Modeling glucose and free fatty acid kinetics during 1 insulin - modified intravenous glucose tolerance test in 2 healthy humans : role of counterregulatory response

29 Insulin administration during insulin-modified intravenous glucose tol30 erance test (IM-IVGTT) can induce transient hypoglycemia in healthy 31 insulin-sensitive subjects. This triggers counterregulatory responses (CRR), 32 which influence the kinetics of glucose and non-esterified fatty acids (NEFA) 33 and undermines the accuracy of mathematical modeling methods that do 34 not explicitly account for CRR. The aim of this study is to evaluate math35 ematical models of glucose and NEFA kinetics against experimental data 36 in presence or absence of CRR. Thirteen healthy non-diabetic subjects 37 underwent a standard IM-IVGTT and a modified test (GC-IM-IVGTT) 38 with a variable glucose infusion preventing hypoglycemia. While model 39 predictions fit very well glucose and NEFA data from GC-IM-IVGTT, 40 they lagged behind observations from IM-IVGTT during recovery from 41 hypoglycemia, independently of insulinemia, which did not differ signifi42 cantly between protocols. A modification to the glucose minimal model, 43 using glucose concentration below a threshold as signal for CRR, improves 44 model predictions for both glucose and NEFA. The associated increase in 45 endogenous glucose production correlates, among various CRR hormones, 46 mainly with the dynamics of glucagon concentration. The modified mini47 mal models introduce new parameters that quantify strength and duration 48 of CRR following hypoglycemia. Although CRR represents an unwanted 49 side effect in IM-IVGTT occurring only in insulin-sensitive subjects, this 50 study provides new insights leading to improved procedures for estimat51 ing insulin sensitivity from IM-IVGTT, which may also allow for assessing 52 the individual capacity of recovery from hypoglycemic events in patients 53