Reduced Insulin Clearance and Insulin-Degrading Enzyme Activity Contribute to Hyperinsulinemia in African Americans

Abstract

Background: African Americans (AAs) are at a higher risk for developing type 2 diabetes compared with non-Hispanic whites (NHWs). The causal role of β-cell glucose sensitivity (β-GS) and insulin clearance in hyperinsulinemia in AA adults is unclear.

Objective: Using a cross-sectional study design, we compared β-cell function and insulin clearance in nondiabetic AAs (n = 36) and NHWs (n = 47) after a mixed meal test (MMT).

Methods: Insulin secretion rate, glucose sensitivity, rate sensitivity, and insulin sensitivity during MMT were derived from a mathematical model. Levels of insulin-degrading enzyme (IDE) and carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1), key players in insulin clearance, were measured (by enzyme-linked immunosorbent assay) in hepatic cytosolic fractions from age-, sex-, and body mass index-matched AA and NHW cadaveric donors (n = 10).

Results: Fasting and mean postprandial plasma glucose levels were similar in both ethnic groups. AAs had significantly higher fasting and mean postprandial plasma insulin levels. However, fasting ISR, total insulin output, and insulin sensitivity during MMT were not different between the groups. β-GS and rate sensitivity were higher in AAs. Fasting and meal plasma insulin clearance were lower in AAs. Hepatic levels of IDE and CEACAM-1 were similar in AAs and NHWs. Hepatic IDE activity was significantly lower in AAs.

Conclusions: In this study, lower insulin clearance contributes to higher plasma insulin levels in AAs. Reduced insulin clearance may be explained by lower IDE activity levels in AAs. Further confirmatory studies are needed to investigate diminished insulin clearance in AAs as a result of lower IDE activity levels.

Trial registration: ClinicalTrials.gov NCT00428987.

Keywords: African Americans; insulin clearance; insulin degrading enzyme; β-cell function.

Figure 1.

Plasma levels of A, glucose, B, insulin, and C, C-peptide, in adult African Americans (AA) and non-Hispanic whites (NHW) during a mixed meal test (MMT). Data shown are mean ± SEM. P values for the effects of racial group and time and the race*time interaction were obtained with repeated-measures ANOVA with post hoc Bonferroni test.

Figure 2.

Plasma levels of A, fasting glucose, B, fasting insulin, C, mean postprandial glucose, and D, mean postprandial insulin in adult African Americans (AA) and non-Hispanic whites (NHW) during a mixed meal test (MMT). Data shown are mean ± SEM. Comparisons between groups were assessed by independent unpaired t test or the Wilcoxon-Mann-Whitney test.

Figure 3.

Model-derived A, insulin secretory rate, B, fasting insulin secretory rate, and C, total insulin output, in adult African Americans (AA) and non-Hispanic Whites (NHW) during a mixed meal test (MMT). Data shown are mean ± SEM. In panel A, P values for the effects of racial group and time and the race*time interaction were obtained with repeated-measures ANOVA with post hoc Bonferroni test. Comparisons between groups (in panels B and C) were assessed by independent unpaired t test or the Wilcoxon-Mann-Whitney test.

Figure 4.

Relationship between insulin secretory rate and A, plasma glucose levels, B, rate sensitivity, C, potentiation factor ratio, and intact D, glucagon-like peptide 1 concentrations in adult African Americans (AA) and non-Hispanic whites (NHW) during a mixed meal test (MMT). Data shown are mean ± SEM. In panel A, P values for the effects of racial group and time and the race*time interaction were obtained with repeated-measures ANOVA with post-hoc Bonferroni test. Comparisons between groups in panel B were assessed by independent unpaired t test or the Wilcoxon-Mann-Whitney test.

Figure 5.

A, Fasting insulin clearance and B, meal insulin clearance in adult African Americans (AA) and non-Hispanic whites (NHW) during a mixed meal test (MMT). C, Insulin degrading enzyme levels and activity were measured in hepatic cytosolic fractions from age-, sex-, and body mass index–matched AA and NHW cadaveric donors (n = 10). Data shown are mean ± SEM. Comparisons between groups were assessed by independent unpaired t test or the Wilcoxon-Mann-Whitney test.