title: 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.
authors.affiliation: Department of Biological Sciences, Graduate School of Science, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Ohashi
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.
authors.forename: Hisako
authors.initials: H
authors.lastname: Komada
authors.affiliation: Department of Biological Sciences, Graduate School of Science, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Uda
authors.affiliation: Department of Biological Sciences, Graduate School of Science, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kubota
authors.affiliation: Department of Computational Biology, Graduate School of Frontier Sciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Toshinao
authors.initials: T
authors.lastname: Iwaki
authors.affiliation: Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Fukuzawa
authors.affiliation: Department of Biological Sciences, Graduate School of Science, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Komori
authors.affiliation: Department of Biological Sciences, Graduate School of Science, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Fujii
authors.affiliation: Department of Biological Sciences, Graduate School of Science, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Toyoshima
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Sakaguchi
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Ogawa
authors.affiliation: Department of Biological Sciences, Graduate School of Science, University of Tokyo, Bunkyo-ku, Tokyo, Japan.|Department of Computational Biology, Graduate School of Frontier Sciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Kuroda
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology; D018450:Disease Progression; D005215:Fasting / Q000378:metabolism / Q000502:physiology; D005260:Female; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique / Q000379:methods; D018149:Glucose Intolerance / Q000378:metabolism / Q000503:physiopathology*; D005951:Glucose Tolerance Test / Q000379:methods; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D008875:Middle Aged; D019518:Postprandial Period / Q000502:physiology
chemical_list: D001786:Blood Glucose; D007328:Insulin; D005947:Glucose