title: Isocaloric Diets High in Animal or Plant Protein Reduce Liver Fat and Inflammation in Individuals With Type 2 Diabetes.
abstract: Nonalcoholic fatty liver disease (NAFLD) is associated with increased risk of hepatic, cardiovascular, and metabolic diseases. High-protein diets, rich in methionine and branched chain amino acids (BCAAs), apparently reduce liver fat, but can induce insulin resistance. We investigated the effects of diets high in animal protein (AP) vs plant protein (PP), which differ in levels of methionine and BCAAs, in patients with type 2 diabetes and NAFLD. We examined levels of liver fat, lipogenic indices, markers of inflammation, serum levels of fibroblast growth factor 21 (FGF21), and activation of signaling pathways in adipose tissue.
  
  
  
  We performed a prospective study of individuals with type 2 diabetes and NAFLD at a tertiary medical center in Germany from June 2013 through March 2015. We analyzed data from 37 subjects placed on a diet high in AP (rich in meat and dairy foods; n = 18) or PP (mainly legume protein; n = 19) without calorie restriction for 6 weeks. The diets were isocaloric with the same macronutrient composition (30% protein, 40% carbohydrates, and 30% fat). Participants were examined at the start of the study and after the 6-week diet period for body mass index, body composition, hip circumference, resting energy expenditure, and respiratory quotient. Body fat and intrahepatic fat were detected by magnetic resonance imaging and spectroscopy, respectively. Levels of glucose, insulin, liver enzymes, and inflammation markers, as well as individual free fatty acids and free amino acids, were measured in collected blood samples. Hyperinsulinemic euglycemic clamps were performed to determine whole-body insulin sensitivity. Subcutaneous adipose tissue samples were collected and analyzed for gene expression patterns and phosphorylation of signaling proteins.
  
  
  
  Postprandial levels of BCAAs and methionine were significantly higher in subjects on the AP vs the PP diet. The AP and PP diets each reduced liver fat by 36%-48% within 6 weeks (for AP diet P = .0002; for PP diet P = .001). These reductions were unrelated to change in body weight, but correlated with down-regulation of lipolysis and lipogenic indices. Serum level of FGF21 decreased by 50% in each group (for AP diet P < .0002; for PP diet P < .0002); decrease in FGF21 correlated with loss of hepatic fat. In gene expression analyses of adipose tissue, expression of the FGF21 receptor cofactor β-klotho was associated with reduced expression of genes encoding lipolytic and lipogenic proteins. In patients on each diet, levels of hepatic enzymes and markers of inflammation decreased, insulin sensitivity increased, and serum level of keratin 18 decreased.
  
  
  
  In a prospective study of patients with type 2 diabetes, we found diets high in protein (either animal or plant) significantly reduced liver fat independently of body weight, and reduced markers of insulin resistance and hepatic necroinflammation. The diets appear to mediate these changes via lipolytic and lipogenic pathways in adipose tissue. Negative effects of BCAA or methionine were not detectable. FGF21 level appears to be a marker of metabolic improvement. ClinicalTrials.gov ID NCT02402985.
authors.affiliation: German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; German Center for Diabetes Research, Germany. Electronic address: mariya.markova@dife.de.
authors.forename: Mariya
authors.initials: M
authors.lastname: Markova
authors.affiliation: German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; German Center for Diabetes Research, Germany; Department of Endocrinology, Diabetes and Nutrition, Campus Benjamin Franklin, Charité University Medicine, Berlin, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Pivovarova
authors.affiliation: German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; German Center for Diabetes Research, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Hornemann
authors.affiliation: German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; German Center for Diabetes Research, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Sucher
authors.affiliation: German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; German Center for Diabetes Research, Germany.
authors.forename: Turid
authors.initials: T
authors.lastname: Frahnow
authors.affiliation: Institute of Food Chemistry, Hamburg School of Food Science, University of Hamburg, Hamburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Wegner
authors.affiliation: German Center for Diabetes Research, Germany; Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany; Section on Experimental Radiology, Department of Diagnostic and Interventional Radiology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Machann
authors.affiliation: German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
authors.forename: Klaus Jürgen
authors.initials: KJ
authors.lastname: Petzke
authors.affiliation: Department of Diagnostic and Interventional Radiology, Ernst von Bergmann Hospital, Potsdam, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Hierholzer
authors.affiliation: Institute of Clinical Chemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Lichtinghagen
authors.affiliation: German Center for Diabetes Research, Germany; Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Herder
authors.affiliation: German Center for Diabetes Research, Germany; Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Carstensen-Kirberg
authors.affiliation: German Center for Diabetes Research, Germany; Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany; Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Roden
authors.affiliation: German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; German Center for Diabetes Research, Germany; Department of Endocrinology, Diabetes and Nutrition, Campus Benjamin Franklin, Charité University Medicine, Berlin, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Rudovich
authors.affiliation: German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Klaus
authors.affiliation: Institut für Getreideverarbeitung GmbH, Nuthetal, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Thomann
authors.affiliation: Institute for Food and Environmental Research, Nuthetal, Germany.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Schneeweiss
authors.affiliation: Institute of Food Chemistry, Hamburg School of Food Science, University of Hamburg, Hamburg, Germany; Institute for Food and Environmental Research, Nuthetal, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Rohn
authors.affiliation: German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; German Center for Diabetes Research, Germany; Department of Endocrinology, Diabetes and Nutrition, Campus Benjamin Franklin, Charité University Medicine, Berlin, Germany.
authors.forename: Andreas F H
authors.initials: AF
authors.lastname: Pfeiffer
mesh_terms: D052242:Adiponectin / Q000378:metabolism; D000273:Adipose Tissue; D000368:Aged; D000818:Animals; D001823:Body Composition; D018932:Chemokine CCL2 / Q000378:metabolism; D003611:Dairy Products; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D004044:Dietary Proteins; D015536:Down-Regulation; D004734:Energy Metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007249:Inflammation; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D020382:Interleukin-18 / Q000378:metabolism; D050356:Lipid Metabolism; D050155:Lipogenesis; D008099:Liver / Q000000981:diagnostic imaging* / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008460:Meat; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000000981:diagnostic imaging / Q000178:diet therapy* / Q000378:metabolism; D014674:Plant Proteins, Dietary / Q000627:therapeutic use*; D011446:Prospective Studies
chemical_list: C499918:ADIPOQ protein, human; D052242:Adiponectin; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D004044:Dietary Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D020382:Interleukin-18; D014674:Plant Proteins, Dietary; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors
keywords: FFA; KLB; NAFLD; NASH