TY - JOUR
T1 - Quantification of the glycemic response to microdoses of subcutaneous glucagon at varying insulin levels
AU - El Youssef, Joseph
AU - Castle, Jessica R.
AU - Bakhtiani, Parkash A.
AU - Haidar, Ahmad
AU - Branigan, Deborah L.
AU - Breen, Matthew
AU - Ward, W. Kenneth
N1 - Publisher Copyright:
© 2014 by the American Diabetes Association.
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.
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U2 - 10.2337/dc14-0803
DO - 10.2337/dc14-0803
M3 - Article
C2 - 25139882
AN - SCOPUS:84910135619
SN - 0149-5992
VL - 37
SP - 3054
EP - 3060
JO - Diabetes care
JF - Diabetes care
IS - 11
ER -