild-type MC4R. The F261S mutation also led to a significant change in the EC50 value compared with the wild-type receptor (P〈0.01). Immunofluorescent assay revealed a marked reduction in plasma membrane localization of the MC4R in cells expressing the F261S mutant receptor. The resting metabolic rate and fat composition of the mutant carriers were not significantly different from those of the non-mutated obese controls. Conclusions The decreased response to α-MSH due to the intracellular retention of MC4R may cause early-onset obesity in the F261S pedigree of Chinese.

Relationship between the level of fasting plasma glucose and beta cell functions in Chinese with or without diabetes

Background Type 2 diabetes is a chronic disease characterized by a progressive loss of beta cell functions. However, the evaluation of beta cell functions is either expensive or inconvenient for clinical practice. We aimed to elucidate the association between the changes of insulin responsiveness and the fasting plasma glucose （FPG） during the development of diabetes. Methods A total of 1192 Chinese individuals with normal blood glucose or hyperglycemia were enrolled for the analysis. The early insulinogenic index （△I30/△G30）, the area under the curve of insulin （AUC-Ⅰ）, and homeostasis model assessment were applied to evaluate the early phase secretion, total insulin secretion, and insulin resistance respectively. Polynomial regression analysis was performed to estimate the fluctuation of beta cell functions. Results The △I30/△G30 decreased much more rapidly than the AUC-Ⅰ accompanying with the elevation of FPG. At the FPG of 110 mg/dl （a pre-diabetic stage）, the AI30/AG30 lost 50% of its maximum while the AUC-Ⅰ was still at a compensated normal level. The AUC-Ⅰ exhibited abnormal and decreased gradually at the FPG of from 130 mg/dl to higher （overt diabetes）, while the △I30/△G30 almost remained at 25% of its maximum value. When hyperglycemia continuously existed at 〉 180 mg/dl, both the AI30/AG30 and AUC-Ⅰ were totally lost. Conclusion The increased fasting plasma glucose reflects progressive decompensation of beta cell functions, and could be used to guide the strategy of clinical treatments.

Metabolic Disorders Increase the Risk to Incident Cardiovascular Disease in Middle-aged and Elderly Chinese

Objective The association of metabolic syndrome （MetS） with cardiovascular diseases （CVD） has not been adequately explored in middle-aged and elderly Chinese. This study aimed to investigate MetS＇ prevalence and its impact on the CVD incidence in this specific population group. Methods A data set of a community-based prospective cohort study was analyzed. A total of 2300 subjects aged 40-94 years were followed up for the CVD events. MetS defined according to the JCDCG criteria was assessed at baseline, and the middle-aged and elderly groups were classified by the WHO definition. Results As compared with the middle-aged group, the prevalence of MetS increased by 0.6 times （34.6% vs. 21.3%） and the incidence density of CVD increased by 4.9 times in the elderly group （52.3/1000 person-year vs. 8.9/1000 person-year）. Furthermore, the multivariate Cox regression revealed that the risk to CVD incidence was independently related to increased waist circumference in the middle-aged group （HR=2.23, P〈0.01） and to elevated blood glucose in the elderly group （HR=1.39, P〈O.01）. Conclusion MetS was highly prevalent in middle-aged and elderly Chinese. MetS significantly increased the risk to OdD incidence in the elderly. All individuals with metabolic disorders should receive active clinical care to reduce the incidence of CVD.

Waist Circumference-dependent Peripheral Monocytes Change after Gliclazide Treatment for Chinese Type 2 Diabetic Patients

Gliclazide used for the treatment of type 2 diabetes mellitus（T2DM） stimulates insulin secretion and influences peripheral blood monocytes.The roles of gliclazide in peripheral monocytes of newly diagnosed T2 DM patients were investigated in this study.A total of 105 newly diagnosed T2 DM patients with no history of antihyperglycemic medication were treated with gliclazide-modified release for 16 weeks.The total and differential leukocyte profiles of peripheral blood were measured at baseline and week 16.The peripheral blood monocyte count at week 16 was significantly lower than that at baseline（P=0.019）.Peripheral monocytes level at baseline was positively correlated with waist circumference.After gliclazide treatment,the peripheral monocytes were decreased [（320.09±15.13）×10~6/L vs.（294.19±14.22）×10~6/L] in non-abdominal obesity group,but increased in abdominal obesity group [（344.36±17.24）×10~6/L vs.（351.87±16.93）×10~6/L].Compared with non-abdominal obese patients,abdominal obese patients showed higher Δmonocytes（P=0.046） and Δacute insulin secretion（P=0.049）,but lower ΔHb A1c（P=0.047）.There was significantly positive correlation between Δmonocytes and Δacute insulin secretion（P=0.015）,which disappeared after adjusting for age,waist circumference and dosage at baseline.In conclusion,waist circumference is correlated with peripheral monocyte change after gliclazide treatment in Chinese newly diagnosed T2 DM patients.Peripheral monocytes are decreased in non-abdominal obesity group and increased in abdominal obesity group after gliclazide treatment.

Relationship of plasma creatinine and lactic acid in type 2 diabetic patients without renal dysfunction

Background As one of most widely-used biguanides, metformin can induce the lactic acidosis in patients with renal failure though its incidence is very low. However, lactic acidemia induced by metformin was reported in patients without renal dysfunction. It is unclear that whether lactatemia exists in diabetic patients with normal renal function in Chinese or not and its influencing factors. This study aimed to clarify the influencing factors of lactic acid, and identify a practiced clinical marker to predict the hyperlactacidemia in diabetics with normal renal function. Methods The clinical data and venous blood samples of 1024 type 2 diabetic patients treated with （n=426） or without metformin （n=599） were collected. The lactic acid was assayed by enzyme-electrode method. The biochemical indexes included creatinine （Cr） and hepatase were measured with enzymatic procedures. The lactic acid concentrations of different Cr subgroups were compared, and the correlation and receiver operating characteristic curve analysis were used. Results The mean lactic acid level and the proportion of hyperlactatemia of metformin group were significantly higher than that of non-metformin group （P 〈0.01）, but no lactic acidosis was found in all patients. The correlation and multiple stepwise regression analysis indicated that the correlative factors of lactic acid in turn were Cr, metformin, alanine transferase （ALT）, body mass index （BMI）, Urine albumin （Ualb）, and blood urea nitrogen （BUN） in total patients; and Cr, ALT, BMI and BUN in non-metformin treated patients; Cr and ALT in metformin-group. The lactate concentration increased with the increment of Cr levels, and reached its peak at Cr 111-130 μmol/L, and the optimal cutoff of Cr in predicting hyperlactacidemia was 96.5 μmol/L. Conclusions Metformin can increase the incidence of lactatemia in type 2 diabetic patients without renal dysfunction. Cr, ALT, and BMI are independent associated factors of blood lactic acid levels. There is low proportion of lactatemia in type 2 diabetics without metformin therapy, the optimal cutoff of Cr to predict lactatemia in these patients is 96.5 μmol/L.

Fibroblast growth factor 21:a novel metabolic regulator from pharmacology to physiology

Fibroblast growth factor 21(FGF21)is a member of the fibroblast growth factor family.It actually functions as endocrine hormones but does not regulate cell growth and differentiation.It is demonstrated that FGF21 acts on multiple tissue to coordinate carbohydrate and lipid metabolism,including enhancing insulin sensitivity,decreasing triglyceride concentrations,causing weight loss,ameliorating obesity-associated hyperglycemia and hyperlipidemia.Moreover,FGF21 also plays important roles in some physiological processes,such as fasting and feeding,growth hormone axis and thermogenic function of brown adipose tissue.Clinical relevance of FGF21 in humans is still unclear,and the basis and consequences of increased FGF21 in metabolic disease remain to be determined.Both the pharmacological actions and physiological roles make FGF21 attractive drug candidates for treating metabolic disease,but some questions remain to be answered.This article concentrates on recent advances in our understanding of FGF21.

Metabolic surgery in China: present and future

Obesity and its related complications comprise a serious public health problem worldwide,and obesity is increasing in China.Metabolic surgery is a new type of treatment with unique advantages in weight loss and obesity-related metabolic complications.The pathogenesis of obesity is complex and not yet fully understood.Here,we review the current efficacy and safety of metabolic surgery,as well as recent progress in mechanistic studies and surgical procedures in China.The exciting and rapid advances in this field provide new opportunities for patients with obesity and strike a balance between long-term effectiveness and safety.