Hepatic insulin metabolism in patients with newly diagnosed diabetes is not yet understood. Insulin clearance seems to be decreased in patients with obesity, visceral adiposity and type 2 diabetes (T2D), but data compared to glucose tolerant humans have been inconclusive. To this end, persons with type 1 diabetes (T1D; n=124) or type 2 diabetes (T2D; n=401) and glucose-tolerant humans (CON; n=245) underwent hyperinsulinemic-euglycemic clamps to assess insulin sensitivity (IS) and whole-body insulin clearance (ICWBIC, ml x kg-1 x min-1). Hepatic insulin clearance was also calculated from the ratio of the areas under the curve of plasma C-peptide and insulin (0-60 min) during intravenous glucose-tolerance test (IVGTT, 0-60 min) and mixed meal tolerance test (MMTT, 0-180 min). Hepatocellular lipid content (HCL) was measured by 1H-magnetic resonance spectroscopy. Analyses were adjusted for age, sex and BMI. In T1D, ICIVGTT (1.71±1.1 vs. 2.3±0.3 and 3.2±0.3, all p<0.05) as well as ICMMT (1.6±0.7 vs. 2.0±0.4 and 2.1±0.3, all p<0.05) were lowest compared to T2D and CON respectively and correlated negatively with HbA1c (r=-0.242 and r=-0.279, both p<0.05). In T2D, ICIVGTT was positively correlated with HbA1c (r=0.178, p<0.05) as well as with IS (r=0.242, p<0.05). T2D patients with hepatic steatosis (n=73) had lower ICIVGTT, ICWBIC as well as ICMMT (2.2±0.31 vs. 2.4±0.31, 1.4±0.4 vs. 1.5±0.4 and 1.9 ±0.3 vs. 2.1±0.2 respectively, (i.e., differences of 8%, 9% and 7%, all p<0.05) compared to T2D without steatosis (n=53). CON with steatosis also had lower ICIVGTT (n=103, 2.1±0.2 vs. 2.3±0.35, p<0.05). ICMMT positively correlated with IS (r=0.338 and r=0.187, both p<0.05) in T1D and T2D, but not in CON.
In conclusion, glycemic control likely impairs insulin clearance particularly in T1D patients, whereas steatosis affects insulin clearance in T2D and in glucose tolerant humans.
S. Antoniou: None. O.P. Zaharia: None. K. Strassburger: None. Y. Karusheva: None. K. Bodis: None. Y. Kupriyanova: None. V. Burkart: None. K. Muessig: None. A. Gastaldelli: Consultant; Self; A. Menarini Diagnostics, Eli Lilly and Company, Genentech, Inc., Gilead Sciences, Inc., Inventiva Pharma. M. Roden: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Poxel SA, Servier. Board Member; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker's Bureau; Self; Novo Nordisk Inc. J. Szendroedi: None.