Enhanced liver but not muscle OXPHOS in diabetes and reduced glucose output by complex I inhibition.

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.

Low serum osteocalcin levels are correlated with left ventricular systolic dysfunction and cardiac death in Chinese men.

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 (ß = 0.095, P = 0.028) and serum N-terminal pro-brain natriuretic peptide (NT-pro-BNP; ß = -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.

Metabolic perturbations of post-load hyperglycemia vs. fasting hyperglycemia.

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 (ß = 0.151, P = 0.035) and HOMA-IR (ß = 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.

Inhibition of mitochondrial complex I improves glucose metabolism independently of AMPK activation.

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.

Association of serum uric acid levels with osteoporosis and bone turnover markers in a Chinese population.

Recent evidence shows that uric acid is protective against some neurological diseases, but can be detrimental in many metabolic and cardiovascular disorders. In this study, we examined the association between serum uric acid levels and bone metabolism in Chinese males and postmenopausal females. A total of 943 males and 4256 postmenopausal females were recruited in Shanghai. The levels of serum uric acid and bone turnover markers (BTMs) were detected along with other biochemical traits. In addition, the fat distribution was calculated through MRI and image analysis software, and bone mineral density (BMD) was determined using dual-energy X-ray absorptiometry. For postmenopausal females, the prevalence of osteoporosis was significantly lower in the hyperuricemia group compared with the normouricemic group (P=4.65E-06). In females, serum uric acid level was significantly associated with osteoporosis, with odds ratio (OR) and 95% confidence interval (95% CI) of 0.844 [0.763; 0.933] (P=0.0009) after adjusting for age, body mass index, HbA1c, lean mass, visceral and subcutaneous fat areas, albumin, 25-hydroxyvitamin D3 [25(OH)D3], and parathyroid hormone (PTH). In females, serum uric acid level was positively correlated with the BMD of the femoral neck (ß±SE: 0.0463±0.0161; P=0.0042), total hip (ß±SE: 0.0433±0.0149; P=0.0038) and L1-4 (ß±SE: 0.0628±0.0165; P=0.0001) after further adjusting for age, BMI, HbA1c, lean mass, VFA, SFA, albumin, 25(OH)D3 and PTH. Regarding BTMs, serum uric acid level was negatively correlated with N-terminal procollagen of type I collagen (PINP) in females (ß±SE: -0.1311±0.0508; P=0.0100). In summary, our results suggest that uric acid has a protective effect on bone metabolism independent of body composition in Chinese postmenopausal females.

Association of bone turnover markers with glucose metabolism in Chinese population.

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 ß-cross-linked C-telopeptide of type I collagen (ß-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 ß-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-ß. PINP was significantly associated with HOMA-ß, GUTT-ISI, Stumvoll first-phase insulin secretion index (STU-1) and Stumvoll second-phase insulin secretion index (STU-2), but ß-CTX was associated only with HOMA-ß (ß±SE: 0.1331±0.0311; P=1.95×10-5) and GUTT-ISI (ß±SE: 0.0727±0.0229; P=0.0015). In males, N-MID was significantly correlated with HOMA-ß (ß±SE: 0.3439±0.0633; P=7.75×10-8), GUTT-ISI (ß±SE: 0.1601±0.0531; P=0.0027) and STU-1 (ß±SE: 0.2529±0.1033; P=0.0146). Significant associations were also detected between ß-CTX and HOMA-ß (ß±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.

Polymorphisms of the KCNQ1 gene are associated with the therapeutic responses of sulfonylureas in Chinese patients with type 2 diabetes.

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 were genotyped 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-rank=0.020) than the C allele carriers. Patients with greater numbers of rs2237892 T alleles exhibited larger augmentations (Δ) in the 2-h glucose levels (P=0.027); and patients with the rs2237892 TT genotype exhibited a higher Δ homeostasis model assessment of ß-cell function (HOMA-ß) 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 Δ glycated hemoglobin (HbA1c) (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 HbA1c compared with the A allele (P=0.009). KCNQ1 polymorphisms are associated with gliclazide MR efficacy in Chinese patients with type 2 diabetes.

The coexistence of carotid and lower extremity atherosclerosis further increases cardio-cerebrovascular risk in type 2 diabetes.

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.

Decreased urine uric acid excretion is an independent risk factor for chronic kidney disease but not for carotid atherosclerosis in hospital-based patients with type 2 diabetes: a cross-sectional study.

BACKGROUND: The associations between urine uric acid excretion (UUAE) and chronic kidney disease (CKD)/atherosclerosis have not been investigated. Our aims were to investigate the relationships between UUAE and CKD and carotid atherosclerotic lesions in hospitalized Chinese patients with type 2 diabetes. METHODS: This was a cross-sectional study that was conducted with 2627 Chinese inpatients with type 2 diabetes. UUAE was determined enzymatically using a single 24-h urine collection. The subjects were stratified into quartiles according to their UUAE levels. Carotid atherosclerotic lesions, including carotid intima-media thickness (CIMT), plaque and stenosis, were assessed by Doppler ultrasound. Both CKD and carotid atherosclerotic lesions were compared between the UUAE quartile groups. RESULTS: After adjustment for confounding factors, there was a significant decrease in the prevalence of CKD in the patients with type 2 diabetes across the UUAE quartiles (16.9%, 8.5%, 5.9%, and 4.9%; p < 0.001). Multiple logistic regression analyses revealed that the UUAE quartiles were significantly and inversely associated with the presence of CKD (p < 0.001). Compared with the diabetics in the highest UUAE quartile, those in the lowest quartile exhibited a nearly 4.2-fold increase in the risk of CKD (95% CI: 2.272-7.568; p < 0.001). The CIMT value (0.91 ± 0.22 mm for the diabetics with CKD and 0.82 ± 0.20 mm for the diabetics without CKD, p = 0.001) and the prevalence of carotid plaques (62.1% for the diabetics with CKD and 41.8% for the diabetics without CKD, p = 0.025) were significantly higher in the diabetics with CKD than in those without CKD. However, there was no obvious difference in carotid atherosclerotic lesions across the UUAE quartiles after controlling for the confounding factors. CONCLUSIONS: Decreased UUAE was closely associated with the presence of CKD but not with carotid atherosclerotic lesions in hospitalized Chinese patients with type 2 diabetes. Our results suggest that UUAE is an independent risk factor for CKD in type 2 diabetes. In selected populations, such as patient with type 2 diabetes, the role of uric acid in atherosclerosis might be the result of other concomitant atherosclerotic risk factors, such as CKD.

Inverse relationship between serum osteocalcin levels and nonalcoholic fatty liver disease in postmenopausal Chinese women with normal blood glucose levels.

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 ß=-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.

Serum vitamin D is associated with non-alcoholic fatty liver disease in Chinese males with normal weight and liver enzymes.

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 (ß=-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.

Serum uric acid levels are associated with polymorphisms in the SLC2A9, SF1, and GCKR genes in a Chinese population.

AIM: Genome-wide association studies have identified several novel loci associated with serum uric acid concentrations in individuals of European descent. In the current study, we aimed to evaluate the associations between these loci and serum uric acid concentrations in a Chinese population. METHODS: Fourteen single nucleotide polymorphisms (SNPs) mapped in or near 11 loci (PDZK1, GCKR, LRP2, SLC2A9, ABCG2, LRRC16A, SLC17A1, SLC17A3, SLC22A11, SLC22A12 and SF1) were genotyped in 2329 Chinese subjects in Shanghai. Serum biochemical parameters including uric acid concentrations were determined. All the variants were analyzed for gender differences since uric acid metabolism differed between genders. RESULTS: In males after adjustments for age and BMI, GCKR rs780094, SLC2A9 rs11722228 and SF1 rs606458 were associated with the uric acid concentrations, which were statistically significant (P=0.016, 0.001 and 0.03, respectively), whereas SLC2A9 rs3775948 was marginally associated with the uric acid concentrations (P=0.071). In females, SLC22A12 rs506338 was also marginally associated with the uric acid concentrations (P=0.057). The meta-analysis for combined data from both males and females revealed that rs3775948 and rs606458 were associated with the uric acid concentrations (P=0.036 and 0.043, respectively). Furthermore, the gender significantly affected the association of rs11722228 with serum uric acid levels (P=0.012). CONCLUSION: The SLC2A9 rs11722228, SF1 rs606458 and GCKR rs780094 variants modulate uric acid concentrations in Chinese males, while SF1 rs606458 and SLC2A9 rs3775948 are associated with the uric acid concentrations in both Chinese males and females.

Relationship between waist circumference and elevation of carotid intima-media thickness in newly-diagnosed diabetic patients.

OBJECTIVE: Waist 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. METHODS: Five 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. RESULTS: After 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). CONCLUSION: Among 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.

Prevalence and clinical characteristics of carotid atherosclerosis in newly diagnosed patients with ketosis-onset diabetes: a cross-sectional study.

BACKGROUND: The features of carotid atherosclerosis in ketosis-onset diabetes have not been investigated. Our aim was to evaluate the prevalence and clinical characteristics of carotid atherosclerosis in newly diagnosed Chinese diabetic patients with ketosis but without islet-associated autoantibodies. METHODS: In total, 423 newly diagnosed Chinese patients with diabetes including 208 ketosis-onset diabetics without islet-associated autoantibodies, 215 non-ketotic type 2 diabetics and 79 control subjects without diabetes were studied. Carotid atherosclerosis was defined as the presence of atherosclerotic plaques in any of the carotid vessel segments. Carotid intima-media thickness (CIMT), carotid atherosclerotic plaque formation and stenosis were assessed and compared among the three groups based on Doppler ultrasound examination. The clinical features of carotid atherosclerotic lesions were analysed, and the risk factors associated with carotid atherosclerosis were evaluated using binary logistic regression in patients with diabetes. RESULTS: The prevalence of carotid atherosclerosis was significantly higher in the ketosis-onset diabetic group (30.80%) than in the control group (15.2%, p=0.020) after adjusting for age- and sex-related differences, but no significant difference was observed in comparison to the non-ketotic diabetic group (35.8%, p=0.487). The mean CIMT of the ketosis-onset diabetics (0.70±0.20 mm) was markedly higher than that of the control subjects (0.57±0.08 mm, p<0.001), but no significant difference was found compared with the non-ketotic type 2 diabetics (0.73±0.19 mm, p=0.582) after controlling for differences in age and sex. In both the ketosis-onset and the non-ketotic diabetes, the prevalence of carotid atherosclerosis was markedly increased with age (both p<0.001) after controlling for sex, but no sex difference was observed (p=0.479 and p=0.707, respectively) after controlling for age. In the ketosis-onset diabetics, the presence of carotid atherosclerosis was significantly associated with age, hypertension, low-density lipoprotein cholesterol and mean CIMT. CONCLUSIONS: The prevalence and risk of carotid atherosclerosis were significantly higher in the ketosis-onset diabetics than in the control subjects but similar to that in the non-ketotic type 2 diabetics. The characteristics of carotid atherosclerotic lesions in the ketosis-onset diabetics resembled those in the non-ketotic type 2 diabetics. Our findings support the classification of ketosis-onset diabetes as a subtype of type 2 diabetes.

Low-grade albuminuria is associated with early but not late carotid atherosclerotic lesions in community-based patients with type 2 diabetes.

BACKGROUND: Low-grade albuminuria is associated with cardiovascular risk factors and mortality. Our aim was to investigate the association between low-grade albuminuria and carotid atherosclerotic lesions in community-based patients with type 2 diabetes. METHODS: A cross-sectional study was performed in 475 community-based patients with type 2 diabetes (190 males and 285 females) with normal urinary albumin-to-creatinine ratios (UACR) (< 3.5 mg/mmol) from Shanghai, China. The subjects were stratified into tertiles based on UACR levels (the lowest tertile was UACR ≤ 1.19 mg/mmol, and the highest tertile was UACR ≥ 2 mg/mmol). Carotid intima-media thickness (CIMT), carotid atherosclerotic plaque formation and stenosis were assessed and compared among the three groups based on ultrasonography. The urinary albumin excretion rate was determined as the mean of the values obtained from three separate early morning urine samples. RESULTS: Compared with the subjects with UACR in the lowest tertile, the subjects with UACR in the middle and highest tertiles had greater CIMT values (0.88 ± 0.35 mm, 0.99 ± 0.43 mm and 1.04 ± 0.35 mm, respectively; all p < 0.05) and a higher prevalence of carotid atherosclerotic plaques (25.3%, 39.0% and 46.2%, respectively; all p < 0.05) after adjusting for sex and age. Fully adjusted multiple linear regression and logistic regression analyses revealed that UACR tertiles were significantly associated with elevated CIMT (p = 0.007) and that, compared with the subjects in the first tertile of UACR, those in the second and third tertiles had 1.878- and 2.028-fold risk of carotid plaques, respectively. However, there was no statistical association between UACR tertile and the prevalence of carotid stenosis. CONCLUSIONS: Higher UACR within the normal range was independently associated with early but not late carotid atherosclerotic lesions in community-based patients with type 2 diabetes. Low-grade albuminuria contributes to the risk of carotid atherosclerosis and may be used as an early marker for the detection of atherosclerosis in patients with type 2 diabetes.

Correlation between waist circumference and carotid intima-media thickness in women from Shanghai, China.

OBJECTIVE: To evaluate whether waist circumference (WC) ≥85 cm is related to asymptomatic preclinical atherosclerosis in women from Shanghai, China. METHODS: A total of 2365 females aged ≥20 years recruited from 4 communities underwent physical examination and carotid artery scanning. Their carotid intima-media thickness (C-IMT) was measured. RESULTS: The C-IMT was significantly higher in overweight or obese women with their BMI ≥25.0 kg/m2(P<0.01) and in those with their WC ≥85 cm than in those with their WC <85 cm (P<0.01). Spearman and partial correlation analysis showed that the C-IMT was significantly correlated with WC which was independent of menopausal status. The C-IMT significantly increased with the increasing WC and reached to a platform in about 85 cm. An increment tendency was found in the subgroup with its WC <85 cm (P<0.01) while no significant tendency was found in the subgroup with its WC≥85 cm (P=0.07).Multiple stepwise regression analysis showed that the WC was an independent risk factor for C-IMT. In logistic regression model, the odd ratio of WC ≥80 cm, ≥80 cm and <85 cm and ≥85 cm for evaluating the risk of C-IMT elevation was 1.632, 1.501, and 1.878, respectively. CONCLUSION: WC is significantly correlated with C-IMT in women from Shanghai, China, and WC≥85 cm may be used in identifying the risk of subclinical carotid atherosclerosis.

[APPL1-mediated effects of leptin on activity of GSK-3ß in C2C12 cell].

OBJECTIVE: To observe the effects of leptin on activity of GSK-3ß and explore its mechanism. METHODS: C2C12 myoblasts differentiated for 3 days into myotubes in differentiation medium. Myotubes were stimulated by leptin (100 nmol/L) for 0, 5, 15 or 30 min respectively. Western blot was used to detect the expression levels of GSK-3ß and phospho-GSK-3ß (ser-9). Co-immunoprecipitation (CO-IP) was performed to determine the relationship among APPL1, leptin receptor and GSK-3ß in the presence or absence of leptin. The expression level of GSK-3ß at phospho-GSK-3ß (ser-9) was detected in APPL1-suppressed C2C12 myotube while that of APPL1 at phospho-APPL1 (ser-401) determined in GSK-3ß overexpressed/inhibited C2C12 cell. RESULTS: Leptin time-dependently increased the phosphorylation level of GSK-3ß at ser-9 in C2C12 cell, and the pGSK-3ß level in cells incubated by leptin for 30 min was as 4.08 times as which in control cells (P < 0.01). The triple complex of APPL1, leptin receptor and GSK-3ß, in the presence of leptin, the binding capacity between APPL1 and GSK-3ß was stronger. The level of phospho-GSK-3ß was significantly lower in APPL1-suppressed C2C12 cell compared with that in control cells. And the phosphorylation of APPL1 at ser-401 could be induced by GSK-3ß. CONCLUSION: Leptin promotes muscle glycogen synthesis by inducing phosphorylation of GSK-3ß in C2C12 cell. Such a function may be mediated by the triple complex of APPL1, leptin receptor and GSK-3ß. Meanwhile, GSK-3ß can also increase the phosphorylation of APPL1 at ser-401.

[Detection rates of atherosclerosis by carotid versus lower limb ultrasonography in newly diagnosed type 2 diabetics].

OBJECTIVE: To compare the detection rates of atherosclerosis by carotid versus lower limb ultrasound in newly diagnosed type 2 diabetics and analyze the relationship between atherosclerosis and cardio-cerebrovascular events. METHODS: A total of 148 newly diagnosed type 2 diabetics were recruited. Both carotid and lower extremity atherosclerosis were assessed by Doppler ultrasound. Diabetic atherosclerosis was defined as the presence of either carotid or lower extremity plaques in any of the above-mentioned arterial segments. A kappa value was computed to document the agreement between isolated carotid (or lower limb) atherosclerosis and diabetic atherosclerosis. The prevalence of cardio-cerebrovascular events was compared among different distribution types of atherosclerosis. RESULTS: According to the diagnostic criteria, the prevalence of diabetic atherosclerosis was 66.2% in the newly diagnosed type 2 diabetes. Based on carotid or lower extremity ultrasound, the prevalence of diabetic atherosclerosis was 27.0% and 62.2% respectively in newly diagnosed type 2 diabetes. The kappa values for the agreement between carotid/lower limb atherosclerosis and diabetic atherosclerosis were 0.32/0.91 (95% confidence interval 0.22-0.42 for carotid vs 0.84-0.98 for lower extremity). The combination of carotid and lower extremity arterial atherosclerosis was associated with a significantly increased detection rate of cardio-cerebrovascular events (26.5%) versus those with either carotid or lower extremity arterial atherosclerosis (0% and 10.3% respectively). CONCLUSION: The combination of carotid and lower extremity ultrasonography can more accurately reflect the atherosclerotic lesions in type 2 diabetes. Due to a higher prevalence of cardio-cerebrovascular events, type 2 diabetics with both carotid and lower extremity atherosclerosis should be managed more aggressively to reduce the risk of cardio-cerebrovascular events.

Association of a SLC30A8 genetic variant with monotherapy of repaglinide and rosiglitazone effect in newly diagnosed type 2 diabetes patients in China.

OBJECTIVE: To 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. METHODS: A 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. RESULTS: Ninety-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. CONCLUSION: The 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.

[Relationship between glycated albumin level and pancreatic ß cell function in newly diagnosed type 2 diabetics].

OBJECTIVE: To explore the relationship between glycated albumin (GA) level and pancreatic ß cell function in newly diagnosed type 2 diabetics. METHODS: The subjects sought the confirmation of diabetes diagnosis or underwent diabetes screening tests in high-risk patients from January 2008 to October 2010. All of them underwent 75 g oral glucose tolerance test (OGTT) and insulin releasing test. The levels of GA and hemoglobin A1c (HbA1c) were analyzed by liquid enzymatic method and high performance liquid chromatography respectively. Homeostasis model assessment (HOMA) was used to evaluate the basal insulin resistance (HOMA-IR) and pancreatic ß cell function (HOMA-ß). ΔI30/ΔG30 was used to evaluate early-phase insulin secretion after a glucose load. RESULTS: (1) Among 500 type 2 diabetics according to the diagnostic criteria of WHO (1999), 279 were males and 221 were females. Average age was 56.3 ± 12.3, GA (21.1 ± 5.4)% and HbA1c (7.0 ± 1.3)%. (2) A significantly positive relationship was shown between HbA1c and GA (r = 0.691, P < 0.01). GA was also positively correlated with fasting plasma glucose (FPG), 0.5 hPG, 1 hPG, 2 hPG and 3 hPG after a glucose load of OGTT test (r = 0.511 - 0.627, P < 0.01). (3) GA was negatively correlated with body mass index (BMI) (r = -0.112, P < 0.01), HOMA-ß (r = -0.350, P < 0.01) and ΔI30/ΔG30 (r = -0.263, P < 0.01). (4) Multivariant stepwise regression analysis showed that HbA1c, FPG, 3 hPG and ΔI30/ΔG30 were independent factors of GA level. CONCLUSION: Glycated albumin level is closely correlated with the function of early-phase insulin secretion in newly diagnosed type 2 diabetics.