Glucagon sensitivity and clearance in type 1 diabetes: Insights from in vivo and in silico experiments

Ling Hinshaw, Ashwini Mallad, Chiara Dalla Man, Rita Basu, Claudio Cobelli, Rickey E. Carter, Yogish C Kudva, Ananda Basu

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)E474-E486
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume309
Issue number5
DOIs
StatePublished - Sep 4 2015

Fingerprint

Glucagon
Type 1 Diabetes Mellitus
Computer Simulation
Hypoglycemia
Glucose
Artificial Pancreas
Indicator Dilution Techniques
Isotopes
Catecholamines
Hormones

Keywords

  • Endogenous glucose production
  • Glucagon
  • Type 1 diabetes

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Endocrinology, Diabetes and Metabolism

Cite this

Glucagon sensitivity and clearance in type 1 diabetes : Insights from in vivo and in silico experiments. / Hinshaw, Ling; Mallad, Ashwini; Man, Chiara Dalla; Basu, Rita; Cobelli, Claudio; Carter, Rickey E.; Kudva, Yogish C; Basu, Ananda.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 309, No. 5, 04.09.2015, p. E474-E486.

Research output: Contribution to journalArticle

Hinshaw, Ling ; Mallad, Ashwini ; Man, Chiara Dalla ; Basu, Rita ; Cobelli, Claudio ; Carter, Rickey E. ; Kudva, Yogish C ; Basu, Ananda. / Glucagon sensitivity and clearance in type 1 diabetes : Insights from in vivo and in silico experiments. In: American Journal of Physiology - Endocrinology and Metabolism. 2015 ; Vol. 309, No. 5. pp. E474-E486.
@article{d9611fe259904aa09690520dabf1dd42,
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.",
keywords = "Endogenous glucose production, Glucagon, Type 1 diabetes",
author = "Ling Hinshaw and Ashwini Mallad and Man, {Chiara Dalla} and Rita Basu and Claudio Cobelli and Carter, {Rickey E.} and Kudva, {Yogish C} and Ananda Basu",
year = "2015",
month = "9",
day = "4",
doi = "10.1152/ajpendo.00236.2015",
language = "English (US)",
volume = "309",
pages = "E474--E486",
journal = "American Journal of Physiology - Renal Fluid and Electrolyte Physiology",
issn = "1931-857X",
publisher = "American Physiological Society",
number = "5",

}

TY - JOUR

T1 - Glucagon sensitivity and clearance in type 1 diabetes

T2 - Insights from in vivo and in silico experiments

AU - Hinshaw, Ling

AU - Mallad, Ashwini

AU - Man, Chiara Dalla

AU - Basu, Rita

AU - Cobelli, Claudio

AU - Carter, Rickey E.

AU - Kudva, Yogish C

AU - Basu, Ananda

PY - 2015/9/4

Y1 - 2015/9/4

N2 - 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.

AB - 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.

KW - Endogenous glucose production

KW - Glucagon

KW - Type 1 diabetes

UR - http://www.scopus.com/inward/record.url?scp=84940844094&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84940844094&partnerID=8YFLogxK

U2 - 10.1152/ajpendo.00236.2015

DO - 10.1152/ajpendo.00236.2015

M3 - Article

C2 - 26152766

AN - SCOPUS:84940844094

VL - 309

SP - E474-E486

JO - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

JF - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

SN - 1931-857X

IS - 5

ER -