Insulin clearance is associated with insulin sensitivity independent from liver fat

Type 2 diabetes mellitus is associated with insulin resistance and decreased insulin clearance. Insulin clearance is mostly determined by a first-pass hepatic uptake of insulin. In turn, liver fat content is associated with insulin resistance and reduced insulin clearance. It is not known whether insulin clearance is associated with insulin sensitivity independent from liver fat content and whether this association is modulated by steatohepatitis. We investigate the association of insulin clearance with insulin sensitivity after adjustment for liver fat, and test the effect of liver fat- and steatohepatitis-associated genetic variants on insulin clearance. 3051 individuals without diabetes underwent oral glucose tolerance tests (oGTT) with assessment of insulin clearance (ratio of C-peptide and insulin during oGTT) and insulin sensitivity. Liver fat was measured with MR-spectroscopy in a subgroup (N = 934). We genotyped rs738409 (PNPLA3) and rs72613567 (HSD17B13) which we used as genetic instruments to test the association of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) with insulin clearance. Insulin clearance associates inversely with liver fat and insulin sensitivity (p < 0.001). Liver fat content and insulin clearance are independently associated with insulin sensitivity (both p < 0.0001). Carriers of one minor allele in rs738409 have by average 2% higher liver fat (p < 0.0001) but show similar insulin clearance (p = 0.3). In subjects with increased liver fat, the risk-allele of rs72613567 was not associated with altered insulin clearance (N = 354, p = 0.3). Insulin clearance is associated with insulin sensitivity independent from hepatic fat content. Furthermore, genetically determined steatohepatitis does not impact insulin clearance.