Modeling glucose and free fatty acid kinetics during insulin-modified intravenous glucose tolerance test in healthy humans: role of counterregulatory response.
Insulin administration during insulin-modified intravenous glucose tolerance test (IM-IVGTT) can induce transient hypoglycemia in healthy insulin-sensitive subjects. This triggers counterregulatory reflex (CRR) responses, which influence the kinetics of glucose and nonesterified fatty acids (NEFA), and undermines the accuracy of mathematical modeling methods that do not explicitly account for CRR. The aim of this study is to evaluate mathematical models of glucose and NEFA kinetics against experimental data in the presence or absence of CRR. Thirteen healthy nondiabetic subjects underwent a standard IM-IVGTT and a modified test (GC-IM-IVGTT) with a variable glucose infusion preventing hypoglycemia. While model predictions fit very well with glucose and NEFA data from GC-IM-IVGTT, they lagged behind observations from IM-IVGTT during recovery from hypoglycemia, independently of insulinemia, which did not differ significantly between protocols. A modification to the glucose minimal model, using the glucose concentration below a threshold as a signal for CRR, improves model predictions for both glucose and NEFA. The associated increase in endogenous glucose production correlates, among various CRR hormones, mainly with the dynamics of glucagon concentration. The modified minimal models introduce new parameters that quantify strength and duration of CRR following hypoglycemia. Although CRR represents an unwanted side-effect in IM-IVGTT occurring only in insulin-sensitive subjects, this study provides new insights leading to improved procedures for estimating insulin sensitivity from IM-IVGTT, which may also allow for assessing the individual capacity of recovery from hypoglycemic events in patients treated with insulin or insulin-releasing drugs.
Institute of Biomedical Engineering, National Research Council, Padua, Italy; karl.thomaseth@ieiit.cnr.it.
Karl
K
Thomaseth
Karl-Landsteiner Institute for Endocrinology and Metabolism at 1st Medical Department, Hanusch Hospital, Vienna, Austria;
Attila
A
Brehm
Institute of Biomedical Engineering, National Research Council, Padua, Italy;
Alessandra
A
Pavan
Institute of Biomedical Engineering, National Research Council, Padua, Italy;
Giovanni
G
Pacini
Department of Endocrinology and Diabetology, University Hospital, Düsseldorf, Germany; and German Center for Diabetes Research, Düsseldorf, Germany.
Michael
M
Roden
D000328:Adult; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D006801:Humans; D007003:Hypoglycemia / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D008954:Models, Biological; D008962:Models, Theoretical
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D005947:Glucose
hypoglycemia; insulin sensitivity; mathematical modeling; nonesterified fatty acids