scholarly journals Role of Insulin Resistance in MAFLD

2021 ◽  
Vol 22 (8) ◽  
pp. 4156
Author(s):  
Yoshitaka Sakurai ◽  
Naoto Kubota ◽  
Toshimasa Yamauchi ◽  
Takashi Kadowaki
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
De Novo Lipogenesis ◽  
Hepatic Insulin Resistance ◽  
Metabolic Dysfunction ◽  
Alcoholic Fatty Liver ◽  
Fat Accumulation

Many studies have reported that metabolic dysfunction is closely involved in the complex mechanism underlying the development of non-alcoholic fatty liver disease (NAFLD), which has prompted a movement to consider renaming NAFLD as metabolic dysfunction-associated fatty liver disease (MAFLD). Metabolic dysfunction in this context encompasses obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and metabolic syndrome, with insulin resistance as the common underlying pathophysiology. Imbalance between energy intake and expenditure results in insulin resistance in various tissues and alteration of the gut microbiota, resulting in fat accumulation in the liver. The role of genetics has also been revealed in hepatic fat accumulation and fibrosis. In the process of fat accumulation in the liver, intracellular damage as well as hepatic insulin resistance further potentiates inflammation, fibrosis, and carcinogenesis. Increased lipogenic substrate supply from other tissues, hepatic zonation of Irs1, and other factors, including ER stress, play crucial roles in increased hepatic de novo lipogenesis in MAFLD with hepatic insulin resistance. Herein, we provide an overview of the factors contributing to and the role of systemic and local insulin resistance in the development and progression of MAFLD.

scholarly journals Physiological Disturbance in Fatty Liver Energy Metabolism Converges on IGFBP2 Abundance and Regulation in Mice and Men

2020 ◽  
Vol 21 (11) ◽  
pp. 4144 ◽  
Author(s):  
Pia Fahlbusch ◽  
Birgit Knebel ◽  
Tina Hörbelt ◽  
David Monteiro Barbosa ◽  
Aleksandra Nikolic ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Energy Metabolism ◽  
Fatty Liver ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Hepatic Insulin Resistance ◽  
Alcoholic Fatty Liver

Fatty liver occurs from simple steatosis with accumulated hepatic lipids and hepatic insulin resistance to severe steatohepatitis, with aggravated lipid accumulation and systemic insulin resistance, but this progression is still poorly understood. Analyses of hepatic gene expression patterns from alb-SREBP-1c mice with moderate, or aP2-SREBP-1c mice with aggravated, hepatic lipid accumulation revealed IGFBP2 as key nodal molecule differing between moderate and aggravated fatty liver. Reduced IGFBP2 expression in aggravated fatty liver was paralleled with promoter hypermethylation, reduced hepatic IGFBP2 secretion and IGFBP2 circulating in plasma. Physiologically, the decrease of IGFBP2 was accompanied with reduced fatty acid oxidation and increased de novo lipogenesis potentially mediated by IGF1 in primary hepatocytes. Furthermore, methyltransferase and sirtuin activities were enhanced. In humans, IGFBP2 serum concentration was lower in obese men with non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) compared to non-obese controls, and liver fat reduction by weight-loss intervention correlated with an increase of IGFBP2 serum levels. In conclusion, hepatic IGFBP2 abundance correlates to its circulating level and is related to hepatic energy metabolism and de novo lipogenesis. This designates IGFBP2 as non-invasive biomarker for fatty liver disease progression and might further provide an additional variable for risk prediction for pathogenesis of fatty liver in diabetes subtype clusters.

scholarly journals Beneficial effect of omarigliptin on diabetic patients with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Sachiko Hattori ◽  
Kazuomi Nomoto ◽  
Tomohiko Suzuki ◽  
Seishu Hayashi
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Liver Function ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Hepatic Insulin Resistance ◽  
Diabetic Patients ◽  
Alcoholic Fatty Liver ◽  
Dpp4 Inhibitor ◽  
Alcoholic Fatty Liver Disease

Abstract Background Dipeptidyl peptidase 4 (DPP4) is a serine exopeptidase able to inactivate various oligopeptides, and also a hepatokine. Hepatocyte-specific overexpression of DPP4 is associated with hepatic insulin resistance and liver steatosis. Method We examined whether weekly DPP4 inhibitor omarigliptin (OMG) can improve liver function as well as levels of inflammation and insulin resistance in type 2 diabetic patients with non-alcoholic fatty liver disease (NAFLD). Further, we investigated the effects of OMG in a diabetic patient with biopsy-confirmed nonalcoholic steatohepatitis (NASH). Results In NAFLD patients, OMG significantly decreased levels of aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, homeostatic model assessment of insulin resistance (HOMA-IR), and high-sensitivity C-reactive protein (hsCRP), while no significant change was seen in hemoglobin A1c or body mass index. In the NASH patient, liver function improved markedly, and levels of the hepatic fibrosis marker FIB-4 decreased in parallel with HOMA-IR and hsCRP. Slight but clear improvements in intrahepatic fat deposition and fibrosis appeared to be seen on diagnostic ultrasonography. Conclusion Weekly administration of the DPP4 inhibitor OMG in ameliorating hepatic insulin resistance may cause beneficial effects in liver with NAFLD/NASH.

scholarly journals A Narrative Review on the Role of AMPK on De Novo Lipogenesis in Non-Alcoholic Fatty Liver Disease: Evidence from Human Studies

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1822
Author(s):  
Christian von Loeffelholz ◽  
Sina M. Coldewey ◽  
Andreas L. Birkenfeld
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Mammalian Cells ◽  
De Novo ◽  
Adenosine Monophosphate ◽  
De Novo Lipogenesis ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

5′AMP-activated protein kinase (AMPK) is known as metabolic sensor in mammalian cells that becomes activated by an increasing adenosine monophosphate (AMP)/adenosine triphosphate (ATP) ratio. The heterotrimeric AMPK protein comprises three subunits, each of which has multiple phosphorylation sites, playing an important role in the regulation of essential molecular pathways. By phosphorylation of downstream proteins and modulation of gene transcription AMPK functions as a master switch of energy homeostasis in tissues with high metabolic turnover, such as the liver, skeletal muscle, and adipose tissue. Regulation of AMPK under conditions of chronic caloric oversupply emerged as substantial research target to get deeper insight into the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Evidence supporting the role of AMPK in NAFLD is mainly derived from preclinical cell culture and animal studies. Dysbalanced de novo lipogenesis has been identified as one of the key processes in NAFLD pathogenesis. Thus, the scope of this review is to provide an integrative overview of evidence, in particular from clinical studies and human samples, on the role of AMPK in the regulation of primarily de novo lipogenesis in human NAFLD.

scholarly journals Hepatic Insulin Resistance Is Not Pathway Selective in Humans With Nonalcoholic Fatty Liver Disease

2020 ◽  
Author(s):  
Kasper W. ter Horst ◽  
Daniel F. Vatner ◽  
Dongyan Zhang ◽  
Gary W. Cline ◽  
Mariette T. Ackermans ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Bariatric Surgery ◽  
Liver Disease ◽  
Fatty Liver ◽  
Insulin Signaling ◽  
Fatty Liver Disease ◽  
De Novo ◽  
Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Alcoholic Fatty Liver

<b>Objective</b>: Both glucose and triglyceride production are increased in Type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). For decades, the leading hypothesis to explain these paradoxical observations has been selective hepatic insulin resistance, wherein insulin drives <i>de novo</i> lipogenesis (DNL), while failing to suppress glucose production. Here, we aimed to test this hypothesis in humans. <p><b>Research Design and Methods</b>: We recruited obese subjects who met criteria for bariatric surgery with (n=16) or without (n=15) NAFLD and assessed: i) insulin-mediated regulation of hepatic and peripheral glucose metabolism using hyperinsulinemic-euglycemic clamps with [6,6-<sup>2</sup>H<sub>2</sub>]glucose, ii) fasting and carbohydrate-driven hepatic DNL using deuterated water (<sup>2</sup>H<sub>2</sub>O), and iii) hepatocellular insulin signaling in liver biopsies collected during bariatric surgery.</p> <p><b>Results</b>: As compared with subjects without NAFLD, subjects with NAFLD demonstrated impaired insulin-mediated suppression of glucose production and attenuated -not increased- glucose-stimulated/high-insulin lipogenesis. Fructose-stimulated/low-insulin lipogenesis was intact. Hepatocellular insulin signaling, assessed for the first time in humans, exhibited a proximal block in insulin-resistant subjects: signaling was attenuated from the level of the insulin receptor through both glucose <i>and</i> lipogenesis pathways. The carbohydrate-regulated lipogenic transcription factor <i>ChREBP</i> was increased in subjects with NAFLD. </p> <b>Conclusions</b>: Acute increases in lipogenesis in humans with NAFLD are not explained by altered molecular regulation of lipogenesis through a paradoxical increase in lipogenic insulin action; rather, increases in lipogenic substrate availability may be the key. <a></a>

Mo1016 Role of Oxidative Stress and Insulin Resistance in the Disease Severity of Non-Alcoholic Fatty Liver Disease

2013 ◽  
Vol 144 (5) ◽  
pp. S-1013
Author(s):  
Billur Canbakan ◽  
Hakan Senturk ◽  
Murat Tuncer ◽  
Ibrahim Hatemi ◽  
Emine Koroglu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Disease Severity ◽  
Fatty Liver Disease ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

scholarly journals Inflammation as a potential link between nonalcoholic fatty liver disease and insulin resistance

2013 ◽  
Vol 218 (3) ◽  
pp. R25-R36 ◽  
Author(s):  
Mohamed Asrih ◽  
François R Jornayvaz
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Metabolic Energy ◽  
Hepatic Insulin Resistance ◽  
Major Health Problem ◽  
Nonalcoholic Fatty Liver

Nonalcoholic fatty liver disease (NAFLD) has become a major health problem in developed countries. It has affected more than 30% of the general population and is commonly associated with insulin resistance, which is a major risk factor for the development of type 2 diabetes and a central feature of the metabolic syndrome. Furthermore, accumulating evidences reveal that NAFLD as well as insulin resistance is strongly related to inflammation. Cytokines and adipokines play a pivotal role in inflammatory processes. In addition, these inflammatory mediators regulate various functions including metabolic energy balance, inflammation, and immune response. However, their role in modulating ectopic lipids involved in the development of insulin resistance, such as diacylglycerols and ceramides, remains unknown. The aim of this review is first to describe the pathophysiology of insulin resistance in NAFLD. In particular, we discuss the role of ectopic lipid accumulation in the liver. Secondly, we also summarize recent findings emphasizing the role of main inflammatory markers in both NAFLD and insulin resistance and their potential role in modulating hepatic fat content in NAFLD and associated hepatic insulin resistance.

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