scholarly journals Genetic Evidence for Different Adiposity Phenotypes and their Opposing Influence on Ectopic Fat and Risk of Cardiometabolic Disease

2021 ◽  
Author(s):  
Susan Martin ◽  
Madeleine Cule ◽  
Nicolas Basty ◽  
Jessica Tyrrell ◽  
Robin N. Beaumont ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Metabolic Profile ◽  
Liver Fat ◽  
Metabolic Effects ◽  
Ectopic Fat ◽  
Alcoholic Fatty Liver ◽  
Cardiometabolic Diseases ◽  
Risk Of Disease

To understand the causal role of adiposity and ectopic fat in type 2 diabetes and cardiometabolic diseases, we aimed to identify two clusters of adiposity genetic variants, one with ‘adverse’ metabolic effects (UFA) and the other with, paradoxically, ‘favourable’ metabolic effects (FA). We performed a multivariate genome-wide association study using body fat percentage and metabolic biomarkers from UK Biobank and identified 38 UFA and 36 FA variants. Adiposity-increasing alleles were associated with an adverse metabolic profile, higher risk of disease, higher CRP, higher fat in subcutaneous and visceral adipose tissue, liver and pancreas for UFA; and a favourable metabolic profile, lower risk of disease, higher CRP, higher subcutaneous adipose tissue but lower liver fat for FA. We detected no sexual dimorphism. The Mendelian randomization studies provided evidence for risk-increasing effect of UFA and protective effect of FA on type 2 diabetes, heart disease, hypertension, stroke, non-alcoholic fatty liver disease and polycystic ovary syndrome. FA is distinct from UFA by its association with lower liver fat, and protection from cardiometabolic diseases; it was not associated with visceral or pancreatic fat. Understanding the difference in FA and UFA may lead to new insights in preventing, predicting and treating of cardiometabolic diseases.

scholarly journals Genetic Evidence for Different Adiposity Phenotypes and their Opposing Influence on Ectopic Fat and Risk of Cardiometabolic Disease

2021 ◽  
Author(s):  
Susan Martin ◽  
Madeleine Cule ◽  
Nicolas Basty ◽  
Jessica Tyrrell ◽  
Robin N. Beaumont ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Metabolic Profile ◽  
Liver Fat ◽  
Metabolic Effects ◽  
Ectopic Fat ◽  
Alcoholic Fatty Liver ◽  
Cardiometabolic Diseases ◽  
Risk Of Disease

To understand the causal role of adiposity and ectopic fat in type 2 diabetes and cardiometabolic diseases, we aimed to identify two clusters of adiposity genetic variants, one with ‘adverse’ metabolic effects (UFA) and the other with, paradoxically, ‘favourable’ metabolic effects (FA). We performed a multivariate genome-wide association study using body fat percentage and metabolic biomarkers from UK Biobank and identified 38 UFA and 36 FA variants. Adiposity-increasing alleles were associated with an adverse metabolic profile, higher risk of disease, higher CRP, higher fat in subcutaneous and visceral adipose tissue, liver and pancreas for UFA; and a favourable metabolic profile, lower risk of disease, higher CRP, higher subcutaneous adipose tissue but lower liver fat for FA. We detected no sexual dimorphism. The Mendelian randomization studies provided evidence for risk-increasing effect of UFA and protective effect of FA on type 2 diabetes, heart disease, hypertension, stroke, non-alcoholic fatty liver disease and polycystic ovary syndrome. FA is distinct from UFA by its association with lower liver fat, and protection from cardiometabolic diseases; it was not associated with visceral or pancreatic fat. Understanding the difference in FA and UFA may lead to new insights in preventing, predicting and treating of cardiometabolic diseases.

scholarly journals Elevated circulating follistatin associates with an increased risk of type 2 diabetes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chuanyan Wu ◽  
Yan Borné ◽  
Rui Gao ◽  
Maykel López Rodriguez ◽  
William C. Roell ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Genome Wide Association Study ◽  
Regulatory Protein ◽  
Alcoholic Fatty Liver ◽  
Increased Risk

AbstractThe hepatokine follistatin is elevated in patients with type 2 diabetes (T2D) and promotes hyperglycemia in mice. Here we explore the relationship of plasma follistatin levels with incident T2D and mechanisms involved. Adjusted hazard ratio (HR) per standard deviation (SD) increase in follistatin levels for T2D is 1.24 (CI: 1.04–1.47, p < 0.05) during 19-year follow-up (n = 4060, Sweden); and 1.31 (CI: 1.09–1.58, p < 0.01) during 4-year follow-up (n = 883, Finland). High circulating follistatin associates with adipose tissue insulin resistance and non-alcoholic fatty liver disease (n = 210, Germany). In human adipocytes, follistatin dose-dependently increases free fatty acid release. In genome-wide association study (GWAS), variation in the glucokinase regulatory protein gene (GCKR) associates with plasma follistatin levels (n = 4239, Sweden; n = 885, UK, Italy and Sweden) and GCKR regulates follistatin secretion in hepatocytes in vitro. Our findings suggest that GCKR regulates follistatin secretion and that elevated circulating follistatin associates with an increased risk of T2D by inducing adipose tissue insulin resistance.

scholarly journals Insulin and Insulin Receptors in Adipose Tissue Development

2019 ◽  
Vol 20 (3) ◽  
pp. 759 ◽  
Author(s):  
Angelo Cignarelli ◽  
Valentina Genchi ◽  
Sebastio Perrini ◽  
Annalisa Natalicchio ◽  
Luigi Laviola ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Insulin Receptor ◽  
Intracellular Signaling ◽  
Insulin Receptors ◽  
Metabolic Effects ◽  
Endocrine Activity ◽  
Differentiated Cells ◽  
And Function

Insulin is a major endocrine hormone also involved in the regulation of energy and lipid metabolism via the activation of an intracellular signaling cascade involving the insulin receptor (INSR), insulin receptor substrate (IRS) proteins, phosphoinositol 3-kinase (PI3K) and protein kinase B (AKT). Specifically, insulin regulates several aspects of the development and function of adipose tissue and stimulates the differentiation program of adipose cells. Insulin can activate its responses in adipose tissue through two INSR splicing variants: INSR-A, which is predominantly expressed in mesenchymal and less-differentiated cells and mainly linked to cell proliferation, and INSR-B, which is more expressed in terminally differentiated cells and coupled to metabolic effects. Recent findings have revealed that different distributions of INSR and an altered INSR-A:INSR-B ratio may contribute to metabolic abnormalities during the onset of insulin resistance and the progression to type 2 diabetes. In this review, we discuss the role of insulin and the INSR in the development and endocrine activity of adipose tissue and the pharmacological implications for the management of obesity and type 2 diabetes.

scholarly journals Ectopic fat, insulin resistance and non-alcoholic fatty liver disease

2013 ◽  
Vol 72 (4) ◽  
pp. 412-419 ◽  
Author(s):  
Christopher D. Byrne
Keyword(s):  
Hepatocellular Carcinoma ◽  
Type 2 Diabetes ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Ectopic Fat ◽  
Obese People ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is now recognised as the hepatic component of metabolic syndrome (MetS). NAFLD is an example of ectopic fat accumulation in a visceral organ that causes organ-specific disease, and affects risk of other related diseases such as type 2 diabetes and CVD. NAFLD is a spectrum of fat-associated liver conditions that can culminate in end stage liver disease, hepatocellular carcinoma and the need for liver transplantation. Simple steatosis, or fatty liver, occurs early in NAFLD and may progress to non-alcoholic steatohepatitis, fibrosis and cirrhosis with increased risk of hepatocellular carcinoma. Prevalence estimates for NAFLD range from 2 to 44% in the general population and it has been estimated that NAFLD exists in up to 70% of people with type 2 diabetes. Although many obese people have NAFLD, there are many obese people who do not develop ectopic liver fat. The aim of this review which is based on a presentation at the Royal Society of Medicine, UK in December 2012 is to discuss development of NAFLD, ectopic fat accumulation and insulin resistance. The review will also describe the relationships between NAFLD, type 2 diabetes and CVD.

scholarly journals Effect of Short Term Intensive Lifestyle Intervention on Hepatic Steatosis Indexes in Adults with Obesity and/or Type 2 Diabetes

2019 ◽  
Vol 8 (6) ◽  
pp. 851 ◽  
Author(s):  
Elisa Reginato ◽  
Roberto Pippi ◽  
Cristina Aiello ◽  
Emilia Sbroma Tomaro ◽  
Claudia Ranucci ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Liver ◽  
Hepatic Steatosis ◽  
Lifestyle Intervention ◽  
Intervention Program ◽  
Liver Fat ◽  
Alcoholic Fatty Liver ◽  
Lifestyle Intervention Program ◽  
Alcoholic Fatty Liver Disease

Background: Non-alcoholic fatty liver disease (NAFLD) has an estimated prevalence of 20–30% in the general population and even higher in individuals with metabolic risk factors. The aim of this study was to evaluate the effect of a lifestyle intervention program on surrogate markers of hepatic steatosis in obesity and/or type 2 diabetes patients, enrolled in the C.U.R.I.A.Mo. (Centro Universitario di Ricerca Interdipartimentale Attività Motoria) trial. Methods: 102 subjects (56 females and 46 males, aged between 23 and 78) with type 2 diabetes, obesity or a BMI of at least 25 kg/m2 with comorbidities, participated in the intensive phase of a multidisciplinary lifestyle intervention program at the Healthy Lifestyle Institute of the University of Perugia (C.U.R.I.A.Mo.). Six indices related to NAFLD (Visceral Adiposity Index, Fatty Liver index, Non-Alcoholic Fatty Liver Disease liver fat score and liver fat equation, hepatic steatosis index and TyG index) were calculated before and after a three-month multidisciplinary lifestyle intervention. Results: The intervention improved the anthropometric and clinical parameters in the total population, the obese and/or diabetics. Data showed a significant weight loss, a reduced waist circumference, triglycerides, and an improvement in Mediterranean diet adherence. Hepatic steatosis indices were significantly reduced in the total population and in different subgroups (males, females, obesity and diabetes).

scholarly journals SGLT2 inhibitors in patients with type 2 diabetes with non-alcoholic fatty liver diseases: an umbrella review of systematic reviews

2020 ◽  
Vol 8 (2) ◽  
pp. e001956
Author(s):  
Shih-Chieh Shao ◽  
Liang-Tseng Kuo ◽  
Rong-Nan Chien ◽  
Ming-Jui Hung ◽  
Edward Chia-Cheng Lai
Keyword(s):  
Type 2 Diabetes ◽  
Liver Cirrhosis ◽  
Liver Cancer ◽  
Systematic Reviews ◽  
Sglt2 Inhibitors ◽  
Liver Fat ◽  
Umbrella Review ◽  
Alcoholic Fatty Liver ◽  
Liver Functions

IntroductionSodium glucose co-transporter 2 (SGLT2) inhibitors have been reported to benefit liver functions in patients with type 2 diabetes (T2D) with non-alcoholic fatty liver disease (NAFLD). The aim of this study is to critically appraise existing systematic reviews in order to consolidate evidence associating the use of SGLT2 inhibitors with beneficial hepatic results for patients with T2D with NAFLD.MethodsThis umbrella review searched relevant published systematic reviews of clinical trials from PubMed and Embase between inception and September 16, 2020. Two independent investigators appraised study quality using AMSTAR2 (Assessment of Multiple Systematic Reviews 2). The hepatic effects from SGLT2 inhibitors were summarized based on liver enzymes, liver fat, liver histology, liver cirrhosis and liver cancer.ResultsOf 25 screened potential systematic reviews, we ultimately included 7 in this study. However, none of them could be rated as being of high methodological quality. Five systematic reviews indicated that SGLT2 inhibitors could effectively decrease liver fat and liver parameters of alanine aminotransferase and gamma-glutamyl transferase in patients with NAFLD. Two systematic reviews indicated that SGLT2 inhibitors could reduce hepatosteatosis, as supported by biopsy-proven evidence of improvement from a small clinical trial, but no evidence of liver fibrosis improvement was found.ConclusionsThere is some association between SGLT2 inhibitor use and observed benefits to liver functions in patients with T2D with NAFLD, although the quality of current systematic reviews remains relatively low. Further evaluation of long-term liver outcomes with SGLT2 inhibitors in cases of liver cirrhosis and liver cancer is warranted.

Cytokeratin-18 and enhanced liver fibrosis scores in type 1 and type 2 diabetes and effects of two different insulins

2017 ◽  
Vol 66 (3) ◽  
pp. 661-668 ◽  
Author(s):  
Arun Sanyal ◽  
Kenneth Cusi ◽  
Mark L Hartman ◽  
Shuyu Zhang ◽  
Edward J Bastyr ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Liver Fibrosis ◽  
Liver Fat ◽  
Phase Iii ◽  
Cytokeratin 18 ◽  
Alcoholic Fatty Liver ◽  
Link Type ◽  
Group Population

Data on cytokeratin-18 (K-18) and enhanced liver fibrosis (ELF) score in insulin-treated diabetes patients with non-alcoholic fatty liver disease (NAFLD) are limited. This study analyzed phase III data comparing basal insulin peglispro (BIL) and insulin glargine in type 1 (T1D), and type 2 diabetes (T2D) (insulin-naïve and insulin-treated). Alanine aminotransferase (ALT), K-18, ELF scores and liver fat content (LFC), measured by MRI, were obtained longitudinally. Baseline K-18 (U/L) was higher in T2D (range: 207‒247) than T1D (range: 148‒183), correlated with ALT in all populations (r (range) 0.264‒0.637, p<0.05), but with LFC only in T2D (r (range) 0.474‒0.586, p<0.05). K-18 increased significantly from baseline in BIL-treated, but not glargine-treated patients. Change from baseline (CFB) K-18 was significantly correlated with CFB in ALT in BIL-treated T2D populations. Baseline ELF scores were higher in T2D (range: 9.12‒9.20) than T1D (range: 8.24‒8.36), correlated with ALT in T1D only (0.209, p<0.05), and not correlated with LFC in any population. ELF scores increased significantly from baseline in BIL-treated but not glargine-treated patients. There were no correlations between CFB in LFC and ELF score at week 52 in any treatment group/population. In all BIL-treated populations, CFB in ALT and CFB in ELF score at week 52 were positively correlated. These data characterize associations of K-18 and ELF score with ALT and LFC in insulin-treated patients with T1D and T2D. Hepatopreferential insulins may be associated with increased K-18 and ELF scores but mechanisms and clinical significance are unknown. ClinicalTrials.gov identifiers are NCT01481779, NCT01435616, NCT01454284 and NCT01582451.

scholarly journals Dapagliflozin plus saxagliptin add‐on to metformin reduces liver fat and adipose tissue volume in patients with type 2 diabetes

2020 ◽  
Vol 22 (7) ◽  
pp. 1094-1101 ◽  
Author(s):  
Lars Johansson ◽  
Paul D. Hockings ◽  
Eva Johnsson ◽  
Nalina Dronamraju ◽  
Jill Maaske ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Liver Fat ◽  
Tissue Volume ◽  
Adipose Tissue Volume
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