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Lamprinou, A. ; Willmann, C. ; Machann, J. ; Schick, F. ; Eckstein, S.S. ; Man, C.D.* ; Visentin, R.* ; Birkenfeld, A.L. ; Peter, A. ; Stefan, N. ; Häring, H.-U. ; Fritsche, A. ; Heni, M. ; Wagner, R.

Determinants of hepatic insulin clearance - results from a Mendelian Randomization study.

Metabolism 119:154776 (2021)
Postprint DOI PMC
Open Access Green
AIMS/HYPOTHESIS: Besides insulin resistance, type 2 diabetes associates with decreased hepatic insulin clearance (HIC). We now tested for causal relationship of HIC to liver fat accumulation or features of the metabolic syndrome. METHODS: HIC was derived from oral glucose tolerance tests with the "Oral C-peptide and Insulin Minimal Models" (n = 3311). Liver fat was quantified by magnetic resonance spectroscopy (n = 1211). Mendelian Randomization was performed using established single nucleotide polymorphisms (SNPs; 115 for liver fat, 155 alanine-aminotransferase, 37 insulin sensitivity, 37 insulin secretion, 72 fasting insulin, 5285 BMI, 163 visceral fat, 270 waist circumference, 442 triglycerides, 620 HDL-Cholesterol, 193C-reactive protein, 53 lipodystrophy-like phenotypes). RESULTS: HIC associated inversely with liver fat (p < 0.003) and insulin sensitivity (p < 0.0001). Both liver fat and HIC were independently associated with insulin sensitivity (p < 0.0001). Neither liver fat nor alanine-aminotransferase were causally linked to HIC, as indicated by Mendelian Randomization (Nliver fat = 1054, NHIC = 2254; Nalanine aminotranferase = 1985, NHIC = 2251). BMI-related SNPs were causally associated with HIC (NBMI = 2772, NHIC = 2259, p < 0.001) but not waist circumference-SNPs (NSNPs-waist circumference = 2751, NHIC = 2280). Genetically determined insulin sensitivity was not causally related to HIC (Ninsulin sensitivity = 2752, NHIC = 2286). C-reactive protein and HDL were causally associated with HIC, with higher C-reactive protein and lower HDL leading to higher HIC (NC-reactive protein = 2660, NHIC = 2240; NHDL = 2694, NHIC = 2275). CONCLUSIONS: This Mendelian Randomization analysis does not support a causal link between hepatic steatosis and HIC. Other components of the metabolic syndrome seem to compensate peripheral hyperinsulinemia by increasing hepatic insulin extraction.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Hepatic Insulin Clearance ; Liver Fat ; Mendelian Randomization ; Snp; Fatty Liver-disease; Metabolic Syndrome; Fetuin-a; Resistance; Extraction; Obesity; Sensitivity; Secretion; Delivery; Risk
Language english
Publication Year 2021
HGF-reported in Year 2021
ISSN (print) / ISBN 0026-0495
e-ISSN 1532-8600
Journal Metabolism: clinical and experimental
Quellenangaben Volume: 119, Issue: , Pages: , Article Number: 154776 Supplement: ,
Publisher Elsevier
Publishing Place 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes Research and Metabolic Diseases (IDM)
POF-Topic(s) 90000 - German Center for Diabetes Research
Research field(s) Helmholtz Diabetes Center
PSP Element(s) G-502400-001
Grants German Federal Ministry of Education and Research (BMBF) via the German Centre for Diabetes Research (DZD)
DOI 10.1016/j.metabol.2021.154776
WOS ID WOS:000649316500010
Scopus ID 85104481573
PubMed ID 33862045
Erfassungsdatum 2021-04-22
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