Activation of innate immunity modulates insulin sensitivity, glucose effectiveness and pancreatic β-cell function in both African ancestry and European ancestry healthy humans

Abstract

Objective: Insulin resistance is a risk factor for type 2 diabetes, and is associated with inflammatory cardiometabolic disease. Given differences between African ancestry (AA) and European ancestry (EA) in the epidemiology of type 2 diabetes as well as in response to inflammatory stress, we investigated potential race differences in glucose homeostasis responses during experimental endotoxemia in humans.

Methods: Healthy volunteers (age 18-45 years, BMI 18-30 kg/m(2), 47% female, African-ancestry (AA, n=42) and European-ancestry (EA, n=106)) were recruited as part of the Genetics of Evoked Responses to Niacin and Endotoxemia (GENE) Study. Subjects underwent an inpatient endotoxin challenge (1 ng/kg LPS) and two frequently-sampled intravenous glucose tolerance tests (FSIGTT). Insulin and glucose values obtained during FSIGTT pre- and 24-hours post-LPS were analyzed using the minimal model.

Results: FSIGTT derived insulin sensitivity index (SI), disposition index (DI) and glucose effectiveness (SG) decreased significantly following LPS (p<0.0001) while the acute insulin response to glucose (AIR(g)) increased (p<0.0001). Although expected race differences were observed in glucose homeostasis parameters at baseline prior to LPS e.g., lower SI (2.5 vs. 4.1 μU/L/min, p<0.0001) but higher AIR(g) (median 848 vs. 290 μU/L/min, p<0.0001) in AA vs. EA, the changes in glucose homeostasis responses to LPS were directionally and proportionally consistent across race e.g., SI median -35% in EA and -29% in AA and AIR(g) median +17% in EA and +26% in AA.

Conclusion: Both EA and AA samples modulated glucose and insulin homeostasis similarly during endotoxemia.

Implications: Race differences in response to environmental inflammatory stress are unlikely to be a substantial contributor to the observed difference in diabetes incidence and complications between EA and AA.

Trial registration: ClinicalTrials.gov NCT00953667.

Keywords: Glucose effectiveness; Insulin sensitivity; LPS; Race differences.

Copyright © 2015 Elsevier Inc. All rights reserved.

Figures

Figure 1. Study Design

Post-screening, subjects underwent a frequently-sampled intravenous glucose tolerance test (FSIGTT) at baseline. 2-4 weeks later, subjects underwent a second FSIGTT 24-hours post-administration of LPS. Paired pre- and post-LPS FSIGTT data for the first 160 individuals to complete the study were analyzed here. Results from the niacin portion of the study are not discussed here.

Figure 2

European ancestry (EA) subjects had significantly higher SI than African ancestry (AA) subjects at baseline (p<0.0001) and post-LPS (p<0.001) (A). SI was reduced by LPS in both EA and AA (p<0.0001). EA subjects had significantly lower AIRG than AA subjects at baseline (p<0.0001) and post-LPS (p<0.0001) (B). AIRg was increased by LPS in both EA and AA (p<0.0001). The Disposition Index (DI) was higher in AA than EA subjects pre-LPS (p<0.0001) and post-LPS (p<0.0001) (C). DI declined in both AA and EA following LPS (p<0.0001). Glucose effectiveness (SG) was not significantly different by race at baseline (p=0.6) but was slightly different post-LPS (p=0.02) (D). SG decreased post-LPS in both EA and AA (p<0.0001). There were no differences by sex in any parameters. * P<0.05; ** P<0.001; *** P<0.0001 (P values for race difference). Data presented as mean and SD.