Determinants of hepatic insulin clearance - Results from a Mendelian Randomization study

Abstract

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, 193 C-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_{alanineaminotranferase} = 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.

Keywords: Hepatic insulin clearance; Liver fat; Mendelian randomization; SNP.