TY - JOUR
T1 - Glucose homeostatic law
T2 - Insulin clearance predicts the progression of glucose intolerance in humans
AU - Ohashi, Kaoru
AU - Komada, Hisako
AU - Uda, Shinsuke
AU - Kubota, Hiroyuki
AU - Iwaki, Toshinao
AU - Fukuzawa, Hiroki
AU - Komori, Yasunori
AU - Fujii, Masashi
AU - Toyoshima, Yu
AU - Sakaguchi, Kazuhiko
AU - Ogawa, Wataru
AU - Kuroda, Shinya
N1 - Funding Information:
We thank laboratory members for critical reading of the manuscript and for technical assistance with the analysis, and Cobelli C. and Dalla Man C. for critical reading of the manuscript and constructive comments. The computations for this work were performed in part on the NIG supercomputer system at ROIS National Institute of Genetics. This work was supported by the Creation of Fundamental Technologies for Understanding and Control of Biosystem Dynamics, CREST, of the Japan Science and Technology Agency (JST); by a Kakenhi Scientific Research grant (A) (#21240025) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; and by a Human Frontier Science Project (HFSP) grant (RGP0061/2011).
Publisher Copyright:
© 2015 Ohashi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0143880
DO - 10.1371/journal.pone.0143880
M3 - Article
C2 - 26623647
AN - SCOPUS:84956497465
SN - 1932-6203
VL - 10
JO - PLoS One
JF - PLoS One
IS - 12
M1 - A38
ER -
