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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)

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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 (N_{liver fat} = 1054, N_HIC = 2254; N_{alanine aminotranferase} = 1985, N_HIC = 2251). BMI-related SNPs were causally associated with HIC (N_BMI = 2772, N_HIC = 2259, p < 0.001) but not waist circumference-SNPs (N_{SNPs-waist circumference} = 2751, N_HIC = 2280). Genetically determined insulin sensitivity was not causally related to HIC (N_{insulin sensitivity} = 2752, N_HIC = 2286). C-reactive protein and HDL were causally associated with HIC, with higher C-reactive protein and lower HDL leading to higher HIC (N_{C-reactive protein} = 2660, N_HIC = 2240; N_HDL = 2694, N_HIC = 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

Corresponding Author

Keywords Hepatic Insulin Clearance ; Liver Fat ; Mendelian Randomization ; Snp; Fatty Liver-disease; Metabolic Syndrome; Fetuin-a; Resistance; Extraction; Obesity; Sensitivity; Secretion; Delivery; Risk

ISSN (print) / ISBN 0026-0495

e-ISSN 1532-8600

Journal Metabolism: clinical and experimental

Quellenangaben Volume: 119, Article Number: 154776

Publisher Elsevier

Publishing Place 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Diabetes Research and Metabolic Diseases (IDM)

Grants German Federal Ministry of Education and Research (BMBF) via the German Centre for Diabetes Research (DZD)