title: Glucagon sensitivity and clearance in type 1 diabetes: insights from in vivo and in silico experiments.
abstract: Glucagon use in artificial pancreas for type 1 diabetes (T1D) is being explored for prevention and rescue from hypoglycemia. However, the relationship between glucagon stimulation of endogenous glucose production (EGP) viz., hepatic glucagon sensitivity, and prevailing glucose concentrations has not been examined. To test the hypothesis that glucagon sensitivity is increased at hypoglycemia vs. euglycemia, we studied 29 subjects with T1D randomized to a hypoglycemia or euglycemia clamp. Each subject was studied at three glucagon doses at euglycemia or hypoglycemia, with EGP measured by isotope dilution technique. The peak EGP increments and the integrated EGP response increased with increasing glucagon dose during euglycemia and hypoglycemia. However, the difference in dose response based on glycemia was not significant despite higher catecholamine concentrations in the hypoglycemia group. Knowledge of glucagon's effects on EGP was used to develop an in silico glucagon action model. The model-derived output fitted the obtained data at both euglycemia and hypoglycemia for all glucagon doses tested. Glucagon clearance did not differ between glucagon doses studied in both groups. Therefore, the glucagon controller of a dual hormone control system may not need to adjust glucagon sensitivity, and hence glucagon dosing, based on glucose concentrations during euglycemia and hypoglycemia.
authors.affiliation: Endocrine Research Unit, Division of Endocrinology, Mayo College of Medicine, Rochester, Minnesota;
authors.forename: Ling
authors.initials: L
authors.lastname: Hinshaw
authors.affiliation: Endocrine Research Unit, Division of Endocrinology, Mayo College of Medicine, Rochester, Minnesota;
authors.forename: Ashwini
authors.initials: A
authors.lastname: Mallad
authors.affiliation: Department of Information Engineering, University of Padova, Padua, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Dalla Man
authors.affiliation: Endocrine Research Unit, Division of Endocrinology, Mayo College of Medicine, Rochester, Minnesota; basu.ananda@mayo.edu.
authors.forename: Rita
authors.initials: R
authors.lastname: Basu
authors.affiliation: Department of Information Engineering, University of Padova, Padua, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Cobelli
authors.affiliation: Department of Health Sciences Research, Mayo College of Medicine, Rochester, Minnesota; and.
authors.forename: Rickey E
authors.initials: RE
authors.lastname: Carter
authors.affiliation: Endocrine Research Unit, Division of Endocrinology, Mayo College of Medicine, Rochester, Minnesota;
authors.forename: Yogish C
authors.initials: YC
authors.lastname: Kudva
authors.affiliation: Endocrine Research Unit, Division of Endocrinology, Mayo College of Medicine, Rochester, Minnesota;
authors.forename: Ananda
authors.initials: A
authors.lastname: Basu
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D003198:Computer Simulation; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D005260:Female; D005934:Glucagon / Q000494:pharmacology*; D005943:Gluconeogenesis / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D050261:Glycogenolysis / Q000187:drug effects*; D006728:Hormones / Q000494:pharmacology*; D006801:Humans; D007003:Hypoglycemia / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019397:Pancreas, Artificial; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D006728:Hormones; D005934:Glucagon; D005947:Glucose
keywords: endogenous glucose production; glucagon; type 1 diabetes