Hepatic but Not Extrahepatic Insulin Clearance Is Lower in African American Than in European American Women

Abstract

African Americans (AAs) tend to have higher plasma insulin concentrations than European Americans (EAs); the increased insulin concentrations have been attributed to increased secretion and/or decreased insulin clearance by liver or other tissues. This work characterizes the contributions of hepatic versus extrahepatic insulin degradation related to ethnic differences between AAs and EAs. By using a recently developed mathematical model that uses insulin and C-peptide measurements from the insulin-modified, frequently sampled intravenous glucose tolerance test (FSIGT), we estimated hepatic versus extrahepatic insulin clearance in 29 EA and 18 AA healthy women. During the first 20 min of the FSIGT, plasma insulin was approximately twice as high in AAs as in EAs. In contrast, insulin was similar in AAs and EAs after the 20-25 min intravenous insulin infusion. Hepatic insulin first-pass extraction was two-thirds lower in AAs versus EAs in the overnight-fasted state. In contrast, extrahepatic insulin clearance was not lower in AAs than in EAs. The difference in insulin degradation between AAs and EAs can be attributed totally to liver clearance. The mechanism underlying reduced insulin degradation in AAs remains to be clarified, as does the relative importance of reduced liver clearance to increased risk for type 2 diabetes.

Figure 1

Average plasma glucose (A), insulin (B), and C-peptide (C) measurements and calculated ISR (D) for both EA and AA participants in the first 60 min of the test.

Figure 2

Measured and modeled plasma insulin profiles in EA (A) and AA (B) participants. Data are mean (SD) for measured and modeled (line and shaded region) profiles.

Figure 3

Hepatic insulin fraction (FE_L) (A) and extrahepatic clearance indices (CL_p) (B) in EA vs. AA participants. Hepatic and extrahepatic contribution to total insulin clearance in the first 120 min of the experiment in EAs (C) and AAs (D). Data are mean + SE. For participants where the saturable hepatic clearance model provided the best fit, FE_L values shown in A were calculated in the prechallenge state.

Figure 4

Distribution of hepatic insulin fractions (FE_L) (A and B) and extrahepatic clearance individual indices (CL_P) (C and D) in EA and AA participants (white and black bars, respectively) in ascending order with average values shown in gray areas.