Natural selection shaped the protective effect of the mtDNA lineage against obesity in Han Chinese populations.

Mitochondria play a key role in lipid metabolism, and mitochondrial DNA (mtDNA) mutations are thus considered to affect obesity susceptibility by altering oxidative phosphorylation and mitochondrial function. In this study, we investigated mtDNA variants that may affect obesity risk in 2,877 Han Chinese individuals from three independent populations. The association analysis of 16 basal mtDNA haplogroups with body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) revealed that only haplogroup M7 was significantly negatively correlated with all three adiposity-related anthropometric traits in the overall cohort (P=0.003 for BMI, P=1×10-5 for WC, P=0.005 for WHR), which was verified by the analysis of a single population, i.e., the Zhengzhou population. Furthermore, subhaplogroup analysis suggested that M7b1a1 was the most likely haplogroup associated with a decreased obesity risk, and the variation T12811C (causing Y159H in ND5) harbored in M7b1a1 may be the most likely candidate for altering mitochondrial function. Specifically, we found that proportionally more nonsynonymous mutations accumulated in M7b1a1 carriers, indicating that M7b1a1 was either under positive selection or subject to a relaxation of selective constraints. We also found that nuclear variants, especially in DACT2 and PIEZO1, may functionally interact with M7b1a1.

A machine-learning approach for predicting the effect of carnitine supplementation on body weight in patients with polycystic ovary syndrome.

The present study aimed to explore the effect of carnitine supplementation on body weight in patients with polycystic ovary syndrome (PCOS) and predict an appropriate dosage schedule using a machine-learning approach. Data were obtained from literature mining and the rates of body weight change from the initial values were selected as the therapeutic index. The maximal effect (Emax) model was built up as the machine-learning model. A total of 242 patients with PCOS were included for analysis. In the machine-learning model, the Emax of carnitine supplementation on body weight was -3.92%, the ET50 was 3.6 weeks, and the treatment times to realize 25%, 50%, 75%, and 80% (plateau) Emax of carnitine supplementation on body weight were 1.2, 3.6, 10.8, and 14.4 weeks, respectively. In addition, no significant relationship of dose-response was found in the dosage range of carnitine supplementation used in the present study, indicating the lower limit of carnitine supplementation dosage, 250 mg/day, could be used as a suitable dosage. The present study first explored the effect of carnitine supplementation on body weight in patients with PCOS, and in order to realize the optimal therapeutic effect, carnitine supplementation needs 250 mg/day for at least 14.4 weeks.

Effects of cimetidine on ciclosporin population pharmacokinetics and initial dose optimization in aplastic anemia patients.

The present study aimed to explore the effects of cimetidine on ciclosporin population pharmacokinetics and initial dose optimization in aplastic anemia patients. Aplastic anemia patients were used to establish a population pharmacokinetic model by the nonlinear mixed effect (NONMEM), and concentrations of ciclosporin were simulated by Monte Carlo method. With the same weight, the ciclosporin clearance rates were 0.387:1 in patients with or without cimetidine, respectively. In the measured ciclosporin concentrations, compared to aplastic anemia patients without cimetidine, ciclosporin concentrations were higher in patients with cimetidine (P < 0.01). Further research found that at the same body weight and same dose, ciclosporin concentrations in aplastic anemia patients with cimetidine were indeed higher than those in patients without cimetidine (P < 0.01). The initial recommended ciclosporin dose for patients without cimetidine were 7mg/kg splited into two doses for weight of 40-60kg, and 6mg/kg splited into two doses for weight of 60-100kg. The patients with cimetidine were recommended to take 3mg/kg ciclosporin splited into two doses for weight of 40-100kg. It was the first time to explore the effects of cimetidine on ciclosporin population pharmacokinetics and initial dose optimization in aplastic anemia patients. Patients coadministration of cimetidine, may need low ciclosporin dose.

Effects of Sodium-Glucose Cotransporter-2 Inhibitors on Weight in Type 2 Diabetes Mellitus and Therapeutic Regimen Recommendation.

Aims: The present study is aimed at exploring the effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on weight in type 2 diabetes mellitus (T2DM) and therapeutic regimen recommendations. Methods: 20,019 patients with T2DM were enrolled. The maximal effect (E max) models, whose evaluation index was change rate of body weight from baseline value, were used to analyze data using nonlinear mixed effect modeling (NONMEM). Results: For SGLT-2 inhibitors, canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin and tofogliflozin, the E max, and treatment duration to reach half of the maximal effects (ET50) were -3.72% and 3.35 weeks, -5.59% and 16.8 weeks, -2.84% and 3.42 weeks, -3.43% and 3.09 weeks, -3.04% and 4.38 weeks, and -2.45% and 3.16 weeks, respectively. In addition, for T2DM patients, 100 mg/day canagliflozin needs to be taken 13.4 weeks for the plateau of effect on weight; 10 mg/day empagliflozin needs to be taken 67.2 weeks for the plateau of effect on weight; 5 mg/day ertugliflozin needs to be taken 13.68 weeks for the plateau of effect on weight; 50 mg/day ipragliflozin needs to be taken 12.36 weeks for the plateau of effect on weight; 2.5 mg/day luseogliflozin needs to be taken 17.52 weeks for the plateau of effect on weight; 20 mg/day tofogliflozin needs to be taken 12.64 weeks for the plateau of effect on weight. Conclusions: This was the first study to explore effects of SGLT-2 inhibitors on weight in T2DM; meanwhile, the optimum dosages and treatment durations on weight from canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, and tofogliflozin were recommended, respectively.

Analysis of Time Course and Dose Effect From Metformin on Body Mass Index in Children and Adolescents.

The purpose of this study was to analyze the time course and dose effect from metformin on body mass index (BMI) in children and adolescents by model-based meta-analysis (MBMA). Searching randomized controlled trial (RCT) studies of metformin on BMI in children and adolescents. The change rates of BMI from baseline values were used as indicator of evaluating metformin efficacy. A total of 18 RCT studies, 1,228 children and adolescents, were included for analysis, including patients with obesity, patients with type 1 diabetes mellitus, patients with nonalcoholic fatty liver, and patients with precocity. In order to achieve better effect of metformin on BMI in children and adolescents, the present study recommended that for patients with obesity, 1,000 mg/day metformin was required for at least 15.2 weeks and 60.8 weeks to achieve the plateau of metformin effect; for patients with type 1 diabetes mellitus, 1,000 mg/day metformin was required for at least 25.2 weeks and 100.8 weeks to achieve the plateau of metformin effect; for patients with nonalcoholic fatty liver, 1,000 mg/day metformin was required for at least 6.57 weeks and 26.28 weeks to achieve the plateau of metformin effect; for patients with precocity, 425 mg/day metformin was required for at least 12.4 weeks and 49.6 weeks to achieve the plateau of metformin effect. It was the first time to analyze the time course and dose effect from metformin on BMI and to recommend dosage and duration of treatment for metformin in children and adolescents with different disease types.

Quantitative efficacy of L-carnitine supplementation on glycemic control in type 2 diabetes mellitus patients.

OBJECTIVES: This study aimed to explore the quantitative efficacy of L-carnitine supplementation on glycemic control in type 2 diabetes mellitus patients using model-based meta-analysis (MBMA). METHODS: Literatures were retrieved from the public database and data from these trials were extracted. The quantitative efficacy of L-carnitine on fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) in type 2 diabetes mellitus patients were evaluated by maximal effect (Emax) models with nonlinear mixed effects modeling (NONMEM). RESULTS: In the model of FPG, Emax and treatment duration to reach half of the maximal effects (ET50) were -9.8% and 36.1 weeks, respectively. In the model of HbA1c, Emax and ET50 were -19.6% and 106 weeks, respectively. In addition, the durations for achieving 25%, 50%, 75%, 80%, and 90% Emax of L-carnitine on FPG were 13, 36.1, 118, 160, and 390 weeks, respectively. The durations for achieving 25%, 50%, 75%, 80%, and 90% Emax of L-carnitine on HbA1c were 38, 106, 334, 449, and 1058 weeks, respectively. CONCLUSIONS: It was the first time to provide valuable quantitative information for efficacy of L-carnitine supplementation on glycemic control in type 2 diabetes mellitus patients.

Glucose fluctuation increased mesangial cell apoptosis related to AKT signal pathway.

INTRODUCTION: Blood glucose fluctuation is an important factor for the development of diabetic complications. Glucose fluctuation aggravated the renal injury in diabetic nephropathy. In the present study, our aim was to investigate the effects of blood glucose fluctuation on the glomerular mesangal cells and its related mechanism. MATERIAL AND METHODS: Mesangial cells were divided into four groups: the normal glucose group (NG) cells were incubated in normal glucose conditions (5.6 mmol/l); the high glucose group (HG) cells were treated with 25 mmol/l; the glucose fluctuation (FG) group received 5.6 mmol/l and 25 mmol/l glucose repeated 3 times; the mannitol group (MG) received 5.6 mmol/l glucose plus 24.4 mmol/l mannitol as a control. Cell viability and apoptosis were detected, reactive oxygen species (ROS) level, superoxide dismutase (SOD) activity and malonaldehyde (MDA) levels were measured. Phosphorylated ser/thr protein kinase (P-AKT, phosphor-Ser473), phosphorylated glycogen synthase kinase-3ß (P-GSK-3ß, phosphor-Ser9) and cleaved cysteinyl aspartate-specific proteinase-3 (cleaved caspase-3) levels were assessed using western blot. RESULTS: Data suggested that mesangial cells in the FG group show higher cell viability in 12 h, and lower cell viability from 48 h. The FG group showed cell apoptosis accompanied by a significant MDA level increase and SOD activity decrease in 48 h. More importantly, glucose fluctuation could aggravate oxidative stress in glomerular mesangial cells. Furthermore, the P-AKT level was lower, and increased P-GSK-3ß and cleaved caspase-3 levels were higher in the FG group than in the HG group. CONCLUSIONS: Glucose fluctuation aggravates mesangial cell apoptosis, which may be partly induced by activating oxidative stress and inhibiting the AKT signaling pathway.

Zeaxanthin improved diabetes-induced anxiety and depression through inhibiting inflammation in hippocampus.

It is generally accepted that inflammation plays a key role in anxiety and depression induced by diabetes. However, the underlying mechanism and effective treatment method of these diabetes-associated behavior disorders remain to be determined. In the present study, we attempted to illuminate the implication of zeaxanthin in anxiety, depression and neuroinflammation caused by hyperglycemia, and further elaborate the relevant mechanism under these neuropsychiatric disorders. In the current work, diabetic rats were induced by high glucose and fat diet followed by a single intraperitoneal injection of streptozocin, and zeaxanthin was orally administration every day (From 6th to 19th week). Diabetes-associated anxiety and depression were assessed using open field test (OFT) and Forced swimming test (FST) respectively. Moreover, the levels of interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) in hippocampus were tested using ELISA and WB. Data showed that long-term zeaxanthin treatment improve diabetic symptoms and alleviate anxiety and depression in diabetic rats. Furthermore, excessive production of IL-6, IL-1ß and TNF-α could be reduced with zeaxanthin treatment. In conclusion, we suggested that zeaxanthin can ameliorate diabetes-associated anxiety and depression, inhibit inflammation in diabetic rats. Our results could provide a potential therapeutic approach for the treatment of abnormal behavior induced by hyperglycemia.

Bamboo leaf extract ameliorates cardiac fibrosis possibly via alleviating inflammation, oxidative stress and apoptosis.

Previous studies have shown that inflammatory process contributes to the pathogenesis of cardiac damage induced by diabetes mellitus. However, the underlying mechanisms and strategies to alleviate inflammatory injury in the diabetic heart are not fully elucidated. In this study, we investigated the potential role and related mechanism of bamboo leaf extract (BLE) on diabetes-induced cardiac fibrosis in rats. Diabetes was induced by streptozocin (STZ) in rats, blood glucose and glycosylated hemoglobin A1c (HbAlc) were measured. Super oxide dismutase (SOD) activity and malondialdehyde (MDA) level in rat heart homogenates were tested using special kits. Cardiac function was evaluated by echocardiography, and myocardial histology was detected by hematoxylin eosin (HE) staining and Masson's trichrome staining. Furthermore, expression of transforming growth factor-ß1 (TGF-ß1), interleukin 6 (IL-6) and Cleaved-cysteinyl aspartate-specific proteinase-3 (Cleaved-caspase-3), and the activity of nuclear factor κB (NF-κB) were examined by western blot analysis. From the data, we found that the BLE treatment inhibits oxidative stress and improved cardiac function in STZ-induced diabetic rats. BLE treatment significantly ameliorated diabetes-induced myocardial morphological changes and cardiac inflammation. Moreover, the protein levels of TGF-ß1, IL-6,Cleaved-caspase-3 and the nuclear transcription of NF-κB in the hearts were markedly reduced in diabetic rats result from BLE treatment. In conclusion, this study suggested that BLE ameliorates cardiac fibrosis in streptozotocin-induced diabetic rats, and this protective effect possibly through inhibiting inflammation, oxidative stress and apoptosis. BLE might serve as a potential therapeutic target for the treatment of the cardiac fibrosis in diabetic patients.

Zeaxanthin improves diabetes-induced cognitive deficit in rats through activiting PI3K/AKT signaling pathway.

Published studies have shown that cognitive deficit is a characteristic manifestation of neurodegenerative disease in diabetes. However, there is no effective prevention and treatment for this diabetes-associated behavior disorder. In the present study, we attempted to elucidate the effect of zeaxanthin on cognitive deficit and the change in the hippocampus correlated with cognitive decline in diabetic rats. Diabetic rats in this study were induced by high-fat diet and low-dose streptozocin (STZ), cognitive ability of rats were evaluated use morris water maze (MWM) and morphology change in hippocampus was assessed by cresyl violet stain. Moreover, we detected the expression of phosphorylated serine/threonine kinase (p-AKT) and Cleaved caspase-3, and the activity of nuclear factor-κB (NF-κB) use western-blot (WB). Results displayed that supplementation with zeaxanthin reduce blood glucose, improve cognitive deficit, survive neural cell, increase p-AKT level, inhibit Cleaved caspase-3 level and NF-κB nuclear transcription in hippocampus. This study demonstrated that zeaxanthin ameliorate diabetes-related cognitive deficit may by means of protecting neural cell from hyperglycemia involved in AKT/NF-κB signaling pathway. This study may provide a potential therapeutic approach for the prevention of diabetes- associated cognitive deficit.

Zeaxanthin ameliorates high glucose-induced mesangial cell apoptosis through inhibiting oxidative stress via activating AKT signalling-pathway.

Oxidative stress is a critical factor in the pathophysiology of diabetic kidney disease. Previous study shows that hyperglycaemia aggravates renal injury through oxidative stress in diabetic model, and antioxidants have beneficial effect on diabetic kidney disease. However, the role of antioxidants in the progression of diabetic kidney disease is poorly understood. The aim of this study was to clarify whether zeaxanthin, an antioxidant, could ameliorate mesangial cell injury and if so, identify the related mechanism underlying this protective effect. To that end, superoxide dismutase (SOD) activity and methane dicarboxylic aldehyde (MDA) levels were measured by an assay kit, and mesangial cell apoptosis and ROS levels were assessed using flow cytometry analysis. Furthermore, The levels of a phosphorylated ser/thr protein kinase (p-AKT), phosphorylated glycogen synthase kinase-3 beta (p-GSK-3ß), Bcl-2 associated X protein (Bax) and cleaved cysteinyl aspartate-specific proteinase-3 (caspase-3) were detected by western blot. We found that zeaxanthin decreases MDA levels and increased SOD activity, as well as inhibits apoptosis and decreases ROS levels in mesangial cells in a high sugar environment. Furthermore, zeaxanthin increased p-AKT levels while decreased the levels of p-GSK-3ß, Bax and cleaved-caspase-3. In addition, LY294002 reversed the protective effect of zeaxanthin on mesangial cells. In conclusion, zeaxanthin ameliorated mesangial cell apoptosis may be involved in inhibiting oxidative stress through activating of the AKT signalling pathway.

Bamboo leaf extract ameliorates diabetic nephropathy through activating the AKT signaling pathway in rats.

Diabetic nephropathy (DN) is one of the most severe diabetic complication and it is becoming become a worldwide epidemic, accounting for approximately one-third of all case of end-stage renal disease. However, the underlying mechanism and strategy to alleviate renal injury remain unclear. In the present study, we assessed the protective effect of bamboo leaf extract on the DN, and investigated the underlying mechanism by which bamboo leaf extract ameliorating DN. Diabetic rats were induced by 4 weeks high sugar and high fat diet, and then injected a single dose of STZ (35mg/kg) into abdominal cavity. Different dose of bamboo extract (50mg/kg, 100mg/kg and 200mg/kg) were orally administered every day for a period of 12 weeks. Body weight, blood glucose, glycosylated hemoglobin A1c (HbAlc), blood urea nitrogen (BUN), serum creatinine (Scr), and 24-hour urinary protein (24 h-UP) were assessed. Total superoxide dismutase (T-SOD) activity and MDA (methane dicarboxylic aldehyde, MDA) level were tested by assay kit. Microstructural changes were observed by hematoxylin-eosin (HE) staining and electron microscopy. Expression of phosphorylated ser/thr protein kinase (P-AKT), phosphorylated glycogen synthase kinase-3 beta (P-GSK-3ß), B cell lymphoma/leukemia 2-associated X protein (BAX) and cleaved-cysteinyl aspartate-specific proteinase-3 (Cleaved Caspase-3) were measured by Western-Blotting (WB). Results showed that diabetic rats had weight loss, high blood glucose, HbAlc, BUN, Scr and 24-UP and T-SOD activity were increased and MDA level was decreased in diabetic rats. Moreover, hyperglycemia could injury renal tissue ultrastructure, inhibit P-AKT level and increase P-GSK-3ß, BAX and Cleaved Caspase-3 levels in rats. However, bamboo leaf extract treatment could reduce body weight loss, BUN, Scr, 24 h-UP and MDA level, improve T-SOD activity and alleviate renal injury in diabetic rats. Furthermore, bamboo leaf extract increased P-AKT level, decreased P-GSK-3ß, BAX and Cleaved Caspase-3 levels in STZ-diabetic rats. In conclusion, our study suggested that bamboo leaf extract ameliorated DN in diabetic rats, and this protective effect is possibly related to suppressing oxidative stress through activating AKT signaling pathway. Bamboo leaf extract treatment may be a potential promising therapy for DN.

Glucose variability aggravates cardiac fibrosis by altering AKT signalling path.

OBJECTIVE: To study the effect of blood glucose variability on cardiac fibrosis and its mechanism in a model of diabetic cardiomyopathy. METHODS: A total of 45 Sprague Dawley rats were randomly divided into three groups: control, control diabetes mellitus and fluctuated blood glucose groups. Fluctuated blood glucose was induced by daily subcutaneous insulin and intraperitoneal glucose injections at different time points. Blood lipids and glycosylated haemoglobin A1c were assessed. Super oxide dismutase activity and malondialdehyde level in rat heart homogenates were determined by assay kit. Structural cardiac tissue changes were observed by haematoxylin and eosin staining and Masson's trichrome staining. Collagen type 3, fibronectin, phosphorylated Ser/Thr protein kinase, phosphorylated glycogen synthase kinase-3 beta, glycogen synthase kinase-3 beta, nuclear factor kappa-light-chain-enhancer of activated B cells, cleaved-cysteinyl aspartate-specific proteinase-3 (caspase-3) and tumour necrosis factor-α levels were determined by western blot. RESULTS: Compared with the control group, cardiac fibrosis and oxidative stress in heart tissue were aggravated in diabetic rats, which were more pronounced in glucose variability rats. However, the expression levels of AKT and glycogen synthase kinase-3 beta were not significantly different in three groups, but the expression levels of phosphorylated Ser/Thr protein kinase and phosphorylated glycogen synthase kinase-3 beta were significantly decreased in the control diabetes mellitus and fluctuated blood glucose groups compared to control group, and levels in the fluctuated blood glucose group were significantly less than in the control diabetes mellitus group. In addition, the expression levels of nuclear factor kappa B and caspase-3 in both the control diabetes mellitus and fluctuated blood glucose groups were higher than in the control group, with the highest levels measured in the fluctuated blood glucose group. CONCLUSION: Blood glucose variability can aggravate heart tissue fibrosis, possibly involving oxidative stress by inhibiting AKT signalling path.