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.

Insulin clearance as the major player in the hyperinsulinaemia of black African men without diabetes

“…This leads us to propose that endogenous insulin clearance in BA may be determined by additional factors that are independent of insulin sensitivity, for example, in the pathways involved in postreceptor insulin metabolism. This assertion is supported by recent evidence from a study investigating ethnic differences in the expression and activity of hepatic insulin‐degrading enzyme (IDE) and carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM‐1) between African Americans and non‐Hispanic white Americans, which reported lower IDE activity in African Americans 51 . While reduced insulin clearance is widely regarded as an early response to insulin resistance, 52,53 it is also possible that changes in insulin clearance are not only a compensatory mechanism but also a primary determinant of peripheral insulin levels 36,54 in BA populations.…”

“…In Americans, which reported lower IDE activity in African Americans. 51 While reduced insulin clearance is widely regarded as an early response to insulin resistance, 52,53 it is also possible that changes in insulin clearance are not only a compensatory mechanism but also a primary determinant of peripheral insulin levels 36,54 in BA populations.…”

“…The strong heritability of insulin clearance has been shown in a Hispanic population 57 and this may also be the case in other ethnic groups. Molecular mechanisms that warrant further exploration include potential ethnic differences in inflammatory activity, 24 the expression and activity of insulin‐degrading enzyme, 51 the liver‐adiponectin pathway, 58 or in liver CEACAM‐1 expression/activity 2 …”

Targeting Insulin-Degrading Enzyme in Insulin Clearance

“…Over the past several decades, numerous studies have identified type 2 diabetes mellitus (T2DM) [ 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 ] and obesity [ 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 ] as determinant factors associated with impaired insulin clearance. Other metabolic abnormalities, such as non-alcoholic steatohepatitis [ 77 , 92 , 93 , 94 , 95 ], hepatic diseases [ 96 , 97 , 98 , 99 ], polycystic ovarian syndrome [ 100 ], and metabolic syndrome [ 101 , 102 ], as well as aging [ 78 , 103 , 104 ] and ethnicity [ 105 , 106 , 107 , 108 , 109 , 110 , 111 ], have also been linked to reduced insulin clearance.…”

Modulation of Insulin Sensitivity by Insulin-Degrading Enzyme

“…Two methods have been used to quantify the degradation of these radiolabeled peptides, the trichloroacetic acid (TCA) precipitation assay and high-performance liquid chromatography (HPLC), the former being the most sensitive [ 44 , 45 ]. Several other IDE activity assays have been developed, such as fluorogenic FRET-based peptide substrates derived from the sequence of bradykinin [ 46 ] or other IDE substrates [ 47 ]. However, IDE appears to process such short peptides markedly differently from intermediate-sized substrates [ 48 ]; for instance, the hydrolysis of such substrates is activated by ATP [ 49 ] and other nucleoside polyphosphates [ 50 ], certain small molecules [ 51 ] and several substrates [ 52 ], while these compounds have no effect or actually inhibit the degradation of more physiological substrates.…”