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Accumulating evidences showed metformin and berberine, well‐known glucose‐lowering agents, were able to inhibit mitochondrial electron transport chain at complex I. In this study, we aimed to explore the antihyperglycaemic effect of complex I inhibition. Rotenone, amobarbital and gene silence of NDUFA13 were used to inhibit complex I. Intraperitoneal glucose tolerance test and insulin tolerance test were performed in db/db mice. Lactate release and glucose consumption were measured to investigate glucose metabolism in HepG2 hepatocytes and C2C12 myotubes. Glucose output was measured in primary hepatocytes. Compound C and adenoviruses expressing dominant negative AMP‐activated protein kinase (AMPK) α1/2 were exploited to inactivate AMPK pathway. Cellular NAD+/NADH ratio was assayed to evaluate energy transforming and redox state. Rotenone ameliorated hyperglycaemia and insulin resistance in db/db mice. It induced glucose consumption and glycolysis and reduced hepatic glucose output. Rotenone also activated AMPK. Furthermore, it remained effective with AMPK inactivation. The enhanced glycolysis and repressed gluconeogenesis correlated with a reduction in cellular NAD+/NADH ratio, which resulted from complex I suppression. Amobarbital, another representative complex I inhibitor, stimulated glucose consumption and decreased hepatic glucose output in vitro, too. Similar changes were observed while expression of NDUFA13, a subunit of complex I, was knocked down with gene silencing. These findings reveal mitochondrial complex I emerges as a key drug target for diabetes treatment. Inhibition of complex I improves glucose homoeostasis via non‐AMPK pathway, which may relate to the suppression of the cellular NAD+/NADH ratio.

Mitochondrial function is critical in energy metabolism. To fully capture how the mitochondrial function changes in metabolic disorders, we investigated mitochondrial function in liver and muscle of animal models mimicking different types and stages of diabetes. Type 1 diabetic mice were induced by streptozotocin (STZ) injection. The db/db mice were used as type 2 diabetic model. High‐fat diet‐induced obese mice represented pre‐diabetic stage of type 2 diabetes. Oxidative phosphorylation (OXPHOS) of isolated mitochondria was measured with Clark‐type oxygen electrode. Both in early and late stages of type 1 diabetes, liver mitochondrial OXPHOS increased markedly with complex IV‐dependent OXPHOS being the most prominent. However, ATP, ADP and AMP contents in the tissue did not change. In pre‐diabetes and early stage of type 2 diabetes, liver mitochondrial complex I and II‐dependent OXPHOS increased greatly then declined to almost normal at late stage of type 2 diabetes, among which alteration of complex I‐dependent OXPHOS was the most significant. In contrast, muscle mitochondrial OXPHOS in HFD, early‐stage type 1 and 2 diabetic mice, did not change. In vitro, among inhibitors to each complex, only complex I inhibitor rotenone decreased glucose output in primary hepatocytes without cytotoxicity both in the absence and presence of oleic acid (OA). Rotenone affected cellular energy state and had no effects on cellular and mitochondrial reactive oxygen species production. Taken together, the mitochondrial OXPHOS of liver but not muscle increased in obesity and diabetes, and only complex I inhibition may ameliorate hyperglycaemia via lowering hepatic glucose production.

Background Both carotid and lower limb atherosclerosis are associated with increased cardiovascular and cerebrovascular risks. However, it is still unclear whether the concomitant presence of carotid and lower extremity atherosclerosis further increases the cardiovascular and cerebrovascular risks. Therefore, our aim is to investigate whether the coexistence of carotid and lower extremity atherosclerosis was associated with higher cardiovascular and cerebrovascular risks in patients with type 2 diabetes. Methods This cross-sectional study was performed in 2830 hospitalized patients with type 2 diabetes. Based on carotid and lower limb Doppler ultrasound results, the patients were divided into three groups including 711 subjects without atherosclerosis, 999 subjects with either carotid or lower limb atherosclerosis, and 1120 subjects with both carotid and lower limb atherosclerosis. And we compared the clinical characteristics and prevalence of both cardio-cerebrovascular events (CCBVEs) and self-reported cardio- cerebrovascular diseases (CCBVDs) among the three groups. Results After adjusting for age, sex, and duration of diabetes, there were significant increases in the prevalence of both CCBVEs (3.8 vs. 11.8 vs. 26.4 %, p < 0.001 for trend) and self-reported CCBVDs (6.9 vs. 19.9 vs. 36.5 %, p < 0.001 for trend) across the three groups (diabetics without atherosclerosis, diabetics with either carotid or lower limb atherosclerosis, and diabetics with both carotid and lower extremity atherosclerosis). A fully adjusted logistic regression analysis also revealed that compared with those without atherosclerosis, those with either carotid or lower limb atherosclerosis had higher risk of CCBVEs (OR 1.724, 95 % CI 1.001–2.966) and self-reported CCBVDs (OR 1.705, 95 % CI 1.115–2.605), and those with concomitant presence of carotid and lower extremity atherosclerosis had the highest risk of CCBVEs (OR 2.869, 95 % CI 1.660–4.960) and self-reported CCBVDs (2.147, 95 % CI 1.388–3.320)(p < 0.001 for trend in CCBVEs and p = 0.002 for trend in CCBVDs, respectively). Conclusions Either carotid or lower limb atherosclerosis was obviously related to increased cardio-cerebrovascular risk in type 2 diabetes. The concomitant presence of carotid and lower extremity atherosclerosis further increased cardio-cerebrovascular risk in patients with type 2 diabetes. The combined application of carotid and lower extremity ultrasonography may help identify type 2 diabetics with higher cardio-cerebrovascular risk.

Osteocalcin is a newly identified type of cytokine secreted by osteoblasts, which has an endocrine function, mediates energy and glycol-lipid metabolism, and is closely related to cardiovascular diseases. In this study, we investigated the value of serum osteocalcin levels in predicting left ventricular systolic dysfunction and cardiac death. A total of 258 patients in the Department of Cardiology were included. Two-dimensional echocardiography was performed in all the subjects. The cardiac death of subjects occurring with a median follow-up of 4.6 years was informed via phone calls or the electronic medical records. The serum osteocalcin levels were measured using electrochemiluminescent immunoassay. We found that the median left ventricular ejection fractions (LVEFs) were 62% in men and 63% in women. In the men with a LVEF > 62%, the serum osteocalcin levels were significantly higher than in those with LVEF ≤ 62% ( P   =  0.042), whereas this difference was absent in the women. Both the serum osteocalcin ( β  = 0.095, P   =  0.028) and serum N-terminal pro-brain natriuretic peptide (NT-pro-BNP; β  = −0.003, P   <  0.01) levels remained independently significantly correlated with LVEF in the men but not in the women. Receiver operating characteristic (ROC) analyses of the men revealed that the serum osteocalcin ( P  = 0.007), serum NT-pro-BNP ( P  = 0.018) and serum osteocalcin + NT-pro-BNP ( P  < 0.01) levels were all significant in identifying left ventricular systolic dysfunction at baseline, but the pairwise comparisons of the three areas under the curves (AUCs) were all non-significant. The men in the lower osteocalcin level group at baseline suffered a greater risk of future cardiac death than those in the higher osteocalcin level group, whereas the result for NT-pro-BNP exhibited the opposite pattern. In conclusion, lower serum osteocalcin levels in the men could identify left ventricular systolic dysfunction and cardiac death in a manner that was not inferior to high serum NT-pro-BNP levels.

Both early- and late-phase images showed enhanced focal retention of Tc–99m MIBI located at the middle-upper part of the right thyroid lobe, and the abnormal signal accumulation was localized specifically at the middle-upper part of the dorsal right thyroid lobe by the fusion imaging of SPECT/CT, which suggested the existence of right-sided parathyroid adenoma [Figure 1A]. The patient provided no significant medical history and family history associated with multiple endocrine adenomatosis (MEN), and her CT scan of adrenal areas and cranial magnetic resonance imaging (MRI) scan demonstrated no obvious abnormality, therefore ruling out the possibility of MEN. [...]we recommend careful and thorough examination of the patients with both pHPT and thyroid nodules before parathyroidectomy to avoid missing concurrent thyroid carcinoma and re-operation.

The association between type 2 diabetes （T2DM） and bone metabolism has been discussed previously but is controversial. In this study we aimed to evaluate the association of bone turnover markers with glucose metabolism in Chinese population, in which 919 males and 4171 postmenopausal females in a region of Shanghai were recruited. Anthropometric and biochemical traits related to glucose and bone metabolism were analyzed. Participants were classified according to their glucose tolerance as normal glucose tolerance （NGT）, impaired glucose regulation （IGR） or T2DM. Males and females were analyzed separately, and then associations between bone turnover markers （BTMs） and glucose metabolism were evaluated. The results showed that in females, the serum levels of N-terminal osteocalcin （N-MID）, N-terminal procollagen of type I collagen （PINP） and β-cross-linked C-telopeptide of type I collagen （β-CTX） were significantly decreased in the T2DM group compared to the NGT group （P〈0.01）. When age, body mass index, serum lipids, fat percentage, visceral fat area, subcutaneous fat area, anti-diabetic medicines, PINP, N-MID and β-CTX were included in one logistic model, N-MID （OR [95% CI]： 0.954 [0.932; 0.976]; P=0.0001） was significantly associated with T2DM in females. In females, N-MID was associated with insulin sensitivity and HOMA-β. PINP was significantly associated with HOMA-β, GUTT-ISI, Stumvo first-phase insulin secretion index （STU-1） and Stumvoll second-phase insulin secretion index （STU-2）, but β-CTX was associated only with HOMA-β （β_＋SE： 0.1331±0.0311; P=1.95×10^-5） and GUTI--ISI （β±SE： 0.0727±0.0229; P=0.0015）. In males, N-MID was significantly correlated with HOMA-β （β±SE： 0.3439±0.0633; P=7.75×10^-8）, GUTT-ISI （β±SE： 0.1601±0.0531; P=0.0027） and STU-1 （β±SE： 0.2529±0.1033; P=0.0146）. Significant associations were also detected between 13-CTX and HOMA-β （β＋SE： 0.2736±0.0812; P=0.0009）. This study reveals that BTMs are highly associated with T2DM, insulin sensitivity and beta cell function in both Chinese males and postmenopausal females.

Aim： Osteocalcin is involved in the progression of nonalcoholic fatty liver disease （NAFLD） in animal models and humans. In this study we investigated the relationship between serum osteocalcin levels and NAFLD in postmenopausal Chinese women. Methods： A total of 733 postmenopausal women （age range： 41-78 years） with normal blood glucose levels were enrolled in this cross-sectional study. Women taking lipid-lowering or anti-hypertensive drugs were excluded. Serum osteocalcin levels were assessed using an electrochemiluminescence immunoassay. The degree of NAFLD progression for each subject was assessed through ultrasonography. The fatty liver index （FLI） of each subject was calculated to quantify the degree of liver steatosis. Results： The median level of serum osteocalcin for all subjects enrolled was 21.99 ng/mL （interquartile range： 17.84-26.55 ng/mL）, Subjects with NAFLD had significantly lower serum osteocalcin levels （18,39 ng/mL; range： 16,03-23,64 ng/mL） compared with those without NAFLD （22,31 ng/mL; range： 18.55-27.06 ng/mL; P〈0.01）. Serum osteocalcin levels decreased with incremental changes in the FLI value divided by the quartile （P-value for trend〈0.01）. The serum osteocalcin levels showed a negative correlation with the FLI values, even after adjusting for confounding factors （standardized 13=-0.124; P〈0.01）. Binary logistic regression analysis identified an individual＇s serum osteocalcin level as an independent risk factor for NAFLD （odds ratio： 0.951; 95% confidence interval： 0.911- 0.992; P=0.02）. Conclusion： Serum osteocalcin levels are inversely correlated with NAFLD in postmenopausal Chinese women with normal blood glucose levels.

KCNQ1 channel is a member of the voltage-gated potassium channel KQT-like subfamily. The KCNQ1 gene has recently been identified as a susceptibility locus for type 2 diabetes mellitus （T2DM）. In the present study, we examined the effects of KCNQ1 variants on the therapeutic response to modified-release gliclazide （gliclazide MR） treatment in Chinese patients newly diagnosed with T2DM. A total of 100 newly diagnosed T2DM patients without a history of any anti-diabetic medications were treated with gliclazide MR for 16 weeks, but 91 patients completed the entire study. The anthropometric parameters were determined at baseline and at the final visit, while clinical laboratory tests were performed at baseline and on weeks 2, 4, 6, 12, 16. Two SNPs, rs2237892 and rs2237895, in the region of the KCNQ1 gene weregenotyped in all the participants. All calculations and statistical analyses were conducted using SPSS. The rs2237892 TT homozygotes exhibited significantly higher 2-h glucose levels at baseline （P〈0.05） and a lower cumulative attainment rate of the target 2-h glucose level （Plog-raok=0.020） than the C allele carriers. Patients with greater numbers of rs2237892 T alleles exhibited larger augmentations （＆） in the 2-h glucose levels （P=0.027）; and patients with the rs2237892 TT genotype exhibited a higher △ homeostasis model assessment of L3-cell function （HOMA-β） than CC and CT genotype carriers （P=0.021 and P=0.043, respectively）. Moreover, the rs2237895 C allele was associated with a greater decrement in ＆ glycated hemoglobin （HbAlc） （P=0.024）; and patients with the CC genotype exhibited greater variance than those with the AA and AC genotypes （P=0.005 and 0.021, respectively）. Compared with the C allele, the odds ratio for treatment success among carriers of the rs2237892 T allele was 2.533 （P=0.007）; and the rs2237895 C allele was associated with a 2.360-fold decrease in HbAlc compared with the A allele （P=0.009）. KCNQ1 polymorphisms are associated with gliclazide MR efficacy in Chinese patients with type 2 diabetes.

There is evidence that post-load/post-meal hyperglycemia is a stronger risk factor for cardiovascular disease than fasting hyperglycemia. The underlying mechanism remains to be elucidated. The current study aimed to compare the metabolic profiles of post-load hyperglycemia and fasting hyperglycemia. All subjects received an oral glucose tolerance test (OGTT) and were stratified into fasting hyperglycemia (FH) or post-load hyperglycemia (PH). Forty-six (FH, n  = 23; PH, n  = 23) and 40 patients (FH, n  = 20; PH, n  = 20) were recruited as the exploratory and the validation set, respectively, and underwent metabolic profiling. Eighty-seven subjects including normal controls (NC: n  = 36; FH: n  = 22; PH: n  = 29) were additionally enrolled and assayed with enzyme-linked immunosorbent assay (ELISA). In the exploratory set, 10 metabolites were selected as differential metabolites of PH (vs. FH). Of them, mannose and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) were confirmed in the validation set to be significantly higher in FH than in PH. In the 87 subjects measured with ELISA, FH had numerically higher mannose (466.0 ± 179.3 vs. 390.1 ± 140.2 pg/ml) and AICAR (523.5 ± 164.8 vs. 512.1 ± 186.0 pg/ml) than did PH. In the pooled dataset comprising 173 subjects, mannose was independently associated with FPG ( β  = 0.151, P  = 0.035) and HOMA-IR ( β  = 0.160, P  = 0.026), respectively. The associations of AICAR with biochemical parameters did not reach statistical significance. FH and PH exhibited distinct metabolic profiles. The perturbation of mannose may be involved in the pathophysiologic disturbances in diabetes.

Aim： Considering the characterization of vitamin D deficiency as a risk factor of ectopic fat deposition, the association of serum 25-hydroxy vitamin D3 [25（OH）D3] levels with non-alcoholic fatty liver disease （NAFLD） was evaluated in Chinese men with normal body mass index （BMI） and enzyme markers of liver function. Methods： A total of 514 participants （22 to 79 years old） with normal BMI and liver enzymes were identified for analysis. Abdominal ultrasound was performed to diagnose NAFLD, and the fatty liver index （FLI） was calculated to quantify liver steatosis. Serum 25（OH）D3 levels were determined by an electrochemiluminescence immunoassay. Results： Among the entire study population, the mean levels of serum 25（OH）D3 were 15.32±5.77 ng/mL. However, when serum 25（OH）D3 levels were compared between non-NAFLD subjects （n=438） and NAFLD subjects （n=76）, the latter showed significantly lower levels （15.65±5.89 ng/mL vs 13.46±4.65 ng/mL, P=0.002）. In addition, serum 25（OH）D3 levels were found to be significantly correlated with FLI after adjustment for age and BMI （r=-0.108, P=0.014）. Logistic regression showed that serum 25（OH）D3 levels were independently correlated with NAFLD （OR： 0.937, 95% CI： 0.884-0.993, P=0.028）. Furthermore, stepwise regression analysis revealed that serum 25（OH）D3 levels were inversely associated with FLI （β=-0.055, P=0.040）. Conclusion： The present study demonstrated that serum 25（OH）D3 levels were inversely associated with NAFLD, even in subjects with normal total body fat, suggesting a potential role of lower levels of vitamin D in the occurrence and development of NAFLD.