Fulminant type 1 diabetes (FT1DM) is a relatively new clinical entity featured by acute destruction of pancreatic beta cells. Clinical consequences of FT1DM could be fatal when timely medications are not provided, suggesting the particular importance of rapid and accurate diagnosis. Here we report a serum metabonomics study of FT1DM patients, together with healthy control subjects (NC), type 2 diabetes (T2DM), classic type 1 diabetes (T1DM), and diabetic ketoacidosis (DKA) patients, with the aim of discovering metabolic markers associated with FT1DM. A total of 79 subjects were enrolled (22 NC, 22 T1DM, 22 T2DM, 8 DKA and 5 FT1DM) and the serum metabolic profiling of fasting blood samples was performed using gas chromatography time-of-flight mass spectrometry (GC-TOFMS) coupled with multivariate and univariate statistical analyses. Serum metabolites differentially expressed in FT1DM relative to NC, or to T2DM, T1DM and DKA were identified. Three metabolite markers, 5-oxoproline, glutamate, and homocysteine, were significantly altered among FT1DM, T2DM, T1DM, and DKA. In addition, the three metabolite markers, 5-oxoproline, glutamate, and homocysteine, presented similar patterns of distribution across groups. The results showed that the metabolic signatures of FT1DM identified in this study could be of potential clinical significance for the accurate diagnosis of FT1DM.Keywords: biomarker; FT1DM; fulminant type 1 diabetes; metabolomics; metabonomics; serum;

The pathological development and the drug intervention of type 2 diabetes mellitus (T2DM) involve altered expression of downstream low molecular weight metabolites including lipids and amino acids, and carbohydrates such as glucose. Currently, a small number of markers used for clinical assessment of T2DM treatment may be insufficient to reflect global variations in pathophysiology. In this study, a metabonomic study was performed to determine metabolic variations associated with T2DM and the drug treatments on 74 patients who were newly diagnosed with T2DM and received a 48 week treatment of a single drug, repaglinide, metformin or rosiglitazone. Fasting overnight and 2 h postprandial blood serum of patients were collected at 24 and 48 weeks to monitor the biochemical indices (FPG, 2hPG, HbA1c, etc.). Gas chromatography/mass spectrometer coupled with multivariate statistical analysis was used to identify the alteration of global serum metabolites associated with T2DM as compared to healthy controls and responses to drug treatment. Significantly altered serum metabolites in diabetic subjects include increased valine, maltose, glutamate, urate, butanoate and long-chain fatty acid (C16:0, C18:1, C18:0, octadecanoate and arachidonate), and decreased glucuronolactone, lysine and lactate. All of the three treatments were able to down-regulate the high level of glutamate to a lower level in serum of T2DM patients, but rosiglitazone treatment was able to reverse more abnormal levels of metabolites, such as valine, lysine, glucuronolactone, C16:0, C18:1, urate, and octadecanoate, suggesting that it is more efficient to alter the metabolism of T2DM patients than the other two drugs.Keywords: gas chromatography/mass spectrometry; metabonomics; metformin; repaglinide; rosiglitazone; Type 2 diabetes mellitus;

Despite the current guideline’s recommendation of a timely stepwise intensification therapy, the “clinical inertia”, termed as the delayed treatment intensification, commonly exists in the real world, which may be partly due to the relatively little substantial evidence and no clear consensus regarding the efficacy and safety of triple oral agents in patients inadequately controlled with dual therapy. In this clinical trial performed in 237 centers in China, 5,535 type 2 diabetic patients inadequately controlled by previous therapies were treated with a stable metformin/sitagliptin dual therapy for 20 weeks. The patients who did not reach the glycated hemoglobin A1c (HbA1c) goal were then further randomized into glimepiride, gliclazide, repaglinide, or acarbose group for an additional 24-week triple therapy. A mean HbA1c reduction of 0.85% was observed when sitagliptin was added to the patients inadequately controlled with metformin in 16 weeks. Further HbA1c reductions in the 24-week triple therapy stage were 0.65% in glimepiride group, 0.70% in gliclazide group, 0.61% in repaglinide group, and 0.45% in acarbose group. The non-inferiority criterion for primary hypotheses was met for gliclazide and repaglinide, but not for acarbose, compared with glimepiride, when added to metformin/sitagliptin dual therapy. The incidences of adverse events (AEs) were 29.2% in the dual therapy stage and 30.3% in the triple therapy stage. Metformin/sitagliptin as baseline therapy, with the addition of a third oral antihyperglycemic agent, including glimepiride, gliclazide, repaglinide, or acarbose, was effective, safe and well-tolerated for achieving an HbA1c <7.0% goal in type 2 diabetic patients inadequately controlled with previous therapies. The timely augmentation of up to three oral antihyperglycemic agents is valid and of important clinical benefit to prevent patients from exposure to unnecessarily prolonged hyperglycemia.

NOS1AP variant rs12742393 is a functional single nucleotide polymorphism (SNP) and has been reported to be associated with schizophrenia and type 2 diabetes (T2DM) susceptibility in different populations. However, the molecular mechanisms are not clear. The main focus of the present study was to identify metabolic differences among different genotypes of the variant and to identify potential physiological and pathological mechanisms for the diseases.In this study, we conducted a comprehensive serum metabolomic analysis in healthy subjects with different genotypes of rs12742393 (n = 49 for AA, AC, and CC, respectively) using gas chromatography–time of flight mass spectrometry and ultra-performance liquid chromatography–quadruple time of flight mass spectrometry. Serotonin was also measured by enzyme-linked immunosorbent assay.Our data showed that there were significant metabolic differences among the different genotypes of rs12742393: compared with AA carriers, serum serotonin and N-acetyl-5-hydroxytryptamine were significantly higher; while tryptophan and kynurenine were significantly lower in CC allele carriers (variable importance in the projection (VIP) >1 and P < 0.05). In addition, CC allele carriers showed low levels of aromatic amino acids (phenylalanine and tyrosine) and fatty acids (lauric acid, 2-methyl-4-pentenoic acid, and adrenic acid), but a high level of isolithocholic acid (VIP >1 and P < 0.05).The influence of rs12742393 variant is involved in a set of complex metabolic alterations, including amino acids, fatty acids and cholic acids, especially those in the serotonin and kynurenine pathway, probably associates with the early development of schizophrenia and T2DM.

Previous studies showed that serum 1,5-anhydroglucitol (1,5-AG) levels are significantly reduced in patients with diabetes mellitus (DM). However, it remains unclear how 1,5-AG levels acutely change in response to a glucose load. This study explored acute changes in 1,5-AG levels after a glucose load and the related influencing factors in individuals with differing degrees of glucose tolerance.A total of 681 participants (353 without DM and 328 with DM) without a prior history of DM were enrolled. All participants underwent an oral glucose tolerance test. Fasting and postload (30, 60, 120, and 180 min) levels of plasma glucose, serum 1,5-AG, and insulin were measured.In all participant groups, serum 1,5-AG levels were slightly elevated after a glucose load and reached peak values at 120 min after loading (all P < 0.05). Regression analysis showed that body weight was negatively associated with the difference between peak and baseline 1,5-AG levels (Δ1,5-AG, standardized β = −0.119, P < 0.01). A strong and positive association between 1,5-AG0 and Δ1,5-AG was also found independent of other confounding factors (standardized β = 0.376, P < 0.01). The ratio of the Δ1,5-AG to the 1,5-AG0 was higher in DM patients (7.3% [3.4–11.5%]) than in those without DM (6.2% [3.6–9.2%]).In contrast to the established decline in 1,5-AG levels with long-term hyperglycemia, the present study showed that serum 1,5-AG levels slightly increased by 6–7% after a glucose load. Further studies in different 1,5-AG transport models are needed to investigate the relevant metabolic pathways.

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 T2DM patients were investigated in this study. A total of 105 newly diagnosed T2DM 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)×106/L vs. (294.19±14.22)×106/L] in non-abdominal obesity group, but increased in abdominal obesity group [(344.36±17.24)×106/L vs. (351.87±16.93)×106/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 ΔHbA1c (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 T2DM patients. Peripheral monocytes are decreased in non-abdominal obesity group and increased in abdominal obesity group after gliclazide treatment.

Roux-en-Y gastric bypass (RYGB) is one of the most effective treatments for long-term weight loss and diabetes remission; however, the mechanisms underlying these changes are not clearly understood. In this study, the serum metabolic profiles of 23 remission and 12 nonremission patients with type 2 diabetes mellitus (T2DM) were measured at baseline, 6- and 12-months after RYGB. A metabolomics analysis was performed based on ultra-performance liquid chromatography–mass spectrometry. Clinical improvements in insulin sensitivity, energy metabolism, and inflammation were related to metabolic alterations of free fatty acids (FFAs), acylcarnitines, amino acids, bile acids, and lipids species. Differential metabolic profiles were observed between the two T2DM subgroups, and patients with severity fat accumulation and oxidation stress may be more suitable for RYGB. Baseline levels of tryptophan, bilirubin, and indoxyl sulfate measured prior to surgery as well as levels of FFA 16:0, FFA 18:3, FFA 17:2, and hippuric acid measured at 6 months after surgery best predicted the suitability and efficacy of RYGB for patients with T2DM. These metabolites represent potential biomarkers that may be clinically helpful in individualized treatment for T2DM patients by RYGB.

Ficolin-3, a soluble molecule of the innate immune system, has a primary role in the activation of the lectin pathway in the complement system. Considering that inflammatory mechanisms are involved in complement activation and take part in the pathophysiology of diabetic peripheral neuropathy (DPN), we conducted this study to explore the link between serum ficolin-3 and DPN in diabetic patients.A total of 466 diabetic patients were enrolled in this cross-sectional study. DPN was evaluated by neurological symptoms, neurological signs, neurothesiometer and electromyogram. The concentration of serum ficolin-3 was determined by enzyme-linked immunosorbent assay.The concentration of serum ficolin-3 was lower in DPN patients compared with non-DPN patients (18.73 ± 4.75 vs. 26.69 ± 5.68 ng/mL, P < 0.001). In addition, it was found negatively correlated to the vibration perception threshold (r = −0.158; P = 0.025). The results of multiple regression analysis of DPN indicated that age, diabetes duration, serum ficolin-3 were all independent impact factors for DPN (P < 0.05). Patients were then assigned into quartiles according to the serum ficolin-3 levels, and the prevalence of DPN ascended as the concentration of ficolin-3 descended (Trend analysis, P < 0.001). Compared with ficolin-3 Quartile 1 (referent), the risk of DPN was significantly greater in Quartile 2 (OR 2.76; 95 % CI 1.56–4.88; P < 0.001), Quartile 3 (OR 3.02; 95 % CI 1.69–5.40; P < 0.001) and Quartile 4 (OR 6.84; 95 % CI 3.39–13.80; P < 0.001).Lower ficolin-3 level is independently associated with DPN, and it may be a potential biomarker for DPN.

To explore the factors mediating the relationship between body mass index (BMI) and diabetic retinopathy (DR) in Chinese type 2 diabetes patients.This is a cross-sectional study. Data of 2,533 patients with type 2 diabetes were studied from the Shanghai Diabetes Registry Database. DR was assessed using non-mydriatic fundus photography and graded as non-DR, mild–moderate (DR I–II), and sight-threatening (DR III–IV). BMI (kg/m2) was classified as normal weight (18.5 ≤ BMI < 25), overweight (25 ≤ BMI < 30), and obese (BMI ≥ 30). β cell function was evaluated by fasting C-peptide (FCP).DR was present in 701 (27.7 %) patients. Patients with DR had lower BMI (24.3 vs. 24.9 kg/m2, P = 0.001) and fasting C-peptide (1.46 vs. 1.86 ng/ml, P < 0.001) than those without DR. The association between BMI (2 kg/m2 interval) and DR was U-shaped; patients with BMI 28–29.9 kg/m2 had the lowest DR rate. Compared with normal weight, overweight was associated with reduced risk of any DR [odds ratio (OR) 0.73], DR I–II (OR 0.76), and DR III–IV (OR 0.64) after adjustment for sex, age at diabetes diagnosis, and duration of diabetes. This negative association attenuated after adjustment for other confounders and became nonsignificant after further adjustment for FCP. Patients with different BMI categories had similar DR risk when stratified by FCP tertiles.Overweight patients have lower DR prevalence than normal weight individuals, which may be attributable to better β cell function in overweight patients.

Three recent genome-wide association studies (GWAS) identified several single-nucleotide polymorphisms (SNPs) with modest effects on diabetic retinopathy in Mexican-American and white patients with diabetes. This study aimed to evaluate the effects of these variants on diabetic retinopathy in Chinese patients with type 2 diabetes.A total of 1,972 patients with type 2 diabetes were recruited to this study, including 819 patients with diabetic retinopathy and 1,153 patients with diabetes of ≥5 years duration but without retinopathy. Forty SNPs associated with diabetic retinopathy in three GWAS were genotyped. Fundus photography was performed to diagnose and classify diabetic retinopathy.rs17684886 in ZNRF1 and rs599019 near COLEC12 were associated with diabetic retinopathy (OR 0.812, p = 0.0039 and OR 0.835, p = 0.0116, respectively) and with the severity of diabetic retinopathy (p = 0.0365 and p = 0.0252, respectively, for trend analysis). Sub-analysis in patients with diabetic retinopathy revealed that rs6427247 near SCYL1BP1 (also known as GORAB) and rs899036 near API5 were associated with severe diabetic retinopathy (OR 1.368, p = 0.0333 and OR 0.340, p = 0.0005, respectively). The associations between rs6427247 and rs899036 and severe diabetic retinopathy became more evident after a meta-analysis of published GWAS data (OR 1.577, p = 2.01 × 10−4 for rs6427247; OR 0.330, p = 5.84 × 10−7 for rs899036).We determined that rs17684886 and rs599019 are associated with diabetic retinopathy and that rs6427247 and rs899036 are associated with severe diabetic retinopathy in Chinese patients with type 2 diabetes.

The aim of this study was to investigate the association of PAX4 variants with therapeutic effect of oral antidiabetic drugs in Chinese type 2 diabtes mellitus (T2DM) patients. A total of 209 newly diagnosed T2DM patients were randomly assigned to treatment with repaglinide or rosiglitazone for 48 weeks, and the therapeutic effects were compared. In the rosiglitazone cohort, rs6467136 GA+AA carriers showed greater decrease in 2-h glucose levels (P=0.0063) and higher cumulative attainment rates of target 2-h glucose levels (Plog rank=0.0093) than GG homozygotes. In the subgroup with defective β-cell function, rs6467136 GA+AA carriers exhibited greater decrements of 2-h glucose level and improvement of homeostasis model assessment of insulin resistance (P=0.0143). Moreover, GA+AA carriers were more likely to attain the target fasting and 2-h glucose level (Plog rank=0.0091 and 0.007, respectively). However, these single-nucleotide polymorphisms showed no effect on repaglinide efficacy. In conclusion, PAX4 variant rs6467136 was associated with the therapeutic effect of rosiglitazone in Chinese T2DM patients.

Emerging evidence has consistently shown that a very low carbohydrate diet (VLCD) can protect against the development of obesity, but the underlying mechanisms are not fully understood. Here we applied a comprehensive metabonomics approach using ultraperformance liquid chromatography–quadrupole time-of-flight mass spectrometry and gas chromatography–time-of-flight mass spectrometry to study the effects of an 8-week dietary intervention with VLCD on serum metabolic profiles in obese subjects. The VLCD intervention resulted in a weight loss and significantly decreased homeostasis model assessment-insulin resistance. The metabonomics analysis identified a number of differential serum metabolites (p < 0.05) primarily attributable to fatty acids, amino acids including branched chain amino acids, amines, lipids, carboxylic acids, and carbohydrates in obese subjects compared to healthy controls. The correlation analysis among time, VLCD intervention, and clinical parameters revealed that the changes of metabolites correlated with the changes of clinical parameters and showed differences in males and females. Fatty acids, amino acids, and carboxylic acids were increased in obese subjects compared with their normal healthy counterparts. Such increased levels of serum metabolites were attenuated after VLCD intake, suggesting that the health beneficial effects of VLCD are associated with attenuation of impaired fatty acid and amino acid metabolism. It also appears that VLCD induced significant metabolic alterations independent of the obesity-related metabolic changes. The altered metabolites in obese subjects post-VLCD intervention include arachidonate, cis-11,14-eicosadienoate, cis-11,14,17-eicosatrienoate, 2-aminobutyrate, acetyl-carnitine, and threonate, all of which are involved in inflammation and oxidation processes. The results revealed favorable shifts in fatty acids and amino acids after VLCD intake in obese subjects, which should be considered biomarkers for evaluating health beneficial effects of VLCD and similar dietary interventions.

Most genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the aim of identifying novel variants for type 2 diabetes in Asians.We performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations.We identified CDKN2A/B and four novel type 2 diabetes association signals with p < 1 × 10−5 from the meta-analysis. Thirteen variants within these four loci were followed up in two independent Chinese cohorts, and rs10229583 at 7q32 was found to be associated with type 2 diabetes in a combined analysis of 11,067 cases and 7,929 controls (pmeta = 2.6 × 10−8; OR [95% CI] 1.18 [1.11, 1.25]). In silico replication revealed consistent associations across multiethnic groups, including five East Asian populations (pmeta = 2.3 × 10−10) and a population of European descent (p = 8.6 × 10−3). The rs10229583 risk variant was associated with elevated fasting plasma glucose, impaired beta cell function in controls, and an earlier age at diagnosis for the cases. The novel variant lies within an islet-selective cluster of open regulatory elements. There was significant heterogeneity of effect between Han Chinese and individuals of European descent, Malaysians and Indians.Our study identifies rs10229583 near PAX4 as a novel locus for type 2 diabetes in Chinese and other populations and provides new insights into the pathogenesis of type 2 diabetes.

Nonalcoholic fatty liver disease (NAFLD) is strongly associated with obesity, hyperlipidemia, and type 2 diabetes mellitus. Several studies have found that fat mass and the obesity-associated (FTO) gene is linked to obesity. The aim of this work is to investigate the expression and function of FTO in liver with lipid metabolism diseases.We investigated the basal FTO expression in an NAFLD rat model and compared it with control subjects. The function of FTO in lipid metabolism was further studied in L02 cells through overexpression experiments.A significant increase in FTO mRNA and protein levels was found in the NAFLD group. In addition, the FTO levels were positively associated with malondialdehyde and superoxide dismutase concentrations. FTO overexpression in L02 cells enhanced lipogenesis and oxidative stress.This study demonstrates that increased FTO levels in the liver are involved in oxidative stress and lipid deposition, which characterize NAFLD.

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.

There is evidence of overlap between susceptibility loci for type 2 diabetes and obesity. The aim of this study is to explore the association between the established type 2 diabetes locus KCNQ1 and obesity in Han Chinese.We recruited 6,667 and 6,606 diabetic case–control samples from Shanghai and Hong Kong, respectively. Of the samples, 7.5% and 6.3% were excluded because of genotyping failure or data missing in the association analyses of rs2237892 and rs2237895 with obesity/BMI, respectively.We found that rs2237892 was associated with lower BMI and lower incidence of overweight/obesity in diabetic patients from Hong Kong (BMI, β = −0.0060 per diabetes risk C allele for log10BMI [95% CI −0.0088, −0.0032; p = 2.83 × 10−5]; overweight/obesity, OR 0.880 for C allele [95% CI 0.807, 0.960; p = 0.004]) and in the meta-analysis of cases from the two regions (BMI, combined β = −0.0048 per C allele for log10BMI [95% CI −0.0070, −0.0026; p = 2.20 × 10−5]; overweight/obesity, combined OR 0.890 for C allele [95% CI 0.830, 0.955; p = 0.001]). rs2237895 was also related to decreased BMI (combined β = −0.0042 per diabetes risk C allele for log10BMI [95% CI −0.0062, −0.0022; p = 4.30 × 10−5]). A significant association with waist circumference was detected for rs2237892 in the pooled analyses (β = −0.0026 per C allele for log10[waist circumference] [95% CI −0.0045, −0.0007; p = 0.007]). However, neither an association with the risk of being overweight or obese nor associations with quantitive traits were detected for rs2237892 or rs2237895 in controls.Our findings indicate that KCNQ1 is associated with obesity in Chinese patients with type 2 diabetes.

Gut microbiota are associated with essential various biological functions in humans through a “network” of microbial–host co-metabolism to process nutrients and drugs and modulate the activities of multiple pathways in organ systems that are linked to different diseases. The microbiome impacts strongly on the metabolic phenotypes of the host, and hence, metabolic readouts can give insights into functional metagenomic activity. We applied an untargeted mass spectrometry (MS) based metabonomics approach to profile normal Wistar rats exposed to a broad spectrum β-lactam antibiotic imipenem/cilastatin sodium, at 50 mg/kg/daily for 4 days followed by a 14-day recovery period. In-depth metabolic phenotyping allowed identification of a panel of 202 urinary and 223 fecal metabolites significantly related to end points of a functional metagenome (p < 0.05 in at least one day), many of which have not been previously reported such as oligopeptides and carbohydrates. This study shows extensive gut microbiota modulation of host systemic metabolism involving short-chain fatty acids, tryptophan, tyrosine metabolism, and possibly a compensatory mechanism of indole–melatonin production. Given the integral nature of the mammalian genome and metagenome, this panel of metabolites will provide a new platform for potential therapeutic markers and mechanistic solutions to complex problems commonly encountered in pathology, toxicology, or drug metabolism studies.

Variants of the human CYP4A11, which belongs to the cytochrome P450, family 4, have been reported to be associated with hypertension in general populations. However, data in the Chinese population are limited. This study sought to assess the effect of CYP4A11 on the prevalence of hypertension and blood pressure in a Chinese population. Three tagging single nucleotide polymorphisms, rs9332982, rs4660980 and rs3890011, were genotyped in 1734 community-based participants. Individuals with secondary hypertension were excluded. Sex-pooled and sex-specific analysis for genotype–phenotype association were both conducted. We found rs9332982 T allele was nominally associated with higher prevalence of hypertension in women after adjustment for covariates (OR: 1.38, 95%CI: 1.06–1.81, P=0.0183). The significance did not retain after Bonferroni correction. In blood pressure analysis restricted to normotensive individuals, rs4660980 was associated with both systolic (β=−3.17, P=0.0011) and diastolic blood pressure (β=−1.75, P=0.0010) in men. A common variant on CYP4A11 was associated with blood pressure in a Chinese population. Future studies are needed to confirm our findings.

The aim of this study was to compare the difference of blood glucose (BG) fluctuation in the patients of type-2 diabetes mellitus (DM-2) with and without clinical diagnosed diabetic nephropathy (DN) by the continuous glucose monitoring system (CGMS). Thirty DM-2 patients with clinical diagnosed DN and fifteen DM-2 patients without complication underwent continuous glucose monitoring for 3 days (72 h) by CGMS. The difference of daily glucose fluctuation in both groups was compared by the parameter of CGMS. The 24-h mean blood glucose (MBG), minimal BG (MIN-BG), area under curve of BG over 7.8 (AUC7.8), percentage of time of BG over 7.8 (PT7.8), area under curve of BG over 11.1 (AUC11.1), percentage of time of BG over 11.1 (PT11.1), as well as mean of daily difference (MODD) were significantly increased in the group of DN, compared with those in the group of DM-2 without complication (all statistic probability P <0.05). No statistical significance of mean amplitude of glycaemic excursion (MAGE) was found. In the group of DN, MBG, standard deviation of blood glucose (SDBG), large amplitude of glycaemic excursion (LAGE), AUC7.8, PT7.8, AUC11.1, PT11.1, MAGE and MODD were (10.7±1.9)mmol/L, (2.5±1.3)mmol/L, (9.2±3.9)mmol/L, 3.2±1.7, (81±18)%, 1.2±1.0, (42±24)%, (5.8±2.5)mmol/L and (2.6±1.5)mmol/L, respectively. The study showed that the BG level of the patients with DN fluctuated throughout the day. MBG of the patients with DN was higher than that of the patients of DM-2 without complications, with the characteristics of long-lasting high BG period, dramatic instability during the day and especially high postprandial blood glucose. CGMS is a useful tool for physicians to know the details of the change of BG in the patients with DN.

The pathological development and the drug intervention of type 2 diabetes mellitus (T2DM) involve altered expression of downstream low molecular weight metabolites including lipids and amino acids, and carbohydrates such as glucose. Currently, a small number of markers used for clinical assessment of T2DM treatment may be insufficient to reflect global variations in pathophysiology. In this study, a metabonomic study was performed to determine metabolic variations associated with T2DM and the drug treatments on 74 patients who were newly diagnosed with T2DM and received a 48 week treatment of a single drug, repaglinide, metformin or rosiglitazone. Fasting overnight and 2 h postprandial blood serum of patients were collected at 24 and 48 weeks to monitor the biochemical indices (FPG, 2hPG, HbA1c, etc.). Gas chromatography/mass spectrometer coupled with multivariate statistical analysis was used to identify the alteration of global serum metabolites associated with T2DM as compared to healthy controls and responses to drug treatment. Significantly altered serum metabolites in diabetic subjects include increased valine, maltose, glutamate, urate, butanoate and long-chain fatty acid (C16:0, C18:1, C18:0, octadecanoate and arachidonate), and decreased glucuronolactone, lysine and lactate. All of the three treatments were able to down-regulate the high level of glutamate to a lower level in serum of T2DM patients, but rosiglitazone treatment was able to reverse more abnormal levels of metabolites, such as valine, lysine, glucuronolactone, C16:0, C18:1, urate, and octadecanoate, suggesting that it is more efficient to alter the metabolism of T2DM patients than the other two drugs.

Recent genome-wide association studies in East Asian populations reported that single nucleotide polymorphisms (SNPs) in KCNQ1 are associated with type 2 diabetes. The aim of this study was to validate this finding in a Chinese population.We genotyped four SNPs, rs2074196, rs2237892, rs2237895 and rs2237897, in a group of 3,503 Shanghai Chinese individuals, comprising 1,769 type 2 diabetic patients and 1,734 normoglycaemic controls. Both the cases and the controls were extensively phenotyped for anthropometric and biochemical traits related to glucose metabolism. Arginine stimulation tests under fasting conditions were performed in a subgroup of 466 cases.All four of the SNPs were associated with type 2 diabetes, with rs2237892 showing strongest evidence for association (OR 1.532, 95% CI 1.381–1.698, p = 5.0 × 10−16). The SNP rs2237897 was associated with both acute insulin and C-peptide response after arginine stimulation in a subgroup of cases (p = 0.0471 and p = 0.0156, respectively). The SNP rs2237895 was associated with both first- and second-phase insulin secretion in the controls (p = 0.0334 and p = 0.0002, respectively).In this study we found that KCNQ1 was associated with type 2 diabetes susceptibility in a Chinese population, possibly through its effect on beta cell function.

Single nucleotide polymorphisms (SNPs) in G6PC2 have been reported to be associated with fasting plasma glucose level in several populations of European descent. However, whether G6PC2 variants have a similar effect in other ethnic groups is unknown. The aim of this study was to investigate the effect of common variants of G6PC2 on type 2 diabetes and related clinical features in a Chinese population.We selected four SNPs, rs13387347, rs2232316, rs492594 and rs16856187, tagging all the common variants spanning the G6PC2 gene (r2 ≥ 0.8) based on HapMap Chinese data, and genotyped them in a group of 3,676 Shanghai Chinese individuals, comprising 1,876 cases and 1,800 controls.Three SNPs were nominally associated with type 2 diabetes, with rs16856187 showing the strongest evidence for association (p = 0.0009, empirical p = 0.0047). Further conditional analysis revealed that the association signal arose from an individual SNP, rs16856187. This SNP was also associated with fasting plasma glucose level in participants with normal glucose regulation (p = 0.0002), with the fasting plasma glucose level observed to increase by 0.067 mmol/l with each copy of the rare C allele.In this study we identified a novel risk-conferring G6PC2 SNP for type 2 diabetes in a Chinese population and confirmed the previous finding that G6PC2 variants are associated with fasting plasma glucose concentration.

ObjectiveTo determine whether smoking increases the risk for developing metabolic syndrome (MetS) in Chinese men.MethodsA total of 693 men with no MetS at baseline were followed for 2.9–5.5 years. Subjects were divided into nonsmokers, ex-smokers, and current smokers according to baseline smoking status.ResultsAfter adjusting for age, education level, alcohol intake, fasting plasma insulin, HOMA-IR index, and BMI at baseline and weight change, current smokers were dose-dependently associated with increased risk for developing new MetS compared with nonsmokers. The odds ratio (OR) was 2.131 (95% CI, 1.264, 3.592; P<0.01) for the NCEPIII definition or 3.083 (95% CI, 1.807, 5.295; P<0.01) for the JCDCG definition of MetS. Ex-smokers who had quit for ≥13 years significantly decreased the risk for developing new MetS defined by the JCDCG definition. Compared with nonsmokers, current smokers were significantly associated with increased incidence of hypertriglyceridemia and low HDL-C.ConclusionSmoking is a risk factor for developing MetS in Chinese men after adjusting for age, education level, alcohol intake, fasting plasma insulin, HOMA-IR, BMI, and weight change. This could be due to an increased incidence of dyslipidemia. Smoking cessation for >13 years decreased the risk for developing MetS defined by the JCDCG definition.

BackgroundSeveral prospective studies have shown that a genetic risk score combining multiple loci could predict incident type 2 diabetes in white people, but few studies elucidated the underlying mechanism. We aimed to assess the combined effects of type 2 diabetes risk variants on predicting deterioration of blood glucose tolerance, and progressive changes in β-cell function and insulin sensitivity in a prospective cohort in the Chinese population.MethodsWe constructed a weighted genetic risk score model based on 40 variants associated with type 2 diabetes validated in an established cross-sectional Chinese population (n=6822). The weighted genetic risk score was categorised into tertiles (low risk<43·0, intermediate risk ≤43·0 to <46·7, high risk ≥46·7) to assess the score's predictive effect on incidence of type 2 diabetes and impaired glucose regulation, as well as changes in Stumvoll first and second phase insulin secretion indices, and Gutt's insulin sensitivity index. We used a community-based prospective cohort by recruiting participants from the Shanghai region of China, including participants with normal glucose tolerance and patients with impaired glucose regulation at baseline. We analysed the data using logistic, Cox, and multiple linear regression tests. Ethical approval was granted by the Institutional Review Board of Shanghai Jiao Tong University Affiliated Sixth People's Hospital. Informed patient consent was given by all participants.FindingsThe study commenced in 1998–99 with the enrolment of 2495 individuals at baseline, including 2192 individuals with normal glucose tolerance and 303 with impaired glucose regulation. Individuals were also invited to participate in another two follow-up examinations in 2002–03 and 2010–12. Over an average follow-up of 9·0 (SD 2·8) years, 260 individuals developed type 2 diabetes and 326 individuals developed impaired glucose regulation. The weighted genetic risk score as a ranked variable predicted incidence of type 2 diabetes and impaired glucose regulation in the logistic regression (odds ratio 1·24, 95% CI 1·10–1·39, p=0·0004) as well as in the Cox model (hazard ratio 1·13, 95% CI 1·03–1·24, p=0·013) after adjusting for age, sex, BMI, and smoking and alcohol status at baseline. Moreover, multiple linear regression revealed that the weighted genetic risk score as a ranked variable had a predictive effect on deterioration of β-cell function (β −0·0480 for first phase insulin secretion, and β −0·0303 for second phase insulin secretion, p<0·0001) but not insulin sensitivity (p=0·38) during the 9 year follow-up period. Only individuals in the lowest group had elevated first and second phase insulin secretion, which compensated for impaired insulin sensitivity. However, individuals in the other two groups had decreased first-phase insulin secretion accompanied by increased second-phase secretion to partly offset the initial low levels.InterpretationThe weighted genetic risk score predicted deterioration of blood glucose control through effects on β-cell function in this Chinese population. Individuals in the intermediate weighted or high weighted genetic risk score group showed progressive deterioration of β-cell function.FundingNational Science Foundation of China, the National 863 programme, the National 973 programme, the National Program for Support of Top-notch Young Professionals, Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support, and the Shanghai Jiao Tong Medical and Engineering Foundation.

•GA is positively correlated with HbA1c (r = 0.832, P < 0.001).•1% increase of the mean HbA1c is associated with a 2.84% increase in mean GA.•For HbA1c of 6.5 and 7.0%, the calculated GA is 18. 3% and 19.7%.•The GA/HbA1c ratio increases with the presence of glucose intolerance.•Increased 30-min glucose and decreased BMI are related to GA/HbA1c ratio.AimsTo determine the relationship between glycated albumin (GA) and glycated hemoglobin (HbA1c) and to explore the association of glycated albumin/glycated hemoglobin (GA/HbA1c) ratio with glucose indices in Chinese subjects with varying glucose tolerance status.MethodsThis hospital-based, cross-sectional study involved 953 participants without known diabetes from 11 centers in China. Oral glucose tolerance test (OGTT) was used to identify three groups of subjects: normal glucose regulation (n = 194), impaired glucose regulation (n = 303) and newly diagnosed type 2 diabetes group (n = 456). The GA, HbA1c and GA/HbA1c ratio were tested.ResultsGA was positively correlated with HbA1c (r = 0.832, P < 0.001). After correcting for age, sex and BMI, the correlations remained significant (r = 0.824, P < 0.001). Linear regression analysis estimated that a 1% increase of HbA1c was associated with a 2.84% increase of GA (GA = 2.843 × HbA1c − 0.203; R2 = 0.692, P < 0.001). GA would be 18.3 (16.7–19.9)% and 19.7 (18.0–21.4)% with HbA1c of 6.5% (48 mmol/mol) and 7.0% (53 mmol/mol). The mean GA/HbA1c ratio was 2.81 ± 0.38, and it significantly increased with the presence of glucose intolerance (all, P < 0.05). In the total study population, GA/HbA1c was correlated with BMI, glucose levels and 30-min insulin during OGTT, the homeostatic model assessment of β-cell function (HOMA-β), and ΔI30/ΔG30 (all, P < 0.05). Increased glucose at 30 min (standardized β = 0.221, P < 0.001), and decreased BMI (standardized β = −0.114, P = 0.008) were associated with elevated GA/HbA1c ratio by multiple linear regression (adjusted R2 = 0.045).ConclusionsThe relationship between GA and HbA1c was strong. The GA/HbA1c ratio was related to acute postprandial glucose fluctuation and BMI level.

•We performed a retrospective study consisted of 605 Chinese patients with T2DM to explore the relationship between TSH and DPN.•TSH level was significantly and independently associated with DPN in patients with T2DM.•The optimal cutoff point of TSH to indicate DPN was 3.045 mIU/L in men and 2.94 mIU/L in women.•High serum TSH level may be a potential risk factor for DPN in Chinese population with T2DM.AimThe association between thyroid stimulating hormone (TSH) and type 2 diabetes mellitus (T2DM) is well known. However, whether TSH is related to diabetic peripheral neuropathy (DPN) has not been studied. The aim of this study was to explore the relationship between TSH and DPN in Chinese patients with T2DM.MethodsIn this cross-sectional study, 605 patients with T2DM were enrolled. Subclinical hypothyroidism (SCH) was defined as an elevated TSH level (>4.0 mIU/L) and a normal free thyroxine level. DPN was evaluated by neurological symptoms, neurological signs, and electromyogram.ResultsSerum TSH levels were significantly higher in DPN and signs of DPN compared with non-DPN T2DM patients (both P < 0.01).The prevalence of DPN and signs of DPN in SCH subjects was higher than that in euthyroid subjects (both P < 0.01). Spearman's correlation analysis showed that the serum TSH level was positively associated with DPN (r = 0.172, P < 0.01). A significant independent association between TSH and DPN was found by multiple logistic regression analysis after adjusting for potential confounding variables [odds ratio (OR) = 1.365, P < 0.01]. The patients were sequentially assigned to quartiles according to TSH level. Compared with quartile 1, patients in quartile 2 (P < 0.01), quartile 3 (P = 0.01), and quartile 4 (P < 0.01) had a higher risk of DPN. Receiver-operating characteristic curve analysis revealed that the optimal cutoff point of TSH to indicate DPN was 3.045 mIU/L in men and 2.94 mIU/L in women.ConclusionTSH level is independently associated with DPN in Chinese population with T2DM. A high serum TSH level may be a potential risk factor for DPN.

ObjectiveWaist circumference, as a brief indicator of visceral obesity, is associated with multi-metabolic disorders and cardiovascular diseases. The present study was aimed to find out the relationship between waist circumference and carotid intima media thickness (C-IMT), as well as the best waist circumference cutoff for identifying C-IMT elevation in Chinese male patients with newly-diagnosed diabetes.MethodsFive hundred and seventy-eight patients from Department of Endocrinology and Metabolism in Shanghai Sixth People's Hospital affiliated to Shanghai Jiao Tong University were enrolled. Both physical examination (for measurement of waist circumference) and carotid ultrasonography (for measurement of C-IMT) were performed.ResultsAfter grouping according to the quartiles of C-IMT, the waist circumference increased across all its quartiles. The waist circumference in 3rd and 4th quartiles (90.7±9.8 cm and 90.8±9.6 cm) was significant higher than in 1st and 2nd quartiles (P<0.05). When subjects were divided into 4 groups according to waist circumference, the C-IMT of subjects with waist circumference 90–95 cm was significant higher than that of subjects with waist circumference 85–90 cm and less than 85 cm respectively (P<0.05). Both spearman and partial correlation analysis showed that C-IMT was positively correlated with waist circumference (P<0.01). C-IMT was found significantly elevated with the increase of waist circumference. Multiple stepwise regression analysis showed that waist circumference was one of the independent risk factors of C-IMT. After an average of 2.23±0.85 years follow up, there was a significant elevation of C-IMT in the group with baseline waist circumference over 90 cm P<0.05), while no significant difference was detected in the group with baseline waist circumference less than 90 cm (P=0.27). Logistic regression showed that baseline waist circumference over 90 cm was associated with a relative risk to C-IMT elevation of 1.132 (95% CI 1.043–1.431, P<0.05).ConclusionAmong newly-diagnosed diabetic male patients, waist circumference over 90 cm not only reflects sub-clinical atherosclerosis in early stage, but also predicts the progression of atherosclerosis.

BackgroundAssociations between demographic data and arterial stiffness have not been examined adequately in Chinese obese patients with type 2 diabetes (T2DM) who underwent Roux-en-Y gastric bypass (RYGB).ObjectiveThis study was designed to examine changes in body fat distribution and metabolic parameters after RYGB and whether these changes correlated with improved arterial stiffness.SettingThe study was performed at the authors’ academic university-affiliated hospital.MethodsA retrospective review of 42 Chinese patients with a diagnosis of obesity and T2DM and 22 health controls was conducted, focusing on metabolic outcomes and aortic pulse wave velocity (PWV) before and 12 months after RYGB.ResultsAt baseline, PWV in the study group was significantly greater than in the control group (6.9±1.5 versus 5.8±.6 ms, respectively; P<.01). PWV was negatively correlated with age, systolic blood pressure, diastolic blood pressure, visceral fat area (VFA), and leptin level (r = .47, P<.01; r = .39, P<.01; r = .31, P = .03; r = .47, P<.01; and r = .30, P = .03, respectively). Multiple stepwise regression found that age and VFA were independently associated with PWV (β = .40, P<.01; β = .30, P = .02, respectively). PWV, body mass index, VFA, and metabolic profiles all improved significantly 12 months after RYGB. The change in PWV was positively correlated with changes in VFA and the leptin level (r = .40, P = .03; r = .40, P = .02, respectively).ConclusionsDecreased VFA resulting from RYGB correlated with improved arterial stiffness in obese Chinese patients with T2DM. Leptin might be an important factor linking PWV and visceral fat accumulation.

ObjectiveTo evaluate the present Chinese body mass index (BMI) criteria with body fat percentage (BF%) in determining obesity in Chinese population.MethodsA total of 4 907 subjects (age: 20-90 yrs) were enrolled in the baseline survey of a longitudinal epidemiological study, and 2 638 of them were reevaluated in 5.5 years later. The Chinese BMI and WHO BF% were used to define obesity, respectively.ResultsThe diagnostic agreement between the Chinese BMI and WHO BF% definitions for obesity was poor for both men (kappa: 0.210, 95% CI: 0.179-0.241) and women (kappa: 0.327, 95% CI: 0.296-0.358). However, BMI had a good correlation with BF% both in men (r: 0.785, P<0.01) and women (r: 0.864, P<0.01). The age and sex-adjusted relative risks (RR) for incidence of type 2 diabetes (T2DM) were significantly higher in subjects with intermediate BF% (BF%:20.1%-25% for men, 30.1%-35% for women) (RR: 2.35, 95% CI: 1.23-4.48) and high BF%(BF%>25% for men and > 35% for women)(RR: 2.89, 95% CI: 1.43-5.81), or in subjects with high BMI (BMI≥28 kg/m2) (RR: 2.46, 95% CI: 1.31-4.63) when compared to those with low BF% (BF%≤20% for men and≤30% for women) or low BMI (BMI24 kg/m2) respectively. No difference in risk could be found in those with intermediate BMI (BMI: 24-27.9 kg/m2) (RR: 1.44, 95% CI: 0.86-2.40), as compared to those with low BMI (BMI<24 kg/m2), whose BF% ranged widely from 7.8 to 50.3%.ConclusionBMI was correlated with BF%. Both BMI and BF% were associated with high risk for T2DM. However, BMI had its limitations in the interpretation of subjects with BMI between 24 and 27.9 kg/m2.

•This is a follow-up randomized cohort study.•We firstly reported MATE1 (rs2289669) gene distribution in Chinese population.•Patients with AA genotype had better long-term hypoglycemic effect of metformin.•Patients with AA genotype had slower elimination of metformin.•SLC47A1 genotype was an independent factor for urine excretion of metformin.AimsThe SLC47A1 gene encodes the multi-drug and toxic excretion-1(MATE1) protein, which plays a key role in the transport and excretion of metformin. This study is to clarify the influence of variants in SLC47A1 (rs2289669 G → A) on metformin pharmacokinetics and the long-term glucose-lowering effect of metformin.MethodsA total of 220 newly diagnosed type 2 diabetes patients were recruited, genotyped and divided into three groups by SLC47A1 genotypes (G/G, G/A, A/A). Ten patients in each group were randomly selected for metformin pharmacokinetics. All the participants received metformin oral treatment and were followed for one year.ResultsAfter one-year follow-up, the decline of HbA1c level was significantly greater in subjects with variant genotype (AA) than other two groups (−2.32% [−25.4 mmol/mol] in AA vs. −1.16% [−12.7 mmol/mol] in GA, −1.07% [−11.7 mmol/mol] in GG, P < 0.05). Then taking GG genotype as the referent, the association between AA genotype and change of HbA1c still existed after adjusted for age, sex, BMI, baseline HbA1c and diabetes duration (P < 0.05). Pharmacokinetic parameters of metformin indicated that patients carrying MATE1 homozygous A had higher area under the plasma concentration versus time curve (AUC12h), but lower renal clearance (CLR) and renal clearance by secretion (CLSR) than other patients (all P < 0.01). Multivariate lineal stepwise analysis further revealed that SLC47A1 genotype was an independent impact factor for urine excretion of metformin (P < 0.01).ConclusionsSLC47A1 rs2289669 G > A variants improve the glucose-lowering effect of metformin through slowing its excretion in type 2 diabetes populations.

Human mitochondrial DNA is a circular DNA molecule that encodes some of the proteins required for oxidative phosphorylation. Different mitochondrial DNA genotypes may coexist within a single cell, a condition known as heteroplasmy. An A-to-G transition at position 3243 of mitochondrial DNA (A3243G) can result in maternally inherited diabetes and deafness (mitochondrial diabetes). However, the commonly used methods of PCR restriction fragment length polymorphism and Sanger sequencing are neither sensitive nor reliable enough to detect this low level of heteroplasmy. Here, we developed a quantitative method based on pyrosequencing to analyze the heteroplasmy of the A3243G mutation in leukocyte DNA obtained from 83 persons of 15 unrelated pedigrees with mitochondrial diabetes. The accuracy and reliability of this method were also measured by comparing the results with those from high-resolution melting analysis, Sanger sequencing, and PCR restriction fragment length polymorphism with artificial heteroplasmy standard samples. The results showed that the accuracy of pyrosequencing was much higher than that of the other methods, and the limitation of heteroplasmy detection with this method reached 2%, based on our artificial control studies. An inverse correlation was found between the level of heteroplasmy and the age of the onset in our patients. This result suggested that the heteroplasmy of the A3243G mutation could become a significant prediction index for the onset of mitochondrial diabetes.

BackgroundMetabolic surgery has been proposed for inadequately controlled type 2 diabetes mellitus (T2DM) in association with obesity. However, prediction of successful T2DM remission after surgery has not been clearly studied in Chinese patients. The objective of this study was to predict the outcome in those with T2DM after metabolic surgery to help in patient selection.MethodsA retrospective review of prospectively collected data of 68 ethnic Chinese with mean body mass index (BMI) of 31.5 and T2DM were examined for the metabolic outcomes at 1 year after Roux-en-Y gastric bypass (RYGB). Visceral and abdominal subcutaneous fat areas were assessed using magnetic resonance imaging before and 1 year after RYGB. Remission was defined as a glycated hemoglobin (HbA1 c)<6.5% and no medications at 1 year. Binary logistic regression analysis was used to identify predictors.ResultsAt 1 year after surgery, the BMI in the study group decreased from 31.5±3.6 to 24.5±2.5 kg/m2. Remission was achieved in 50 patients (73.5%) at 1 year. Compared with patients in the nonremission group, patients in the remission group had a shorter duration of diabetes, lower preoperative HbA1 c level, higher fasting C-peptide level, and more visceral fat area (VFA). Preoperative BMI and waist circumference did not differ between the 2 groups.ConclusionThe metabolic improvement in T2DM after RYGB in the mildly obese is greater with a shorter duration of diabetes, higher fasting C-peptide. Those who have more visceral adiposity may obtain greater benefit from RYGB.

AimsTo investigate the association between non-alcoholic fatty liver disease (NAFLD) and carotid and lower limb atherosclerotic lesions in a large group of hospitalized-based type 2 diabetic population and to assess the prevalence and characteristics of NAFLD in Chinese subjects with type 2 diabetes (T2DM).MethodsA total of 8571 patients (4804 men) with T2DM were included in this cross-sectional study. The main outcome measures were detection of NAFLD, carotid intima-media thickness (C-IMT), carotid and lower limb atherosclerotic plaque formation, and classical risk factors.ResultsThe prevalence of carotid (56.5% vs. 44.5%; p < 0.001) and lower limb plaque (56.2% vs. 48.7%; p < 0.001), and carotid (11.2% vs. 6.8%; p < 0.001) and lower limb stenosis (15.1% vs. 10.3%; p < 0.001) was markedly higher in the diabetic patients with NAFLD than in those without, after controlling for age. However, there was no significant difference in C-IMT between diabetic patients with and without NAFLD (0.82 ± 0.30 mm vs. 0.85 ± 0.39 mm) after controlling for age. Fully adjusted multiple linear regression and logistic regression analyses revealed that NAFLD was significantly associated with increased prevalence of carotid and lower limb atherosclerotic plaque but not with C-IMT. NAFLD, age, sex, longer duration of diabetes and the presence of hypertension were independently associated with carotid and lower limb atherosclerotic plaque (p < 0.05).ConclusionNAFLD was not associated with elevated C-IMT but was associated with carotid and lower limb atherosclerotic plaque independent of conventional cardiovascular disease risk factors and metabolic syndrome in Chinese inpatients with T2DM.

Aims/hypothesisThe aim of this study was to investigate clinical spectrum of hepatocyte nuclear factor-1β (HNF-1β) mutation in Chinese diabetic patients with renal dysfunction and/or structure abnormalities.Materials and methodsA total of 104 diabetic patients with renal structural abnormalities and/or non-diabetic renal dysfunction were recruited and HNF-1β mutation was screened by direct sequencing.ResultsThree heterozygous missense mutations including c.494G>A (p.R165H), c.662A>T (p.D221V) and c.780G>C (p.E260D) were identified. Progression of diabetes and mild decline of renal function were observed in the mutation carriers during the follow-up. The p.R165H mutation carrier had severe β-cell dysfunction and different extrapancreatic phenotypes. Compared with type 2 diabetes and normoglycemics, the p.R165H mutation carrier had a lower basal C-peptide (0.30, 0.61 ± 0.07 and 0.50 ± 0.04 nmol/L for p.R165H, type 2 diabetes and normoglycemics, respectively) and low values of acute C-peptide response to arginine (0.15, 0.48 ± 0.18 and 0.76 ± 0.08 nmol/L for p.R165H, type 2 diabetes and normoglycemics, respectively).ConclusionPatients with the HNF-1β mutation in our population can have different pancreatic and extrapancreatic phenotypes. The exact contributions of mutations to the phenotypes await functional confirmation.

ObjectiveTo investigate a potential relationship between Solute carrier family 30 (zinc transporter) member 8 (SLC30A8) rs13266634 variant and efficacy of rosiglitazone or repaglinide in treating newly diagnosed Chinese type 2 diabetes patients.MethodsA total of 209 diabetic patients without any antihyperglycemic history were recruited and treated with repaglinide or rosiglitazone randomly for 48 weeks (104 and 105 patients, respectively). Anthropometric measurements and clinical laboratory tests were carried out before and after the treatment. An non-synonymous variant rs13266634 was genotyped by matrix-assisted laser desorption ionization-time of flight mass spectroscopy.ResultsNinety-one patients in repaglinide group and ninety-three patients in rosiglitazone group completed the study. Δ value of homeostasis model assessment of beta cell function (HOMA-B) and Δ value of fasting proinsulin levels were statistically significant between three genotype groups (P=0.0149 and 0.0246, respectively) after rosiglitazone treatment. However, no genotype association was observed in the repaglinide or rosiglitazone group with other parameters.ConclusionThe SLC30A8 variant was associated with the efficacy of insulin sensitizer monotherapy on insulin secretion in patients with newly diagnosed type 2 diabetes mellitus in Shanghai, China.

ObjectiveThe 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.MethodsA 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.ResultsAs 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<0.01).ConclusionMetS was highly prevalent in middle-aged and elderly Chinese. MetS significantly increased the risk to CVD incidence in the elderly. All individuals with metabolic disorders should receive active clinical care to reduce the incidence of CVD.

ObjectiveTo investigate the relationship of liver enzymes with hyperglycemia in a large population in Shanghai and identify the association between liver enzymes and insulin resistance.MethodsA total of 3 756 participants were enrolled. Each participant underwent an oral glucose tolerance test and completed a questionnaire. Anthropometric indices were recorded and serum samples were collected for measurement.ResultsLiver enzymes concentrations were independently associated with i-IGT, IFG+IGT, and diabetes. With the increase of ALT and GGT concentrations, ORs for i-IGT, IFG+IGT, and diabetes increased gradually. By comparing patients in the highest quartile of GGT concentrations or ALT concentrations with those in the lowest quartile (Q1), ORs for i-IGT, IFG+IGT, or diabetes was significant after adjustment. Both ALT and GGT concentrations were linearly correlated with HOMA-IR and independently associated with HOMA-IR [ALT OR (95% CI): 2.56 (1.51-4.34) P=0.00; GGT OR (95% CI): 2.66 (1.53-4.65) P=0.00].ConclusionSerum ALT and GGT concentrations were closely related to pre-diabetes and diabetes in the Shanghai population and positively associated with insulin resistance.

Obesity is a medical condition with excess body fat accumulation to the extent which leads to serious health consequences. Abdominal obesity, also known as central obesity, refers to the presence of excess fat in the abdominal area. Obesity, especially abdominal obesity, contributes to many metabolic disorders including metabolic syndrome (MetS), type 2 diabetes (T2DM) and cardiovascular diseases (CVD). The incidence of obesity has increased dramatically in recent years worldwide. In China, more than one-third of adults are overweight or obese and 10%-20% of all adults are affected by MetS. The pathogenesis underlying the abdominal obesity remains unclear. The ultimate health outcome of obesity and its related metabolic disorders have prompted physicians to take aggressive treatments (lifestyle changes, pharmacological interventions and surgical therapies) before a serious consequence becomes clinically apparent. In this review, we discuss the prevalence, pathogenesis and clinic features of obesity in China.

Retinol binding protein 4 (RBP4) is a protein secreted by adipocytes, and closely associated with insulin resistance. Whereas RBP4 is also mainly expressed in hepatocytes as the principal transport protein for retinol (vitamin A) in the circulation, and its pathophysiological role in liver remain unclear. The aim of this paper was to investigate the association between RBP4 and nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). Serum RBP4 and adiponectin concentrations were measured by radioimmunoassay in 52 diabetic patients who had NAFLD and 50 sex- and age-matched diabetic patients without any clinical features of liver diseases who had normal liver ultrasonic appearance and normal liver function. Serum RBP4 levels were elevated in diabetic patients with NAFLD (32.0 ± 8.9 μg/ml vs. 41.3 ± 9.8 μg/ml, p < 0.001), while adiponectin decreased (17.4 ± 9.3 μg/ml vs. 13.8 ± 7.0 μg/ml, p = 0.032). Male diabetic patients had higher serum RBP4 concentration and lower serum adiponectin concentration than female diabetic patients (38.5 ± 9.9 μg/ml vs. 34.0 ± 10.7 μg/ml, p = 0.031 and 12.7 ± 5.7 μg/ml vs. 20.23 ± 9.8 μg/ml, p < 0.001, respectively). Multiple logistic regression analysis revealed RBP4 and triglyceride as independent association factors for NAFLD, while the association between serum adiponectin and NAFLD was not significant. Increasing concentrations of RBP4 were independently and significantly associated with NAFLD in diabetic patients. In multiple linear regression analysis, alanine aminotransferase, fasting serum insulin and adiponectin were independent factors for serum RBP4 level. The study demonstrates that retinol binding protein 4 might contribute to the pathogenesis of nonalcoholic fatty liver disease.

The prevalence of diabetes in China has increased substantially over recent decades, with more than 100 million people estimated to be affected by the disease presently. During this period there has been an increase in the rates of obesity and a reduction in physical activity. Many of the changes in lifestyle and diet are a result of increased economic development and urbanisation. In addition to an increasingly westernised diet, the traditional Chinese diet also plays a part, with the quantity and quality of rice intake linked to the risk of type 2 diabetes. Familial factors including inherited genetic variants are important, although differences in the genetic architecture suggest a different combination of genetic variants could be most relevant in Chinese when compared with Europeans. Recent advances have also emphasised the role of early life factors in the epidemic of diabetes and non-communicable diseases: maternal undernutrition, maternal obesity, and gestational diabetes are all linked to increased risk of diabetes in offspring. A mismatch between developmentally programmed biology and the modern environment is relevant for countries like China where there has been rapid economic transformation. Multisectoral efforts to address the risks will be needed at different stages throughout the lifecourse to reduce the burden of diabetes.

BackgroundGlycemic variability after Roux-en-Y Gastric Bypass (RYGB) has not been adequately examined in Chinese obese patients with type 2 diabetes (T2D).ObjectiveWe aimed to evaluate glucose variability after RYGB by continuous glucose monitoring (CGM) and then evaluate the remission rate based on the complete diabetes remission criteria combined with normal ranges of CGM for the Chinese population, which we defined as “dual-remission.”SettingThe study was done at our academic university-affiliated hospital.MethodsOver a 3-day period, CGM was performed on 43 Chinese obese T2D patients combined with a mixed-meal test before and 1 year after RYGB. Mean amplitude of glucose excursions (MAGE), standard deviations (SD), and the time that patients’ blood glucose levels were≥7.0 mmol/L,≥7.8 mmol/L,≥11.1 mmol/L, and≤3.9 mmol/L within 24 hours was analyzed. Multiple logistic regression analyses were used to identify predictors of “dual-remission.”ResultsComplete diabetes remission was achieved in 27 patients (62.8%) 1 year after RYGB. However, MAGE didn’t change in the group, and only 18.6% patients met “dual-remission.” Compared with patients in the complete remission group, patients in the dual-remission group had a shorter duration of diabetes, younger age, lower glycated hemoglobin (HbA1c) level, and no insulin usage at baseline. Correlation analysis showed MAGE after RYGB was positively correlated with diabetes duration (r = .43, P<.01). Multiple logistic regressions indicated a shorter duration was associated with a higher possibility to achieve dual-remission after adjusting for age, gender, HbA1c, and insulin therapy.ConclusionGlucose variability can’t be effectively improved in most Chinese obese diabetic patients after RYGB. Shorter diabetes duration was associated with higher possibility to achieve “dual-remission.”

BackgroundThere is increasing evidence that serum betatrophin levels, a hormone derived from adipose tissue and liver, are elevated in type 2 diabetes (T2D).ObjectiveTo investigate the relationships among betatrophin and metabolic control, insulin resistance, and pancreatic β-cell function in obese Chinese patients with T2D who underwent Roux-en-Y gastric bypass (RYGB).SettingUniversity hospital, China.MethodsThis 1-year follow-up study included 34 obese individuals with T2D (18 males, 16 females) who underwent RYGB in our hospital. Anthropometric results, glucose levels, lipid profiles, and serum betatrophin levels were determined before and 1 year after RYGB.ResultsThe serum betatrophin level decreased significantly after RYGB (72.0 ng/mL [33.4–180.9] versus 35.7 ng/mL [14.8–103.3]); P<.001]. The change in betatrophin was significantly positively correlated with the changes in hemoglobin A1c and fasting plasma glucose and negatively correlated with the changes in the 2-hour C-peptide/fasting C-peptide and homeostasis model of assessment of β-cell function (P<.05). Multiple stepwise regression analysis indicated that the change in the serum betatrophin level was independently and significantly associated with the changes in fasting plasma glucose (β = .586, P<.001) and 2-hour C-peptide/fasting C-peptide (β = –.309, P = .021).ConclusionCirculating betatrophin might be involved in the regulation of glucose control and insulin secretion in obese Chinese with T2D soon after RYGB.

Overweight or obesity has become a serious public health problem in the world, scientists are concentrating their efforts on exploring novel ways to treat obesity. Nowadays, the availabilities of bariatric surgery and pharmacotherapy have enhanced obesity treatment, but it should has support from diet, physical exercise and lifestyle modification, especially the functional food. Resistant starch, an indigestible starch, has been studied for years for its beneficial effects on regulating blood glucose level and lipid metabolism. The aim of this review is to summarize the effect of resistant starch on weight loss and the possible mechanisms. According to numerous previous studies it could be concluded that resistant starch can reduce fat accumulation, enhance insulin sensitivity, regulate blood glucose level and lipid metabolism. Recent investigations have focused on the possible associations between resistant starch and incretins as well as gut microbiota. Resistant starch seems to be a promising dietary fiber for the prevention or treatment of obesity and its related diseases.

BackgroundUnlike in western countries, premixed insulin is widely used as the starter insulin in Asian patients instead of basal insulin. The use of basal-bolus therapy as an intensification regimen is not common in Asia despite poor glycaemic control after starting insulin therapy. An alternative insulin intensification regimen with a similar efficacy and safety profile to basal-bolus therapy, but of higher convenience, is urgently needed. The efficacy and safety of insulin lispro mix thrice-daily was compared with basal-bolus therapy in Asian patients with type 2 diabetes who were insufficiently controlled on twice-daily premixed insulin.MethodsThis open-label, randomised, active comparator-controlled, parallel-group trial was done at 24 centres in China, Taiwan, and South Korea. Patients with type 2 diabetes who were inadequately controlled on twice-daily premixed insulin were randomly assigned (1:1) to receive either insulin lispro mix (mix 50 before breakfast and lunch plus mix 25 before dinner) or basal-bolus therapy (insulin glargine at bedtime plus prandial insulin lispro thrice-daily) for 24 weeks. Randomisation was done by a computer-generated random sequence and was stratified by country or region and baseline HbA1c. Treatment assignments were masked from the study team assessing outcomes but not from investigators and patients. The primary outcome was change from baseline in HbA1c at week 24 in all randomly assigned patients who received at least one dose of study drug. Analysis was by modified intention to treat, with the per-protocol population used as a supportive analysis. This study is registered with ClinicalTrials.gov, number NCT01175811.FindingsBetween Feb 7, 2011, and Nov 7, 2012, 402 patients were enrolled (199 in the premix group, 203 in the basal-bolus group) and 399 were included in the primary analysis (197 in the premix group, 202 in the basal-bolus group). HbA1c change at week 24 was −1·1% for both treatment groups. The least squares mean difference between groups in HbA1c change from baseline was 0% (95% CI −0·1 to 0·2). Insulin lispro mix was non-inferior to basal-bolus therapy based on the prespecified margin of 0·4%. The frequency of adverse events, and the incidences and 30-day rates of nocturnal and overall hypoglycaemia were comparable between groups. No severe hypoglycaemia was reported.InterpretationA premixed insulin lispro regimen thrice-daily was non-inferior to basal-bolus therapy in terms of overall glycaemic control and thus could be an option for intensified insulin regimen in Asian patients with type 2 diabetes who are inadequately controlled with twice-daily premixed insulin.FundingEli Lilly and Company.