Introduction: Type 2 diabetes is not only associated with insulin resistance but also with decreased insulin clearance. Insulin is mostly eliminated from portal blood during the first pass through the liver. The magnitude of this effect is closely related to systemic insulin sensitivity. As insulin resistance is often accompanied by fatty liver, we here investigated whether there is a causal link between liver fat and hepatic insulin clearance (IC).
Methods: We computed IC using data from oral glucose tolerance tests in 3391 non diabetic individuals and the oral C-peptide and Insulin Minimal Models. Liver fat was quantified by 1H-MR-spectroscopy in 1211 participants. We performed Mendelian randomization analyses to test for causal determination of IC by liver fat and potentially related traits using established single nucleotide polymorphisms (liver fat: 115 SNPs, alanine-aminotransferase: 155 SNPs, insulin sensitivity: 37 SNPs, C-reactive protein: 193 SNPs).
Results: IC associated inversely with liver fat content (β=-0.1±0.03, p<0.003) and insulin sensitivity (β=0.6±0.03, p < 0.0001). Both liver fat content and IC were independently associated with insulin sensitivity (β=-0.2±0.03 and β=0.1±0.02 respectively, both p < 0.0001). Neither liver fat content nor alanine-aminotransferase were causally linked to IC (p=0.6 and 0.2, respectively), as indicated by the Mendelian randomization. On the other hand, both genetically determined insulin sensitivity and C-reactive protein levels influenced IC (β=0.3±0.1, p=0.04 and β=0.1±0.07, p=0.03, respectively).
Conclusion: This study supports the hypothesis that systemic effects such as inflammatory activity and/or genetic factors determining insulin resistance might modulate insulin extraction in the liver.
A. Lamprinou: None. J. Machann: None. F. Schick: None. S.S. Eckstein: None. C. Dalla Man: Research Support; Self; Sanofi-Aventis Deutschland GmbH. R. Visentin: None. N. Stefan: None. A.L. Birkenfeld: None. A. Peter: None. H. Haering: None. A. Fritsche: None. M. Heni: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker’s Bureau; Self; Novo Nordisk A/S. R. Wagner: Advisory Panel; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Novo Nordisk A/S. Other Relationship; Self; Eli Lilly and Company.
German Center of Diabetes Research (01GI0925)