Abstract
Glucose effectiveness, defined as the ability of glucose itself to increase glucose utilization and inhibit hepatic glucose production, is an important mechanism maintaining normoglycemia. We conducted a minimal modeling analysis of glucose effectiveness at zero insulin (GEZI) using intravenous glucose tolerance test data from subjects with type 2 diabetes (T2D, n=154) and non-diabetic (ND) subjects (n=343). A hierarchical statistical analysis was performed, which provided a formal mechanism for pooling the data from all study subjects, to yield a single composite population model that quantifies the role of subject specific characteristics such as weight, height, age, sex, and glucose tolerance. Based on the resulting composite population model, GEZI was reduced from 0.021 min–1 (standard error – 0.00078 min–1) in the ND population to 0.011 min–1 (standard error – 0.00045 min–1) in T2D. The resulting model was also employed to calculate the proportion of the non–insulin-dependent net glucose uptake in each subject receiving an intravenous glucose load. Based on individual parameter estimates, the fraction of total glucose disposal independent of insulin was 72.8% ± 12.0% in the 238 ND subjects over the course of the experiment, indicating the major contribution to the whole-body glucose clearance under non-diabetic conditions. This fraction was significantly reduced to 48.8% ± 16.9% in the 30 T2D subjects, although still accounting for approximately half of the total in the T2D population based on our modeling analysis. Given the potential application of glucose effectiveness as a predictor of glucose intolerance and as a potential therapeutic target for treating diabetes, more investigations of glucose effectiveness in other disease conditions can be conducted using the hierarchical modeling framework reported herein.
Highlights
Glucose homeostasis is governed by the interaction of many processes, central among these are insulin secretion, insulin action, insulin clearance and glucose effectiveness
The resulting population model was used to quantify the role of subject characteristics and test type (IVGTT/IM-intravenous glucose tolerance test (IVGTT)) on glucose effectiveness and other minimal model (MM) parameters
The addition of other covariates did not further explain remaining inter-subject variability in glucose effectiveness at zero insulin (GEZI), beyond that predicted by glucose tolerance status
Summary
Glucose homeostasis is governed by the interaction of many processes, central among these are insulin secretion, insulin action, insulin clearance and glucose effectiveness. Glucose effectiveness, defined as the ability of glucose itself to increase glucose utilization and inhibit hepatic glucose production via mass action and other mechanisms (1), exerts an earlier temporal influence relative to insulin in maintaining normoglycemia. It has been shown in (2) that glucose effectiveness may be divided into two components: Basal Insulin Effect (BIE) and Glucose Effectiveness at Zero Insulin. In patients with defective insulin action, the impact of insulin on glucose disposal is limited but it is partially compensated by the crucial contribution of glucose effectiveness in the attempt of restoring a good glucose tolerance (1). There have been only limited studies aimed at quantifying glucose effectiveness in subjects with normal and impaired glucose tolerance, and there are inconsistencies in those studies (1)
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