Glucose Homeostatic Law: Insulin Clearance Predicts the Progression of Glucose Intolerance in Humans

Abstract

Homeostatic control of blood glucose is regulated by a complex feedback loop between glucose and insulin, of which failure leads to diabetes mellitus. However, physiological and pathological nature of the feedback loop is not fully understood. We made a mathematical model of the feedback loop between glucose and insulin using time course of blood glucose and insulin during consecutive hyperglycemic and hyperinsulinemic-euglycemic clamps in 113 subjects with variety of glucose tolerance including normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM). We analyzed the correlation of the parameters in the model with the progression of glucose intolerance and the conserved relationship between parameters. The model parameters of insulin sensitivity and insulin secretion significantly declined from NGT to IGT, and from IGT to T2DM, respectively, consistent with previous clinical observations. Importantly, insulin clearance, an insulin degradation rate, significantly declined from NGT, IGT to T2DM along the progression of glucose intolerance in the mathematical model. Insulin clearance was positively correlated with a product of insulin sensitivity and secretion assessed by the clamp analysis or determined with the mathematical model. Insulin clearance was correlated negatively with postprandial glucose at 2h after oral glucose tolerance test. We also inferred a square-law between the rate constant of insulin clearance and a product of rate constants of insulin sensitivity and secretion in the model, which is also conserved among NGT, IGT and T2DM subjects. Insulin clearance shows a conserved relationship with the capacity of glucose disposal among the NGT, IGT and T2DM subjects. The decrease of insulin clearance predicts the progression of glucose intolerance.

System identification of signaling dependent gene expression with different time-scale data

“…In particular, in the case of estimating I-O relationships including nonlinear biochemical reactions without prior knowledge like in this study, the estimation of I-O relationships by ODE model is difficult and NARX model is useful. We also compared the parameter estimation cost between the NARX model for c-Jun, c-Fos and Egr1 and ODE model in our previous study because the model size can be considered similar [ 56 ], indicating that the parameter estimation cost of NARX model in this study is relatively small. In addition to that, it is possible to apply to unequally spaced time-series data in the NARX model developed in this study.…”

“…Parameter estimation was performed by using 2.6 GHz CPU (Xeon E5 2670) of the super computer system of the National Institute of Genetics (NIG), Research Organization of Information and Systems (ROIS). The CPU time was 7.9 hours for the parameter estimation of the NARX model for c-Jun, c-Fos and Egr1, and that of ODE model in our previous study which can be considered similar model size was 25 hours in the same condition [ 56 ] ( Table 2 ).…”

Logical design of oral glucose ingestion pattern minimizing blood glucose in humans

“…The quantitative difference of duration of intermediate period among subjects may relate to differences in glucose tolerance among subjects. Glucose tolerance is determined by the balance between insulin secretion, sensitivity, and clearance; as glucose tolerance decreases, insulin secretion, sensitivity, and clearance also decrease (Antuna-Puente et al, 2011; Ohashi et al, 2018, 2015; Polidori et al, 2016; Schofield and Sutherland, 2012). Therefore, we examined the effect of the parameters for the reaction rates for insulin secretion, sensitivity and clearance on duration of the intermediate period (Figure S5).…”

“…Many mathematical models use average values of blood glucose from many subjects of all subjects. Some models that use data from individual subjects used data with only a single dose of glucose (Dalla Man et al, 2013; De Gaetano et al, 2013; Ohashi et al, 2018, 2015). Here, we used data from individual subjects using 3 different doses and 2 different durations of glucose ingestion.…”

Association of increased hepatic insulin clearance and change in serum triglycerides or β‐hydroxybutyrate concentration via the sodium/glucose‐cotransporter 2 inhibitor tofogliflozin

“…Furthermore, a decline in hepatic insulin clearance was observed from the early stages of type 2 diabetes . In particular, the presence of FL and type 2 diabetes decreased hepatic insulin clearance. Therefore, optimization of hepatic insulin clearance is considered useful to prevent various metabolic disorders, including glucose intolerance and complications caused by inappropriate hyperinsulinaemia.…”