Physical Activity, Fatty Liver, and Glucose Metabolism Over the Life Course: The Lifelines Cohort.
Byambasukh Oyuntugs,Zelle Dorien,Corpeleijn Eva
The American journal of gastroenterology
OBJECTIVES:We examined the dose-dependent association of habitual moderate-to-vigorous physical activity (MVPA) with the biochemical markers for nonalcoholic fatty liver disease (NAFLD) and whether this association changes with age and degree of impaired glucose metabolism. We also investigated whether the associations depend on the domain of MVPA. METHODS:In this study, using data from the population-based Lifelines cohort (N = 42,661), MVPA was self-reported on the short questionnaire to assess health-enhancing physical activity. NAFLD was defined as a fatty liver index value of >60, based on body mass index, waist circumference, plasma triglycerides, and gamma-glutamyltransferase. Glucose metabolism was defined as normal (NGM), impaired (IGM), and type 2 diabetes mellitus (T2DM). Exclusion criteria were previously diagnosed hepatitis or cirrhosis and excessive alcohol use. All analyses were adjusted for age, sex, and education. RESULTS:Higher MVPA was dose dependently associated with a lower risk of having NAFLD: compared with "No MVPA," the odds ratios (ORs) (95% confidence intervals) for MVPA quintiles were 0.78 (0.71-0.86), 0.64 (0.58-0.70), 0.53 (0.48-0.59), 0.51 (0.46-0.56), and 0.45 (0.41-0.50) for the highest level of MVPA. The association between MVPA and NAFLD was stronger for more impaired glucose status (ORNGM = 0.49 (0.42-0.57), ORIGM = 0.46 (0.40-0.54), ORT2DM = 0.42 (0.27-0.66)) and for older age (OR20-40 years = 0.51 (0.42-0.62), OR60-80 years = 0.37 (0.29-0.48)) with the highest level of MVPA, relative to No MVPA. No favorable association was observed for occupational MVPA. With regard to MVPA and fibrosis, associations with fibrosis markers showed contradictory results. CONCLUSIONS:Higher MVPA levels are dose dependently associated with a lower NAFLD risk. This association is stronger in people with diabetes and older adults.
10.14309/ajg.0000000000000168
Liraglutide, Sitagliptin, and Insulin Glargine Added to Metformin: The Effect on Body Weight and Intrahepatic Lipid in Patients With Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease.
Yan Jinhua,Yao Bin,Kuang Hongyu,Yang Xubin,Huang Qin,Hong Tianpei,Li Yushu,Dou Jingtao,Yang Wenying,Qin Guijun,Yuan Huijuan,Xiao Xinhua,Luo Sihui,Shan Zhongyan,Deng Hongrong,Tan Ying,Xu Fen,Xu Wen,Zeng Longyi,Kang Zhuang,Weng Jianping
Hepatology (Baltimore, Md.)
To investigate the effect of antidiabetic agents on nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM), 75 patients with T2DM and NAFLD under inadequate glycemic control by metformin were randomized (1:1:1) to receive add-on liraglutide, sitagliptin, or insulin glargine in this 26-week trial. The primary endpoint was the change in intrahepatic lipid (IHL) from baseline to week 26 as quantified by magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF). Secondary endpoints included changes in abdominal adiposity (subcutaneous adipose tissue [SAT] and visceral adipose tissue [VAT]), glycated hemoglobin, and body weight from baseline to week 26. We analysed data from intent-to-treat population. MRI-PDFF, VAT, and weight decreased significantly with liraglutide (15.4% ± 5.6% to 12.5% ± 6.4%, P < 0.001; 171.4 ± 27.8 to 150.5 ± 30.8, P = 0.003; 86.6 ± 12.9 kg to 82.9 ± 11.1 kg, P = 0.005, respectively) and sitagliptin (15.5% ± 5.6% to 11.7% ± 5.0%, P = 0.001; 153.4 ± 31.5 to 139.8 ± 27.3, P = 0.027; 88.2 ± 13.6 kg to 86.5 ± 13.2 kg, P = 0.005, respectively). No significant change in MRI-PDFF, VAT, or body weight was observed with insulin glargine. SAT decreased significantly in the liraglutide group (239.9 ± 69.0 to 211.3 ± 76.1; P = 0.020) but not in the sitagliptin and insulin glargine groups. Changes from baseline in MRI-PDFF, VAT, and body weight were significantly greater with liraglutide than insulin glargine but did not differ significantly between liraglutide and sitagliptin. Conclusion: Combined with metformin, both liraglutide and sitagliptin, but not insulin glargine, reduced body weight, IHL, and VAT in addition to improving glycemic control in patients with T2DM and NAFLD.
10.1002/hep.30320
How May GIP Enhance the Therapeutic Efficacy of GLP-1?
Samms Ricardo J,Coghlan Matthew P,Sloop Kyle W
Trends in endocrinology and metabolism: TEM
Glucagon-like peptide-1 (GLP-1) receptor agonists improve glucose homeostasis, reduce bodyweight, and over time benefit cardiovascular health in type 2 diabetes mellitus (T2DM). However, dose-related gastrointestinal effects limit efficacy, and therefore agents possessing GLP-1 pharmacology that can also target alternative pathways may expand the therapeutic index. One approach is to engineer GLP-1 activity into the sequence of glucose-dependent insulinotropic polypeptide (GIP). Although the therapeutic implications of the lipogenic actions of GIP are debated, its ability to improve lipid and glucose metabolism is especially evident when paired with the anorexigenic mechanism of GLP-1. We review the complexity of GIP in regulating adipose tissue function and energy balance in the context of recent findings in T2DM showing that dual GIP/GLP-1 receptor agonist therapy produces profound weight loss, glycemic control, and lipid lowering.
10.1016/j.tem.2020.02.006
Emerging Targets for Cardiovascular Disease Prevention in Diabetes.
Stitziel Nathan O,Kanter Jenny E,Bornfeldt Karin E
Trends in molecular medicine
Type 1 and type 2 diabetes mellitus (T1DM and T2DM) increase the risk of atherosclerotic cardiovascular disease (CVD), resulting in acute cardiovascular events, such as heart attack and stroke. Recent clinical trials point toward new treatment and prevention strategies for cardiovascular complications of T2DM. New antidiabetic agents show unexpected cardioprotective benefits. Moreover, genetic and reverse translational strategies have revealed potential novel targets for CVD prevention in diabetes, including inhibition of apolipoprotein C3 (APOC3). Modeling and pharmacology-based approaches to improve insulin action provide additional potential strategies to combat CVD. The development of new strategies for improved diabetes and lipid control fuels hope for future prevention of CVD associated with diabetes.
10.1016/j.molmed.2020.03.011
Obesity-induced excess of 17-hydroxyprogesterone promotes hyperglycemia through activation of glucocorticoid receptor.
Lu Yan,Wang E,Chen Ying,Zhou Bing,Zhao Jiejie,Xiang Liping,Qian Yiling,Jiang Jingjing,Zhao Lin,Xiong Xuelian,Lu Zhiqiang,Wu Duojiao,Liu Bin,Yan Jing,Zhang Rong,Zhang Huijie,Hu Cheng,Li Xiaoying
The Journal of clinical investigation
Type 2 diabetes mellitus (T2DM) has become an expanding global public health problem. Although the glucocorticoid receptor (GR) is an important regulator of glucose metabolism, the relationship between circulating glucocorticoids (GCs) and the features of T2DM remains controversial. Here, we show that 17-hydroxyprogesterone (17-OHP), an intermediate steroid in the biosynthetic pathway that converts cholesterol to cortisol, binds to and stimulates the transcriptional activity of GR. Hepatic 17-OHP concentrations are increased in diabetic mice and patients due to aberrantly increased expression of Cyp17A1. Systemic administration of 17-OHP or overexpression of Cyp17A1 in the livers of lean mice promoted the pathogenesis of hyperglycemia and insulin resistance, whereas knockdown of Cyp17A1 abrogated metabolic disorders in obese mice. Therefore, our results identify a Cyp17A1/17-OHP/GR-dependent pathway in the liver that mediates obesity-induced hyperglycemia, suggesting that selectively targeting hepatic Cyp17A1 may provide a therapeutic avenue for treating T2DM.
10.1172/JCI134485
Pleiotropic effects of polyphenols on glucose and lipid metabolism: Focus on clinical trials.
Matacchione Giulia,Gurău Felicia,Baldoni Simone,Prattichizzo Francesco,Silvestrini Andrea,Giuliani Angelica,Pugnaloni Armanda,Espinosa Emma,Amenta Francesco,Bonafè Massimiliano,Procopio Antonio Domenico,Rippo Maria Rita,Olivieri Fabiola,Sabbatinelli Jacopo
Ageing research reviews
Epidemiological evidence from observational studies suggests that dietary polyphenols (PPs) - phytochemicals found in a variety of plant-based foods - can reduce the risk of developing type 2 diabetes mellitus (T2DM). Clinical trials have also indicated that PPs may help manage the two key features of T2DM, hyperglycemia and dyslipidemia. Since the incidence of T2DM is dramatically increasing worldwide, identifying food-based approaches that can reduce the risk of developing it and help manage its main risk factors in early-stage disease has clinical and socioeconomic relevance. After a brief overview of current epidemiological data on the incidence of T2DM in individuals consuming PP-rich diets, we review the evidence from clinical trials investigating PP-enriched foods and/or PP-based nutraceutical compounds, report their main results, and highlight the knowledge gaps that should be bridged to enhance our understanding of the role of PPs in T2DM development and management.
10.1016/j.arr.2020.101074