Quantification of the glycemic response to microdoses of subcutaneous glucagon at varying insulin levels

Joseph El Youssef, Jessica Castle, Parkash A. Bakhtiani, Ahmad Haidar, Deborah L. Branigan, Matthew Breen, W. Kenneth Ward

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

OBJECTIVE: Glucagon delivery in closed-loop control of type 1 diabetes is effective in minimizing hypoglycemia. However, high insulin concentration lowers the hyperglycemic effect of glucagon, and small doses of glucagon in this setting are ineffective. There are no studies clearly defining the relationship between insulin levels, subcutaneous glucagon, and blood glucose. RESEARCH DESIGN AND METHODS: Using a euglycemic clamp technique in 11 subjects with type 1 diabetes, we examined endogenous glucose production (EGP) of glucagon (25, 75, 125, and 175 m g) at three insulin infusion rates (0.016, 0.032, and 0.05 units/kg/h) in a randomized, crossover study. Infused 6,6-dideuterated glucose was measured every 10 min, and EGP was determined using a validated glucoregulatory model. Area under the curve (AUC) for glucose production was the primary outcome, estimated over 60 min. RESULTS: At low insulin levels, EGP rose proportionately with glucagon dose, from 5 6 68 to 112 6 152 mg/kg (P = 0.038 linear trend), whereas at high levels, there was no increase in glucose output (19 6 53 to 26 6 38 mg/kg, P = NS). Peak glucagon serum levels and AUC correlated well with dose (r2 = 0.63, P <0.001), as did insulin levels with insulin infusion rates (r2 = 0.59, P <0.001). CONCLUSIONS: EGP increases steeply with glucagon doses between 25 and 175 mg at lower insulin infusion rates. However, high insulin infusion rates prevent these doses of glucagon from significantly increasing glucose output and may reduce glucagon effectiveness in preventing hypoglycemia when used in the artificial pancreas.

Original languageEnglish (US)
Pages (from-to)3054-3060
Number of pages7
JournalDiabetes Care
Volume37
Issue number11
DOIs
StatePublished - Nov 1 2014

Fingerprint

Glucagon
Insulin
Glucose
Type 1 Diabetes Mellitus
Hypoglycemia
Area Under Curve
Artificial Pancreas
Glucose Clamp Technique
Cross-Over Studies
Blood Glucose
Research Design

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Advanced and Specialized Nursing

Cite this

Quantification of the glycemic response to microdoses of subcutaneous glucagon at varying insulin levels. / El Youssef, Joseph; Castle, Jessica; Bakhtiani, Parkash A.; Haidar, Ahmad; Branigan, Deborah L.; Breen, Matthew; Ward, W. Kenneth.

In: Diabetes Care, Vol. 37, No. 11, 01.11.2014, p. 3054-3060.

Research output: Contribution to journalArticle

El Youssef, Joseph ; Castle, Jessica ; Bakhtiani, Parkash A. ; Haidar, Ahmad ; Branigan, Deborah L. ; Breen, Matthew ; Ward, W. Kenneth. / Quantification of the glycemic response to microdoses of subcutaneous glucagon at varying insulin levels. In: Diabetes Care. 2014 ; Vol. 37, No. 11. pp. 3054-3060.
@article{8a340fae69c24eada1b1bf470ed25926,
title = "Quantification of the glycemic response to microdoses of subcutaneous glucagon at varying insulin levels",
abstract = "OBJECTIVE: Glucagon delivery in closed-loop control of type 1 diabetes is effective in minimizing hypoglycemia. However, high insulin concentration lowers the hyperglycemic effect of glucagon, and small doses of glucagon in this setting are ineffective. There are no studies clearly defining the relationship between insulin levels, subcutaneous glucagon, and blood glucose. RESEARCH DESIGN AND METHODS: Using a euglycemic clamp technique in 11 subjects with type 1 diabetes, we examined endogenous glucose production (EGP) of glucagon (25, 75, 125, and 175 m g) at three insulin infusion rates (0.016, 0.032, and 0.05 units/kg/h) in a randomized, crossover study. Infused 6,6-dideuterated glucose was measured every 10 min, and EGP was determined using a validated glucoregulatory model. Area under the curve (AUC) for glucose production was the primary outcome, estimated over 60 min. RESULTS: At low insulin levels, EGP rose proportionately with glucagon dose, from 5 6 68 to 112 6 152 mg/kg (P = 0.038 linear trend), whereas at high levels, there was no increase in glucose output (19 6 53 to 26 6 38 mg/kg, P = NS). Peak glucagon serum levels and AUC correlated well with dose (r2 = 0.63, P <0.001), as did insulin levels with insulin infusion rates (r2 = 0.59, P <0.001). CONCLUSIONS: EGP increases steeply with glucagon doses between 25 and 175 mg at lower insulin infusion rates. However, high insulin infusion rates prevent these doses of glucagon from significantly increasing glucose output and may reduce glucagon effectiveness in preventing hypoglycemia when used in the artificial pancreas.",
author = "{El Youssef}, Joseph and Jessica Castle and Bakhtiani, {Parkash A.} and Ahmad Haidar and Branigan, {Deborah L.} and Matthew Breen and Ward, {W. Kenneth}",
year = "2014",
month = "11",
day = "1",
doi = "10.2337/dc14-0803",
language = "English (US)",
volume = "37",
pages = "3054--3060",
journal = "Diabetes Care",
issn = "1935-5548",
publisher = "American Diabetes Association Inc.",
number = "11",

}

TY - JOUR

T1 - Quantification of the glycemic response to microdoses of subcutaneous glucagon at varying insulin levels

AU - El Youssef, Joseph

AU - Castle, Jessica

AU - Bakhtiani, Parkash A.

AU - Haidar, Ahmad

AU - Branigan, Deborah L.

AU - Breen, Matthew

AU - Ward, W. Kenneth

PY - 2014/11/1

Y1 - 2014/11/1

N2 - OBJECTIVE: Glucagon delivery in closed-loop control of type 1 diabetes is effective in minimizing hypoglycemia. However, high insulin concentration lowers the hyperglycemic effect of glucagon, and small doses of glucagon in this setting are ineffective. There are no studies clearly defining the relationship between insulin levels, subcutaneous glucagon, and blood glucose. RESEARCH DESIGN AND METHODS: Using a euglycemic clamp technique in 11 subjects with type 1 diabetes, we examined endogenous glucose production (EGP) of glucagon (25, 75, 125, and 175 m g) at three insulin infusion rates (0.016, 0.032, and 0.05 units/kg/h) in a randomized, crossover study. Infused 6,6-dideuterated glucose was measured every 10 min, and EGP was determined using a validated glucoregulatory model. Area under the curve (AUC) for glucose production was the primary outcome, estimated over 60 min. RESULTS: At low insulin levels, EGP rose proportionately with glucagon dose, from 5 6 68 to 112 6 152 mg/kg (P = 0.038 linear trend), whereas at high levels, there was no increase in glucose output (19 6 53 to 26 6 38 mg/kg, P = NS). Peak glucagon serum levels and AUC correlated well with dose (r2 = 0.63, P <0.001), as did insulin levels with insulin infusion rates (r2 = 0.59, P <0.001). CONCLUSIONS: EGP increases steeply with glucagon doses between 25 and 175 mg at lower insulin infusion rates. However, high insulin infusion rates prevent these doses of glucagon from significantly increasing glucose output and may reduce glucagon effectiveness in preventing hypoglycemia when used in the artificial pancreas.

AB - OBJECTIVE: Glucagon delivery in closed-loop control of type 1 diabetes is effective in minimizing hypoglycemia. However, high insulin concentration lowers the hyperglycemic effect of glucagon, and small doses of glucagon in this setting are ineffective. There are no studies clearly defining the relationship between insulin levels, subcutaneous glucagon, and blood glucose. RESEARCH DESIGN AND METHODS: Using a euglycemic clamp technique in 11 subjects with type 1 diabetes, we examined endogenous glucose production (EGP) of glucagon (25, 75, 125, and 175 m g) at three insulin infusion rates (0.016, 0.032, and 0.05 units/kg/h) in a randomized, crossover study. Infused 6,6-dideuterated glucose was measured every 10 min, and EGP was determined using a validated glucoregulatory model. Area under the curve (AUC) for glucose production was the primary outcome, estimated over 60 min. RESULTS: At low insulin levels, EGP rose proportionately with glucagon dose, from 5 6 68 to 112 6 152 mg/kg (P = 0.038 linear trend), whereas at high levels, there was no increase in glucose output (19 6 53 to 26 6 38 mg/kg, P = NS). Peak glucagon serum levels and AUC correlated well with dose (r2 = 0.63, P <0.001), as did insulin levels with insulin infusion rates (r2 = 0.59, P <0.001). CONCLUSIONS: EGP increases steeply with glucagon doses between 25 and 175 mg at lower insulin infusion rates. However, high insulin infusion rates prevent these doses of glucagon from significantly increasing glucose output and may reduce glucagon effectiveness in preventing hypoglycemia when used in the artificial pancreas.

UR - http://www.scopus.com/inward/record.url?scp=84910135619&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84910135619&partnerID=8YFLogxK

U2 - 10.2337/dc14-0803

DO - 10.2337/dc14-0803

M3 - Article

C2 - 25139882

AN - SCOPUS:84910135619

VL - 37

SP - 3054

EP - 3060

JO - Diabetes Care

JF - Diabetes Care

SN - 1935-5548

IS - 11

ER -