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

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.

[1]  T. Abe,et al.  The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance. , 2013, The Journal of clinical investigation.

[2]  Shinsuke Uda,et al.  Sensitivity control through attenuation of signal transfer efficiency by negative regulation of cellular signalling , 2012, Nature Communications.

[3]  Frank Bretz,et al.  Nonparametric All‐Pairs Multiple Comparisons , 2001 .

[4]  R. DeFronzo,et al.  A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. , 2003, Diabetes.

[5]  Claudio Cobelli,et al.  Oral Glucose Tolerance Test Minimal Model Indexes of β-Cell Function and Insulin Sensitivity , 2001 .

[6]  Bruce H. Frank,et al.  Use of biosynthetic human C-peptide in the measurement of insulin secretion rates in normal volunteers and type I diabetic patients. , 1986, The Journal of clinical investigation.

[7]  Alessandra Bertoldo,et al.  IVGTT glucose minimal model covariate selection by nonlinear mixed-effects approach. , 2010, American journal of physiology. Endocrinology and metabolism.

[8]  M. Hubert,et al.  A Robust Measure of Skewness , 2004 .

[9]  A. Scheen,et al.  How to measure insulin clearance. , 1994, Diabetes/metabolism reviews.

[10]  B H Frank,et al.  Quantitative study of insulin secretion and clearance in normal and obese subjects. , 1988, The Journal of clinical investigation.

[11]  E. Choi,et al.  A new mixture ratio of heparin for the cell salvage device , 2011, Korean journal of anesthesiology.

[12]  A. Pfeiffer,et al.  Reduced hepatic insulin extraction in response to gastric inhibitory polypeptide compensates for reduced insulin secretion in normal-weight and normal glucose tolerant first-degree relatives of type 2 diabetic patients. , 2004, Diabetes.

[13]  R. Bergman,et al.  Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose. , 1981, The Journal of clinical investigation.

[14]  R. Hovorka,et al.  Pancreatic beta-cell responsiveness during meal tolerance test: model assessment in normal subjects and subjects with newly diagnosed noninsulin-dependent diabetes mellitus. , 1998, The Journal of clinical endocrinology and metabolism.

[15]  S. Seino,et al.  Postprandial serum C-peptide to plasma glucose concentration ratio correlates with oral glucose tolerance test- and glucose clamp-based disposition indexes. , 2013, Metabolism: clinical and experimental.

[16]  R. Bergman,et al.  Insulin Clearance and the Incidence of Type 2 Diabetes in Hispanics and African Americans , 2013, Diabetes Care.

[17]  S. Seino,et al.  Age‐dependent decline in β‐cell function assessed by an oral glucose tolerance test‐based disposition index , 2011, Journal of diabetes investigation.

[18]  C Cobelli,et al.  Oral glucose tolerance test minimal model indexes of beta-cell function and insulin sensitivity. , 2001, Diabetes.

[19]  Roman Hovorka,et al.  Pancreatic β-Cell Responsiveness during Meal Tolerance Test: Model Assessment in Normal Subjects and Subjects with Newly Diagnosed Noninsulin-Dependent Diabetes Mellitus1 , 1998 .

[20]  K Thomaseth,et al.  Integrated mathematical model to assess beta-cell activity during the oral glucose test. , 1996, The American journal of physiology.

[21]  C. Schofield,et al.  Disordered insulin secretion in the development of insulin resistance and Type 2 diabetes , 2012, Diabetic medicine : a journal of the British Diabetic Association.

[22]  R. Bergman,et al.  Critical evaluation of the combined model approach for estimation of prehepatic insulin secretion. , 1998, The American journal of physiology.

[23]  Claudio Cobelli,et al.  The oral glucose minimal model: Estimation of insulin sensitivity from a meal test , 2002, IEEE Transactions on Biomedical Engineering.

[24]  Ovide Arino,et al.  Mathematical modelling of the intravenous glucose tolerance test , 2000, Journal of mathematical biology.

[25]  Shinya Kuroda,et al.  The selective control of glycolysis, gluconeogenesis and glycogenesis by temporal insulin patterns , 2013 .

[26]  Jeffrey C. Lagarias,et al.  Convergence Properties of the Nelder-Mead Simplex Method in Low Dimensions , 1998, SIAM J. Optim..

[27]  Andrea Mari,et al.  Meal and oral glucose tests for assessment of beta -cell function: modeling analysis in normal subjects. , 2002, American journal of physiology. Endocrinology and metabolism.

[28]  K. Polonsky,et al.  Alterations in the glucose-stimulated insulin secretory dose-response curve and in insulin clearance in nondiabetic insulin-resistant individuals. , 1997, The Journal of clinical endocrinology and metabolism.

[29]  C Cobelli,et al.  Minimal model assessment of hepatic insulin extraction during an oral test from standard insulin kinetic parameters. , 2009, American journal of physiology. Endocrinology and metabolism.

[30]  C Cobelli,et al.  Quantitative indexes of beta-cell function during graded up&down glucose infusion from C-peptide minimal models. , 2001, American journal of physiology. Endocrinology and metabolism.

[31]  R. DeFronzo,et al.  Glucose clamp technique: a method for quantifying insulin secretion and resistance. , 1979, The American journal of physiology.

[32]  R. Bergman,et al.  Calculated Pattern of Intraportal Insulin Appearance Without Independent Assessment of C-Peptide Kinetics , 1987, Diabetes.

[33]  R. Hovorka,et al.  ISEC: a program to calculate insulin secretion. , 1996, Computer methods and programs in biomedicine.

[34]  E. Disse,et al.  How can we measure insulin sensitivity/resistance? , 2011, Diabetes & metabolism.

[35]  V. Bolie,et al.  Coefficients of normal blood glucose regulation. , 1961, Journal of applied physiology.

[36]  P. Butler,et al.  Mechanisms of Impaired Fasting Glucose and Glucose Intolerance Induced by a ∼50% Pancreatectomy , 2006, Diabetes.

[37]  Mats O Karlsson,et al.  An Integrated Glucose‐Insulin Model to Describe Oral Glucose Tolerance Test Data in Healthy Volunteers , 2010, Journal of clinical pharmacology.

[38]  Claudio Cobelli,et al.  Cellular modeling: insight into oral minimal models of insulin secretion. , 2010, American journal of physiology. Endocrinology and metabolism.

[39]  F. Arturi,et al.  Differences in insulin clearance between metabolically healthy and unhealthy obese subjects , 2014, Acta Diabetologica.

[40]  Claudio Cobelli,et al.  Minimal model estimation of glucose absorption and insulin sensitivity from oral test: validation with a tracer method. , 2004, American journal of physiology. Endocrinology and metabolism.

[41]  B. Zinman,et al.  Hyperbolic Relationship Between Insulin Secretion and Sensitivity on Oral Glucose Tolerance Test , 2008, Obesity.

[42]  R. Bergman,et al.  Variable Hepatic Insulin Clearance with Attendant Insulinemia is the Primary Determinant of Insulin Sensitivity in the Normal Dog , 2013, Obesity.

[43]  Ronald Gieschke,et al.  An Integrated Model for Glucose and Insulin Regulation in Healthy Volunteers and Type 2 Diabetic Patients Following Intravenous Glucose Provocations , 2007, Journal of clinical pharmacology.

[44]  C. Kahn,et al.  Insulin signalling and the regulation of glucose and lipid metabolism , 2001, Nature.

[45]  C Cobelli,et al.  Insulin Secretion and Hepatic Extraction in Humans by Minimal Modeling of C-Peptide and Insulin Kinetics , 1988, Diabetes.

[46]  C Cobelli,et al.  Estimation of β-Cell Sensitivity From Intravenous Glucose Tolerance Test C-Peptide Data: Knowledge of the Kinetics Avoids Errors in Modeling the Secretion , 1995, Diabetes.

[47]  E. Bonora,et al.  Decreased hepatic insulin extraction in subjects with mild glucose intolerance. , 1983, Metabolism: clinical and experimental.

[48]  Maciej J. Swat,et al.  The impact of mathematical modeling on the understanding of diabetes and related complications , 2013, CPT: pharmacometrics & systems pharmacology.

[49]  Y. Z. Ider,et al.  Quantitative estimation of insulin sensitivity. , 1979, The American journal of physiology.

[50]  Hiroyuki Kubota,et al.  Decoupling of Receptor and Downstream Signals in the Akt Pathway by Its Low-Pass Filter Characteristics , 2010, Science Signaling.

[51]  Ronald Gieschke,et al.  An Integrated Glucose‐Insulin Model to Describe Oral Glucose Tolerance Test Data in Type 2 Diabetics , 2007, Journal of clinical pharmacology.

[52]  M. Matsuda,et al.  Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. , 1999, Diabetes care.

[53]  M. Hubert,et al.  Outlier detection for skewed data , 2008 .

[54]  P. Butler,et al.  Mechanisms of impaired fasting glucose and glucose intolerance induced by an approximate 50% pancreatectomy. , 2006, Diabetes.

[55]  Shinya Kuroda,et al.  Temporal coding of insulin action through multiplexing of the AKT pathway. , 2012, Molecular cell.

[56]  A. Ciccarone,et al.  Insulin Degradation In Vitro and In Vivo: A Comparative Study in Men: Evidence That Immunoprecipitable, Partially Rebindable Degradation Products Are Released From Cells and Circulate in Blood , 1994, Diabetes.

[57]  G. Pacini,et al.  A Model-Based Method for Assessing Insulin Sensitivity From the Oral Glucose Tolerance Test. Diabetes Care 2001;24:539–548 , 2014, Diabetes Care.

[58]  K. M. Erickson,et al.  Prehepatic insulin production in man: kinetic analysis using peripheral connecting peptide behavior. , 1980, The Journal of clinical endocrinology and metabolism.

[59]  Claudio Cobelli,et al.  A minimal model of insulin secretion and kinetics to assess hepatic insulin extraction. , 2006, American journal of physiology. Endocrinology and metabolism.