A modified Mediterranean diet is associated with the greatest reduction in alanine aminotransferase levels in obese type 2 diabetes patients: results of a quasi-randomised controlled trial

AIM: The aim of the study was to compare the effect of different dietary interventions on alanine aminotransferase (ALT) in obese patients with diabetes. METHODS: A post hoc analysis of an open label, parallel design, quasi-randomised (allocation by alternation), controlled trial, conducted in Israel. Obese patients with diabetes (n = 259), treated in the community, were centrally allocated to one of three diets: (1) the 2003 recommended American Diabetes Association diet (ADA): 50-55% carbohydrate, 30% fat and 20% protein, n = 85; (2) a low glycaemic index (LGI) diet: 50-55% LGI carbohydrate, 30% fat, 15-20% protein, n = 89; or (3) a modified Mediterranean diet (MMD): 35% LGI carbohydrate, 45% fat that was high in monounsaturated fat, 15-20% protein, n = 85. ALT was measured at 6 and 12 months. RESULTS: ALT levels decreased in all arms; however, the MMD was associated with the lowest ALT levels at month 6 (n = 201: ADA n = 64, LGI n = 73, MMD n = 64) and month 12 of follow-up (n = 179). At 12 months mean ALT levels were 19.8 +/- 1.4 U/l in the ADA diet arm (n = 54), 18.0 +/- 1.5 U/l in the LGI diet arm (n = 64) and 14.4 +/- 1.7 in the MMD arm (n = 61, p < 0.001). Evidence for an effect of diet on ALT levels persisted when controlling for post-randomisation changes in waist to hip ratio, BMI, homeostasis model assessment (HOMA) or triacylglycerol. CONCLUSIONS: A Mediterranean diet may have a beneficial effect on liver steatosis in obese patients with diabetes. Results of trials assessing the effect of dietary composition on clinical outcomes should be awaited before a decisive conclusion can be reached. In addition to clinical outcomes, such studies should address the issue of primary prevention of steatosis in high-risk and healthy individuals.     

SGLT2 inhibitors in the treatment of type 2 diabetes

The kidney plays an important role in glucose homeostasis via its production, utilization, and, most importantly, reabsorption of glucose from glomerular filtrate which is largely mediated via the sodium glucose co-transporter 2 (SGLT2). Pharmacological inhibition of SGLT2 increases urinary glucose excretion and decreases plasma glucose levels in an insulin-independent manner. Agents that inhibit SGLT2 represent a novel class of drugs, which has recently become available for treatment of type 2 diabetes. This article summarizes the rationale for use of these agents and reviews available clinical data on their efficacy, safety, and risks/benefits.     

Persistent alanine aminotransferase elevation among the general Iranian population： Prevalence and causes

AIM： To determine the prevalence and causes of persistently elevated alanine aminotransferase （ALT） levels among the general population in northern Iran.
METHODS： A total of 2292 （1376 female, aged 18-75 year）, were selected by systematic clustered random sampling from the cities and villages of Gonbad and Kalaleh in Golestan Province and invited to participate in the study. A comprehensive history regarding alcohol drinking and medication was taken. Body mass index （BMI）, viral markers and ALT levels were measured. If ALT level was ≥ 40 U/L, it was rechecked twice within 6 mo. Those with ≥ 2 times elevation of ALT were considered as having persistently elevated ALT level. Non-alcoholic fatty liver disease （NAFLD） was diagnosed based on evidence of fatty liver upon sonography and excluding other etiology.
RESULTS： A total of 2049 （1351 female） patients participated in the study, 162 （7.9%） had elevated ALT level at the first measurement. Persistently elevated ALT level was detected in 64 （3.1%） participants, with51 （79.6%） with no obvious etiology, six （9.3%） with Hepatitis B, four （6.2%） with Hepatitis C virus （HCV） infection and three （4.6%） with alcoholic hepatitis. The prevalence of NAFLD and alcoholic hepatitis was 2.04% （42 patients） and 0.1% （three）, respectively. There was correlation between NAFLD and male gender, overweight, diabetes and living in an urban area [odds ratio = 3.03 （95% CI： 1.6-5.72）, 4.21 （95% CI： 1.83-9.68）, 2.86 （95% CI： 1.05-7.79） and 2.04 （95% CI： 1.00-4.16） respectively].
CONCLUSION： NAFLD is the most common cause of persistently elevated serum ALT level among the general population of Iran.     

Meta‐analysis on the efficacy and safety of SGLT2 inhibitors and incretin based agents combination therapy vs. SGLT2i alone or add‐on to metformin in type 2 diabetes

We aimed to determine whether sodium‐glucose cotransporter type 2 inhibitors (SGLT2is) and incretin‐based agents combination therapy produces more benefits than SGLT2is alone in patients with type 2 diabetes mellitus (T2DM). PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) comparing SGLT2is plus Dipeptidyl‐Peptidase 4 inhibitors (SGLT2is/DPP4is) or glucagon like peptide‐1 receptor agonists (SGLT2is/GLP‐1RAs) against SGLT2is as monotherapy or add‐on to metformin in T2DMs. A total of 13 studies with 7350 participants were included. Combination with GLP‐1RAs exhibited more HbA1c reduction (WMD: ?0.8; 95% CI, ?1.14 to ?0.45%), weight loss (?1.46; 95% CI, ?2.38 to ?0.54 kg), and systolic blood pressure (SBP) reduction (?2.88; 95% CI, ?4.52 to ?1.25 mmHg) versus SGLT2is alone but increased the gastrointestinal disorder risk (RR: 1.68; 95% CI, 1.14‐2.47). Combination with DPP4is exhibited an extra effect on HbA1c reduction (?0.47; 95% CI, ?0.58 to ?0.37%), a neutral effect on weight (0.19; 95% CI, ?0.11 to 0.48 kg) and SBP (?0.01; 95% CI, ?0.85 to 0.63 mmHg), and ameliorated the genital infections risk (0.73; 95% CI, 0.54‐0.97) versus SGLT2is. Meta‐regression indicated the hypoglycemic efficacy of SGLT2is/DPP4is is higher in Asians than in other ethnics, and the differences in BMI across ethnic groups may mediate this effect. SGLT2is and incretin‐based agents combination therapy is efficacious and safe versus SGLT2is alone in T2DMs. Particularly, combination with GLP‐1RAs shows additional benefits to glycemic, weight, and SBP control to a larger extent than DPP4is, while combination with DPP4is ameliorates the risk for genital infection seen with SGLT2is. We highlight the need for individualized treatment related to the selection of this novel combination therapy.     

Serum alanine transaminase levels predict type 2 diabetes risk among a middle-aged and elderly Chinese population

Introduction and aimIt is indicated that high levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are associated with increased incident type 2 diabetes risk. However, whether serum ALT levels could improve the discrimination of type 2 diabetes remains unclear.MethodsThe data was derived from the Dongfeng-Tongji cohort study, which was established in 2008 and followed until October 2013. A total of 17,173 participants free of type 2 diabetes at baseline were included and 1159 participants developed diabetes after 4.51 (0.61) years of follow-up. Cox proportional hazard regression model was used to calculate the hazard ratios (HRs) for the association between ALT and AST levels with incident diabetes risk. Receiver-operating characteristic (ROC) curves analysis was used to evaluate the predictive accuracy of models incorporating traditional risk factors with and without ALT.ResultsCompared with the lowest quartile of ALT and AST levels, the highest quartile had a significantly higher risk of developing type 2 diabetes (HR: 2.17 [95% CI: 1.78–2.65] and 1.29 [1.08–1.54], respectively) after adjustment for potential confounders. The addition of ALT levels into the traditional risk factors did not improve the predictive ability of type 2 diabetes, with AUC increase from 0.772 to 0.774; P = 0.86.ConclusionsAlthough elevated ALT or AST levels increased incident type 2diabetes risk, addition of ALT levels into the prediction model did not improve the discrimination of type 2 diabetes.     

SGLT2 inhibitors and renal outcomes in type 2 diabetes with or without renal impairment: A systematic review and meta-analysis

Background

Sodium–glucose co-transporter 2 (SGLT2) inhibitors may have renal protective effects in people with impaired kidney function. We assessed the use of SGLT2 inhibitors in people with type 2 diabetes with or without renal impairment [defined as estimated glomerular filtration rate (eGFR) of ≥30 and <60 ml/min/1.73 m² and/or UACR > 300 and ≤5000 mg/g] by conducting a systematic review and meta-analysis of available studies.

Nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and its association with cardiovascular disease

Introduction

Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver disease that ranges from hepatic steatosis to non-alcoholic steatohepatitis. Obesity and diabetes mellitus are the prime risk factors for NAFLD. The aim of this study was to find out the prevalence of NAFLD among patients with type 2 diabetes mellitus and to detect the association of NAFLD with cardiovascular disease in them.

Effects of SGLT2 inhibitors on cardiovascular and renal outcomes in type 2 diabetes: A meta-analysis with trial sequential analysis

Background:It is unclear whether there are false positive or negative results in the effects of sodium-glucose transporter 2 (SGLT2) inhibitors on various cardiovascular and renal outcomes in patients with type 2 diabetes. We aimed to explore this issue by a meta-analysis with trial sequential analysis.Methods:We included randomized trials evaluating the effects of SGLT2 inhibitors on cardiorenal endpoints in type 2 diabetic patients. Eight endpoints evaluated in the study were fatal or nonfatal myocardial infarction (MI), fatal or nonfatal stroke, major adverse cardiovascular events (MACE), cardiovascular death or hospitalization for heart failure (CVD or HHF), all-cause death (ACD), cardiovascular death (CVD), hospitalization for heart failure (HHF), and kidney function progression (KFP). Meta-analysis and trial sequential analysis was conducted for each endpoint.Results:Seven randomized trials of SGLT2 inhibitors were included for pooled analysis. Compared with placebo, SGLT2 inhibitors significantly reduced the risk of MACE (HR 0.89, 95% confidence interval [CI] 0.84–0.94), MI (HR 0.91, 95% CI 0.84–0.99), CVD (HR 0.86, 95% CI 0.79–0.93), CVD or HHF (HR 0.77, 95% CI 0.73–0.82), HHF (HR 0.67, 95% CI 0.62–0.74), KFP (HR 0.63, 95% CI 0.56–0.70), and ACD (HR 0.88, 95% CI 0.83–0.94), whereas SGLT2 inhibitors did not have significant effects on stroke (HR 0.98, 95% CI 0.88–1.09). Trial sequential analyses for MI and stroke showed that cumulative Z curve did not cross trial sequential monitoring boundary and required information size, whereas those for the other 6 endpoints showed that cumulative Z curve crossed trial sequential monitoring boundary and/or required information size.Conclusions:Compared with placebo, SGLT2 inhibitors conclusively reduce the risk of MACE, CVD or HHF, ACD, CVD, HHF, and KFP in patients with type 2 diabetes, whereas the effects of SGLT2 inhibitors on MI and stroke are not conclusive and need to be further assessed in future studies with the adequate sample size to reject or accept the effect size.     

非酒精性脂肪性肝病合并2型糖尿病患者血浆促甲状腺激素水平变化及其临床意义*

目的 研究非酒精性脂肪性肝病（NAFLD）合并2型糖尿病（T2DM）患者血清促甲状腺激素（TSH）水平的变化及其临床意义。方法 纳入NAFLD合并T2DM患者43例和T2DM患者40例,比较两组年龄、性别、身高、体质指数（BMI）、血压和血生化指标及血清糖化血红蛋白（HbAlc）、空腹胰岛素（FINS）、游离三碘甲状腺原氨酸（FT3）、游离甲状腺素（FT4）、促甲状腺激素（TSH）等指标的差异,采用Logistic回归分析影响NAFLD患者发生T2DM的独立危险因素。结果 NAFLD合并T2DM患者体质指数（BMI）为（28.4±3.8） kg/m²,显著大于T2DM患者的（23.8±3.1） kg/m²,P<0.05）; NAFLD合并T2DM患者血清ALT、AST、GGT、TG、HOMA-IR和TSH水平显著高于T2DM患者（P<0.05）;不同血清TSH的NAFLD患者血清TC、TG、LDL-C和FT3水平存在显著性差异（P<0.05）;经Logistic回归分析显示,BMI（RR=1.720,95%CI为1.154~3.015）、HOMA-IR（RR=2.632,95%CI为1.010~3.654）、血清TSH（RR=2.577,95%CI为1.214~3.689）和TG水平（RR=1.538,95%CI为1.240~2.658）是影响NAFLD患者发生T2DM的独立危险因素。结论 了解NAFLD患者发生T2DM的危险因素有助于早期预防和干预,检测血清TSH水平可能对筛查合并T2DM的NAFLD患者有一定的临床意义。     

Histopathological differences utilizing the nonalcoholic fatty liver disease activity score criteria in diabetic (type 2 diabetes mellitus) and non-diabetic patients with nonalcoholic fatty liver disease

AIM: To study clinical and histopathological features of nonalcoholic fatty liver disease(NAFLD) in patients with and without type 2 diabetes mellitus(T2DM) using updated nonalcoholic steatohepatitis clinical research network(NASH-CRN) grading system.METHODS: We retrospectively analyzed data of 235 patients with biopsy proven NAFLD with and without T2 DM.This database was utilized in the previously published study comparing ethnicity outcomes in NAFLD by the same corresponding author.The pathology database from University of Chicago was utilized for enrolling consecutive patients who met the criteria for NAFLD and their detailed clinical and histopathology findings were obtained for comparison.The relevant clinical profile of patients was collected from the Electronic Medical Records around the time of liver biopsy and the histology was read by a single well-trained histopathologist.The updated criteria for type 2 diabetes have been utilized for analysis.Background data of patients with NASH and NAFLD has been included.The mean differences were compared using χ2 and t-test along with regression analysis to evaluate the predictors of NASH and advanced fibrosis.RESULTS: Patients with NAFLD and T2 DM were significantly older(49.9 vs 43.0,P 0.01),predominantly female(71.4 vs 56.3,P 0.02),had higher rate of metabolic syndrome(88.7 vs 36.4,P 0.01),had significantly higher aspartate transaminase(AST)/alanine transaminase(ALT) ratio(0.94 vs 0.78,P 0.01) and Fib-4 index(1.65 vs 1.06,P 0.01) as markers of NASH,showed higher mean NAFLD activity score(3.5 vs 3.0,P = 0.03) and higher mean fibrosis score(1.2 vs 0.52,P 0.01) compared to patients with NAFLD without T2 DM.Furthermore,advanced fibrosis(32.5 vs 12.0,P 0.01) and ballooning(27.3 vs 13.3,P 0.01) was significantly higher among patients with NAFLD and T2 DM compared to patients with NAFLD without T2 DM.On multivariate analysis,T2 DM was independently associated with NASH(OR = 3.27,95%CI: 1.43-7.50,P 0.01) and advanced fibrosis(OR = 3.45,95%CI: 1.53-7.77,P 0.01) in all patients with NAFLD.There was a higher rate of T2DM(38.1 vs 19.4,P 0.01) and cirrhosis(8.3 vs 0.0,P = 0.01) along with significantly higher mean Bilirubin(0.71 vs 0.56,P = 0.01) and AST(54.2 vs 38.3,P 0.01) and ALT(78.7 vs 57.0,P = 0.01) level among patients with NASH when compared to patients with steatosis alone.The mean platelet count(247 vs 283,P 0.01) and high-density lipoprotein cholesterol level(42.7 vs 48.1,P = 0.01) was lower among patients with NASH compared to patients with steatosis.CONCLUSION: Patients with NAFLD and T2 DM tend to have more advanced stages of NAFLD,particularly advanced fibrosis and higher rate of ballooning than patients with NAFLD without T2 DM.     

血清谷丙转氨酶在正常范围内对非酒精性脂肪性肝病的预测

目的:分析血清谷丙转氨酶(ALT)与非酒精性脂肪性肝病(NAFLD)之间的关系,探讨正常范围ALT对NAFLD发生的预测价值.方法:选择2006-04-07/2010-01-09湖南省人民医院体检个体共4076例,排除过量饮酒、乙肝标志物阳性、严重感染及MS资料不全者,共2830例纳入研究,其中1367例在1-3年后再...     

SGLT2 inhibition increases serum copeptin in young adults with type 1 diabetes

AimsCopeptin, a surrogate of vasopressin, is elevated in type 1 diabetes (T1D) and predicts kidney disease and cardiovascular mortality. Given the cardiorenal protective effects of SGLT2 inhibition (SGLT2i), our aim was to examine: 1) the relationship between serum copeptin, metabolic, renal and systemic hemodynamic parameters in adults with T1D; and 2) serum copeptin after SGLT2i with empagliflozin.Materials and methodsIn this post-hoc, exploratory analysis, serum copeptin, glomerular filtration rate (GFR_Inulin), effective renal plasma flow (ERPF_PAH), plasma renin angiotensin aldosterone system markers, HbA_1c, 24-hour urine volume and sodium excretion were measured in 40 participants with T1D (24.3 ± 5.1 years) during eu- and hyperglycaemia before and after 8 weeks of 25 mg of daily empagliflozin.ResultsHigher baseline copeptin correlated with higher HbA_1c, lower 24-hour urine volume and sodium excretion, after correcting for age, sex, systolic blood pressure, and HbA_1c. Copeptin concentrations increased in response to empagliflozin under euglycaemia (4.1 ± 2.1 to 5.1 ± 2.8 pmol/L, P = 0.0053) and hyperglycaemia (3.3 ± 1.4 to 5.6 ± 2.8 pmol/L, P < 0.0001). The rise in copeptin in response to empagliflozin correlated with change in 24-hour urine volume, but was independent of changes in fractional excretion of sodium and haematocrit.ConclusionsElevated serum copeptin was associated with worse glycaemic control and lower diuresis and natriuresis. SGLT2i increased serum copeptin in adults with T1D, and the rise correlated with change in diuresis, but not natriuresis and hemo-concentration. Further work is required to evaluate the clinical implications of elevated copeptin with SGLT2i, including whether it is simply a marker of diuresis or may contribute to cardiorenal disease long-term.     

Effects of SGLT2 inhibitors on systemic and tissue low-grade inflammation: The potential contribution to diabetes complications and cardiovascular disease

Chronic low-grade inflammation is a recognized key feature associated with type 2 diabetes mellitus (T2DM) and its complications. In prospective randomized trials, sodium-glucose cotransporter type 2 (SGLT2) inhibitors have demonstrated benefits related to several cardiovascular and renal risk factors, including HbA_1c, blood pressure, body weight, renal hyperfiltration, and improvement of cardiorenal outcomes. SGLT2 inhibitors may improve adipose tissue function and induce decreases in serum leptin, TNF-α and IL-6 while increasing adiponectin. While data on high-sensitivity C-reactive protein and other inflammatory markers are relatively scarce in humans, in animals, a number of reports have shown reductions in cytokine and chemokine concentrations in parallel with protective effects against progression of atherosclerotic lesions. Experimental findings also suggest that part of the renoprotective effects of SGLT2 inhibition may be related to anti-inflammatory actions at the kidney level. Underlying mechanisms to explain this anti-inflammatory effect are multiple, but may involve weight loss, and reduction in adipose tissue inflammation, slight increase in ketone bodies and diminution of uric acid levels or attenuation of oxidative stress. However, further studies in diabetes patients with specific assessment of inflammatory markers are still necessary to determine the specific contribution of the anti-inflammatory action of SGLT2 inhibitors to the reduction of cardiovascular and renal complications and mortality observed with this class of antidiabetic drugs.     

2型糖尿病对非酒精性脂肪性肝病的影响

2型糖尿病与非酒精性脂肪性肝病关系密切,其对非酒精性脂肪性肝病流行病学与抗糖尿病治疗对非酒精性脂肪性肝病病情转归均有影响。此文就2型糖尿病对NAFLD发病、进展及抗糖尿病治疗中生活方式干预和胰岛素增敏剂应用对NAFLD的影响作一综述,旨在为临床决策提供参考。     

Visceral fat volume predicts new-onset type 2 diabetes in patients with chronic hepatitis C

Ninety seven patients with chronic hepatitis C (CHC) and 72 with non-alcoholic fatty liver disease (NAFLD) were enrolled. Increased visceral fat area (VFA) was associated with high values of HbA1c. The variables associated with a high risk of new-onset diabetes had a VFA > 101 cm² in CHC, but not in NAFLD.