Lean Subjects with Fatty Liver Show Decreased GLP-1 and GIP Response during OGTT

Abstract

Subjects with nonalcoholic fatty liver disease (NAFLD) are at high risk of type 2 diabetes even if they are not obese and recent studies have indicated that liver fat (LF)>2.5% was already associated with alteration in glucose and insulin metabolism. Our aim was to investigate if having LF as low as 2.5% was associated to impairment in insulin sensitivity, secretion (ISR) and/or incretin hormones glucagon-like peptide (GLP) 1 and glucose-dependent insulinotropic peptide (GIP) released during an oral glucose tolerance test (OGTT). We studied 49 nondiabetic non-obese subjects (age 52±4; BMI 24.2±0.4 kg/m2). All subjects underwent a 2 h OGTT with plasma insulin, C-peptide, GLP-1, and GIP concentrations were measured every 15-30 min and ISR was quantitated by C-peptide deconvolution. Insulin sensitivity was quantified by HOMA and Matsuda index. Liver fat (LF) accumulation was quantified by magnetic resonance spectroscopy (MRS). In this group of non-obese subjects the great majority were non-NAFLD (31 had LF<2.5%), while 18 had NAFLD (9 had LF 2.5-5% and 9 had LF>5%). Age, BMI, HOMA (1.4±0.2 vs. 1.1±0.2), Matsuda index (7.3±0.7 vs. 10.6±1.3), fasting glucose (5.2±0.1 vs. 5.2±0.1 mmol/l), insulin (6.1±0.7 vs. 4.7±0.7 mU/l), ALT (20±1 vs. 19±1 U/l) and TG (96±22 vs. 88±6 mg/dl) were similar in NAFLD and non-NAFLD. Subjects with LF>2.5% had lower GLP-1 [GLP-1_AUC0-120 was 2.8±0.3 vs. 3.7±0.3, p=0.03], insulin secretion [ISR_AUC60-120 was 61±5 vs. 78±5 nmol, p=0.03] and insulin clearance [MCRI0-120 69±6 vs. 91±7 ml/kg/min, p=0.01] but not GIP [GIP_AUC0-120 was 4.6±0.3 vs. 5.3±0.3, p=ns] response compared to NAFLD; glucose and insulin concentrations during OGTT were similar [Glu0-120 6.7±0.3 vs. 7.3±0.3 mmol/l; Ins0-120 39.9±3.7 vs. 37.5±3.3 mU/l]. Conclusions: Liver fat accumulation (LF>2.5%) is associated with reduced GLP-1, ISR and MCRI; this can help to explain the increased risk of T2D of subjects with NAFLD. Disclosure A. Gastaldelli: Advisory Panel; Self; Gilead Sciences, Inc.. Other Relationship; Self; European Foundation for the Study of Diabetes. Consultant; Self; INVENTIVA SA. J. Garduno-Garcia: Speaker's Bureau; Self; Sanofi-Aventis, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., AstraZeneca. R.A. DeFronzo: Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc.. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. N. Musi: None.