title: Glucose uptake saturation explains glucose kinetics profiles measured by different tests.
abstract: It is known that for a given insulin level glucose clearance depends on glucose concentration. However, a quantitative representation of the concomitant effects of hyperinsulinemia and hyperglycemia on glucose clearance, necessary to describe heterogeneous tests such as euglycemic and hyperglycemic clamps and oral tests, is lacking. Data from five studies (123 subjects) using a glucose tracer and including all the above tests in normal and diabetic subjects were collected. A mathematical model was developed in which glucose utilization was represented as a Michaelis-Menten function of glucose with constant Km and insulin-controlled Vmax, consistently with the basic notions of glucose transport. Individual values for the model parameters were estimated using a population approach. Tracer data were accurately fitted in all tests. The estimated Km was 3.88 (2.83-5.32) mmol/l [median (interquartile range)]. Median model-derived glucose clearance at 600 pmol/l insulin was reduced from 246 to 158 ml·min(-1)·m(-2) when glucose was raised from 5 to 10 mmol/l. The model reproduced the characteristic lack of increase in glucose clearance when moderate hyperinsulinemia was accompanied by hyperglycemia. In all tests, insulin sensitivity was inversely correlated with BMI, as expected (R(2) = 0.234, P = 0.0001). In conclusion, glucose clearance in euglycemic and hyperglycemic clamps and oral tests can be described with a unifying model, consistent with the notions of glucose transport and able to reproduce the suppression of glucose clearance due to hyperglycemia observed in previous studies. The model may be important for the design of reliable glucose homeostasis simulators.
authors.affiliation: CNR Institute of Neuroscience, Padua, Italy; roberto.bizzotto@isib.cnr.it.
authors.forename: Roberto
authors.identifier: 0000-0002-8251-1730
authors.initials: R
authors.lastname: Bizzotto
authors.affiliation: Department of Internal Medicine, University of Pisa School of Medicine, Pisa, Italy;
authors.forename: Andrea
authors.initials: A
authors.lastname: Natali
authors.affiliation: CNR Institute of Clinical Physiology, Pisa, Italy;
authors.forename: Amalia
authors.initials: A
authors.lastname: Gastaldelli
authors.affiliation: Department of Internal Medicine, University of Pisa School of Medicine, Pisa, Italy;
authors.forename: Elza
authors.initials: E
authors.lastname: Muscelli
authors.affiliation: Hanusch Hospital, Vienna, Austria;
authors.forename: Martin
authors.initials: M
authors.lastname: Krssak
authors.affiliation: Hanusch Hospital, Vienna, Austria;
authors.forename: Attila
authors.initials: A
authors.lastname: Brehm
authors.affiliation: Heinrich-Heine University, Düsseldorf, Germany; German Diabetes Center, Düsseldorf, Germany; and German Center of Diabetes Research, München-Neuherberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Roden
authors.affiliation: Department of Internal Medicine, University of Pisa School of Medicine, Pisa, Italy; CNR Institute of Clinical Physiology, Pisa, Italy;
authors.forename: Ele
authors.initials: E
authors.lastname: Ferrannini
authors.affiliation: CNR Institute of Neuroscience, Padua, Italy;
authors.forename: Andrea
authors.initials: A
authors.lastname: Mari
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D006946:Hyperinsulinism / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical
chemical_list: D001786:Blood Glucose; D007328:Insulin; D005947:Glucose
keywords: glucose metabolism; glucose tracers; insulin sensitivity; mathematical models; uptake saturation