Richa Goswami

AMP-kinase pathway is involved in tumor necrosis factor alpha-induced lipid accumulation in human hepatoma cells

AIM It is well known that lipid accumulation and inflammation are two important steps in pathogenesis and progress of nonalcoholic fatty liver disease (NAFLD). However, fewer studies have explored the direct relationship between lipid accumulation and inflammation in early NAFLD. Tumor necrosis factor alpha (TNF-α) is one of the classical inflammatory cytokines. AMP-activated protein kinase (AMPK) is known as a critical regulator of energy homeostasis in metabolic processes. This study aims to investigate the role of TNF-α on lipid deposition of HepG2 cells and examine the modification of AMPK pathway. MAIN METHODS TNF-α was added in HepG2 cells and lipid accumulation was analyzed by Oil Red O staining and quantitative test of triglyceride (TG). The expressions of phosphorylated AMPK and its pathway (including mTOR and SREBP-1) were determined. Furthermore, an AMPK agonist (metformin or AICAR) or antagonist (compound C) was co-administrated with TNF-α in HepG2 cells to investigate its effect on TNF-α induced lipid deposition. KEY FINDINGS A significant increment of TG content in HepG2 cells was observed after TNF-α treatment. Meanwhile, substantially suppressed AMPK and ACC phosphorylation, enhanced mTOR and p70S6K phosphorylation, and increased protein expression of FAS and SREBP-1 were found. Co-treatment with metformin or AICAR decreased the TNF-α-induced intracellular TG, accompanied by significantly enhanced AMPK and ACC phosphorylation, suppressed mTOR and p70S6K phosphorylation, and reduced SREBP-1 and FAS expressions. On the contrary, while co-incubated with compound C, AMPK and ACC phosphorylation were suppressed and the inhibitory effect of metformin on HepG2 cell lipid deposition was also attenuated. SIGNIFICANCE Our results suggest that TNF-α directly induces lipid accumulation in HepG2 cells, at least in part, through the inhibition of AMPK/mTOR/SREBP-1 pathway.

Combined effects of sex hormone-binding globulin and sex hormones on risk of incident type 2 diabetes

The aim of the present study was to investigate the combined effects of sex hormone‐binding globulin (SHBG) and sex hormones on the risk of type 2 diabetes (T2D).

Serum bisphenol A as a predictor of chronic kidney disease progression in primary hypertension: a 6-year prospective study.

Objective: Hypertensive nephropathy is one of the major causes of chronic kidney disease (CKD). Bisphenol A (BPA) is associated with elevated blood pressure and urinary albuminuria. The aim of this study is to evaluate the association between serum BPA with the progression of CKD in patients with primary hypertension. Methods: In this prospective study, 302 patients with primary hypertension were followed up for 6 years (195 men and 107 women, 65.29 ± 9.78 years at baseline). The baseline values of serum BPA were measured. Renal function was measured as estimated glomerular filtration rate (eGFR) calculated by the Chronic Kidney Disease Epidemiology Collaboration creatinine–cystatin C equation (eGFRcr–cys). Regression models were used to calculate associations of serum BPA with the annual change in eGFR and the risk of CKD progression. Results: Baseline serum BPA concentration was 0.61(0.26, 2.44) ng/ml and was significantly negatively correlated with the annual change in eGFR (R = −0.197, P < 0.001). After adjusting for clinical factors, baseline serum BPA level had a significant negative association with the annual change in eGFR (&bgr; = −0.132, P = 0.007). Univariate logistic regression analysis showed that the baseline age, SBP, eGFR, and serum BPA levels were predictors of CKD stage 3 or greater. In multivariate logistic regression analysis, patients with high serum BPA levels exhibited a five-fold increased risk of developing CKD stage 3 or greater compared with patients with low serum BPA levels [odds ratio 4.79 (95% confidence interval 1.81, 14.25), P = 0.004]. Conclusion: Serum BPA may be a predictor of CKD progression in patients with primary hypertension.

Serum LBP Is Associated with Insulin Resistance in Women with PCOS.

Introduction Lipopolysaccharide-binding protein (LBP) is closely associated with many metabolic disorders. However, no study has been done to explore the relationship between LBP and polycystic ovary syndrome (PCOS). The objective of this study was to investigate whether the serum LBP level is elevated and associated with insulin resistance (IR) in PCOS. Participants and Design In this cross-sectional study, 117 PCOS patients and 121 age-matched controls were recruited. Hyperinsulinemic-euglycemic clamp was performed with an expression of M value for insulin sensitivity. Fasting serum samples were collected to detect LBP, lipids, insulin, sex hormones and high sensitive C reactive protein (hs-CRP). Pearson’s correlation and multiple linear regression was used to analyze the associations between M value and LBP level. Settings The study was performed in a clinical research center. Results Compared with controls, PCOS subjects had a significantly higher LBP concentration (33.03±14.59 vs. 24.35±10.31 μg/ml, p<0.001), and lower M value (8.21±3.06 vs. 12.31±1.72 mg/min/kg, p<0.001). Both in lean and overweight/obese individuals, serum LBP level was higher in PCOS subjects than that in controls. M value was negatively correlated with body mass index (BMI), fasting serum insulin, triglycerides, low-density lipoprotein cholesterol (LDL-c), free testosterone, high sensitive C reactive protein (hs-CRP) and LBP, whereas positively correlated with high-density lipoprotein cholesterol (HDL-c) and sex hormone binding globulin (SHBG). Serum LBP level was associated with M value after adjusting for BMI, fasting serum insulin, SHBG, as well as hs-CRP. Conclusion Serum LBP level significantly is elevated in PCOS, and is independently associated with IR in PCOS.

Association Between Serum Cortisol and Chronic Kidney Disease in Patients with Essential Hypertension

Background/Aims: Serum cortisol level is elevated in patients with essential hypertension. We aimed at investigating the association of serum cortisol levels with parameters of renal function in essential hypertension. Methods: One hundred and seventy-eight patients with essential hypertension participated in the study. Fasting serum samples were collected at 8:00 am. Renal function was measured as estimated glomerular filtration rate (eGFR) calculated by the Chronic Kidney Disease Epidemiology Collaboration creatinine- cystatin C equation (eGFRcr-cys). Correlation analysis and stepwise regression analysis were used to detect the relationship between cortisol and eGFRcr-cys. The distributions of serum cortisol were split by the tertiles and subjects were stratified into those with low, median and high levels accordingly. Results: Serum cortisol levels were significantly higher in subjects whose eGFRcr-cys<90 ml/min/1.73 m2 than subjects whose eGFRcr-cys>90 ml/min/1.73 m2 (394.0±93.4 vs. 343.2±98.4 nmol/L, P=0.001). Age, systolic blood pressure, and serum total cholesterol, uric acid, cortisol levels were significantly associated with eGFRcr-cys, serum levels of creatinine and cystatin C. After adjusting for clinical factors, serum cortisol level had a statistically significant negative association with the eGFRcr-cys (β=-0.19, P=0.027), and positive associations with cystatin C (β=0.31, P=0.001) and creatinine (β=0.14, P=0.044). With the increment of cortisol tertile, the eGFRcr-cys significantly decreased (93.18±14.36 vs. 84.61±14.67 vs. 81.29±12.36 ml/min/1.73 m2 for low, median and high tertile, respecively, P=0.001). Conclusion: Serum cortisol level was negatively correlated with eGFRcr-cys in subjects with essential hypertension. Further studies are needed to investigate whether cortisol plays a role in hypertensive nephropathy development.

Aldosterone/direct renin concentration ratio as a screening test for primary aldosteronism: A meta-analysis

Objective: The accuracy of aldosterone/direct renin concentration ratio (ADRR) as a screening test in patients with primary aldosteronism (PA) varies widely across the studies. Therefore, we conducted a meta-analysis to assess the accuracy of ADRR. Methods: A literature search was performed in PubMed, Embase, and the Cochrane library published between April 1971–February 2016. Studies focusing on the accuracy of ADRR for PA screening were included. Two authors independently extracted information regarding patient characteristics, antihypertensives status, true positives, true negatives, false positives, and false negatives. The random-effects model was used for statistical analysis. Heterogeneity was explored by subgroup analysis and meta-regression. Results: Nine studies involving 974 patients were included. The overall sensitivity, specificity, area under the curve, and diagnostic odds ratio of ADRR were 0.89 (95% confidence interval (CI) 0.84–0.93), 0.96 (95% CI 0.95–0.98), 0.985 and 324 respectively, with substantial heterogeneity. Meta-regression showed that antihypertensive status affects the ADRR and may account for the heterogeneity (p=0.03). Subgroup analysis of patients who discontinued the antihypertensives revealed a sensitivity of 0.99 (95% CI, 0.95–1.00) and a specificity of 0.98 (95% CI, 0.96–0.99). Conclusions: This study demonstrates the efficacy of ADRR as a screening test for PA. However, as antihypertensive drugs can interfere with the interpretation of ADRR, it is recommended to interrupt therapy or at least replace with analogues that do not significantly affect the ADRR value.

Sarcopenia is independently associated with diabetic foot disease

The aim of this study was to investigate the association of sarcopenia and diabetic foot disease (DFD) in a cross-sectional study. Body composition was assessed using dual-energy X-ray-absorptiometry (DXA) among 1105 patients with type 2 diabetes (120 patients with newly diagnosed DFD [DFD duration less than 3 months]). Severity of DFD was assessed, referring to foot ulcers, Wagner grade and the percentage of amputation. Skeletal muscle index (SMI) was calculated, and sarcopenia was defined as SMI less than 7.0 kg/m2 (in men) or 5.4 kg/m2 (in women). SMI was significantly decreased in patients with DFD compared to patients without (6.79 ± 1.20 vs. 7.21 ± 1.05 kg/m2, P < 0.001). The percentage of sarcopenia in DFD patients was more than double than those without DFD (35.3% vs. 16.4%, P < 0.001). Multivariable logistic regression analysis showed that sarcopenia was independently associated with DFD (OR 2.05[95% CI 1.15,3.89], P = 0.027) after controlling confounders including age, diabetic duration and diabetic chronic complications. In DFD group, patients with sarcopenia exhibited more foot ulcers, higher Wagner grade and greater percentage of amputation compared to patients without sarcopenia. We conclude that sarcopenia is independently associated with DFD. Worse prognosis is seen in patients with DFD accompanied by sarcopenia.

Associations between abdominal and general obesity and diabetic kidney disease: a cross-sectional study and a prospective study

Abstract Background Compared with general obesity, abdominal obesity has been shown to be more closely correlated to chronic diabetic complications such as cardiovascular disease and diabetic retinopathy. The association between obesity and diabetic kidney disease is unclear. We did two independent studies, one cross-sectional study and one 5 year prospective study, to investigate the association of general and abdominal obesity with diabetic kidney disease. Methods In the cross-sectional study in a hospital in Chongqing, China, body composition was assessed with dual-energy X-ray absorptiometry in 1016 patients with type 2 diabetes. Variables measured to define general obesity were BMI, total body fat percentage, and fat-mass index (ratio of fat mass to height squared). Abdominal obesity variables were waist circumference, waist-to-height ratio, and visceral adipose tissue. Diabetic kidney disease was defined as chronic kidney disease stage 3–5 (estimated glomerular filtration rate [eGFR] 2 ). In the prospective study, 279 patients with type 2 diabetes without diabetic kidney disease at baseline were followed up for 5 years after initial assessment in a community centre. BMI, waist circumference, waist-to-height ratio, and waist-to-hip ratio were used as indicators of obesity type in the prospective study. Obesity-related variables were split into low, median, and high tertiles and patients were stratified by values accordingly for both studies. Ethical approval was granted by the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University. Informed consent was provided by all participants. Multivariate logistic analysis was done to determine whether parameters of obesity could be risk factors for diabetic kidney disease and adjustments made for confounding factors. The odds ratios (ORs) of general obesity parameters and abdominal obesity parameters were calculated, with reference to the lowest tertile of those parameters; OR was 1. Findings In the cross-sectional study, 470 patients had stage 1 chronic kidney disease, 374 patients had stage 2 disease, and 172 patients had stages 3–5 disease. Participants with higher BMI (24·67 kg/m 2 [SD 3·33] in those with stage 1 chronic kidney disease vs 24·78 kg/m 2 [3·14] in those with stage 2 chronic kidney disease vs 25·40 kg/m 2 [3·18] in those with stages 3–5 chronic kidney disease; p=0·040), total body fat percentage (29·21% [6·17] vs 29·57% [6·16] vs 30·74% [6·18]; p=0·024), fat-mass index (7·31 kg/m 2 [2·21] vs 7·43 kg/m 2 [2·21] vs 7·89 kg/m 2 [2·14]; p=0·014), waist circumference (92·71 cm [9·31] vs 93·98 cm [9·08] vs 95·52 cm [8·88]; p=0·047), waist-to-height ratio (0·57 [IQR 0·54–0·61] vs 0·58 [0·55–0·62] vs 0·61 [0·56–0·65]; p 2 [43·34] vs 121·67 cm 2 [43·10] vs 133·31 cm 2 [45·01]; p=0·0022) were more likely to have a lower eGFR, compared with those with lower values. Logistic regression analyses showed that variables of general obesity were associated with a risk of diabetic kidney disease (in the median vs high tertiles, for BMI p trend =0·0371; for total body fat percentage p trend =0·044; for fat-mass index p trend =0·0053). However, there was no correlation when visceral adipose tissue was adjusted (in the median vs high tertiles, for BMI p trend =0·18; for total body fat percentage p trend =0·66; for fat-mass index p trend =0·26). In the prospective study, 41 patients developed diabetic kidney disease after 6 years follow-up. No association was noted between BMI and risk of diabetic kidney disease or in the crude or adjusted models (in the crude model 1·11 [0·49–2·50] in the median tertile vs 1·10 [0·48–2·47] in the high tertile, p=0·81; in the waist-to-height ratio-adjusted model 0·43 [0·26–1·18] vs 0·76 [0·32–1·80], p=0·24; in the multivariable model 0·44 [0·13–5·54] vs 1·33 [0·25–6·97], p=0·40). Abdominal obesity variables were associated with risk of diabetic kidney disease after adjustment for BMI (for waist circumference 1·39 [1·10–8·03] in the median tertile vs 2·59 [1·45–9·31] in the high tertile, p=0·022; for waist-to-hip ratio 2·63 [0·71–5·79] vs 5·16 [1·38–9·31], p=0·015; for waist-to-height ratio 3·35 [0·86–7·08] vs 5·96 [1·51–13·06], p=0·03). The associations between the risk of diabetic kidney disease and waist circumference, waist-to-hip ratio, waist-to-height ratio were the same after adjustment for other confounders. Interpretation Abdominal obesity is more closely associated with the risk of diabetic kidney disease than general obesity in China. Funding National Key Clinical Specialties Construction Program of China, the National Natural Science Foundation of China and The Fundamental Science and Advanced Technology Research of Chongqing.

Lispro administered by the QS-M Needle-Free Jet Injector generates an earlier insulin exposure

ABSTRACT Objective: The aim of this study is to evaluate the pharmacokinetic and pharmacodynamic (PK-PD) profiles of lispro administered by the QS-M needle-free jet injector in Chinese subjects. Research design and methods: A randomized, double-blind, double-dummy, cross-over study was performed. Eighteen healthy volunteers were recruited. Lispro (0.2 units/kg) was administered by the QS-M needle-free jet injector or by conventional pen. Seven-hour euglycemic clamp tests were performed. Results: A larger area under the curve (AUCs) of insulin concentration and glucose infusion rate (GIR) during the first 20 minutes after lispro injection by the jet injector compared to the insulin pen was observed (24.91 ± 15.25 vs. 12.52 ± 7.60 mg. kg−1, P < 0.001 for AUCGIR,0–20 min; 0.36 ± 0.24 vs. 0.10 ± 0.04 U min L−1, P < 0.001 for AUCINS, 0–20 min). Needle-free injection showed a shorter time to reach maximum insulin concentration (37.78 ± 11.14 vs. 80.56 ± 37.18 min, P < 0.001) and GIR (73.24 ± 29.89 vs. 116.18 ± 51.89 min, P = 0.006). There were no differences in total insulin exposure and hypoglycemic effects between the two devices. Conclusion: Lispro administered by QS-M needle-free injector results in earlier and higher insulin exposure than conventional pen, and a greater early glucose-lowering effect with similar overall potency.

Abdominal Obesity Is More Closely Associated With Diabetic Kidney Disease Than General Obesity.

General and abdominal obesity are the major subtypes of obesity. Compared with general obesity, abdominal obesity was considered to be more closely associated with chronic diabetes complications, such as cardiovascular diseases and diabetic retinopathy (1,2). Although the association between abdominal obesity and urinary albumin was reported in previous studies (3–5), whether abdominal obesity is more closely associated with diabetic kidney disease (DKD) than general obesity has not been reported yet. Two studies were carried out to investigate the association of general and abdominal obesity with DKD. Study A was a cross-sectional study. Body composition was assessed using DXA among 1,016 patients with type 2 diabetes (T2D). General obesity parameters, including BMI, total body fat percentage (TBF), and fat mass index (FMI), and abdominal obesity parameters, including waist circumference (WC), waist-to-height ratio (WHtR), and visceral adipose tissue (VAT), were measured. DKD is defined as chronic kidney disease (CKD) stage 3–5 (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2). Study B was a 5-year prospective study in which 279 T2D patients without DKD at baseline were followed up. BMI, WC, and …