Effect of Repeated Glucagon Doses on Hepatic Glycogen in Type 1 Diabetes: Implications for a Bihormonal Closed-Loop System.
OBJECTIVE
To evaluate subjects with type 1 diabetes for hepatic glycogen depletion after repeated doses of glucagon, simulating delivery in a bihormonal closed-loop system.


METHODS
Eleven adult subjects with type 1 diabetes participated. Subjects underwent estimation of hepatic glycogen using (13)C MRS. MRS was performed at the following four time points: fasting and after a meal at baseline, and fasting and after a meal after eight doses of subcutaneously administered glucagon at a dose of 2 µg/kg, for a total mean dose of 1,126 µg over 16 h. The primary and secondary end points were, respectively, estimated hepatic glycogen by MRS and incremental area under the glucose curve for a 90-min interval after glucagon administration.


RESULTS
In the eight subjects with complete data sets, estimated glycogen stores were similar at baseline and after repeated glucagon doses. In the fasting state, glycogen averaged 21 ± 3 g/L before glucagon administration and 25 ± 4 g/L after glucagon administration (mean ± SEM) (P = NS). In the fed state, glycogen averaged 40 ± 2 g/L before glucagon administration and 34 ± 4 g/L after glucagon administration (P = NS). With the use of an insulin action model, the rise in glucose after the last dose of glucagon was comparable to the rise after the first dose, as measured by the 90-min incremental area under the glucose curve.


CONCLUSIONS
In adult subjects with well-controlled type 1 diabetes (mean A1C 7.2%), glycogen stores and the hyperglycemic response to glucagon administration are maintained even after receiving multiple doses of glucagon. This finding supports the safety of repeated glucagon delivery in the setting of a bihormonal closed-loop system.
Department of Medicine, Division of Endocrinology, Harold Schnitzer Diabetes Health Center Oregon Health & Science University, Portland, OR castleje@ohsu.edu.
Jessica R
JR
Castle
Department of Medicine, Division of Endocrinology, Harold Schnitzer Diabetes Health Center Oregon Health & Science University, Portland, OR.
Joseph
J
El Youssef
Department of Medicine, Division of Endocrinology, Harold Schnitzer Diabetes Health Center Oregon Health & Science University, Portland, OR.
Parkash A
PA
Bakhtiani
Advanced Imaging Research Center, Oregon Health & Science University, Portland, OR.
Yu
Y
Cai
Advanced Imaging Research Center, Oregon Health & Science University, Portland, OR.
Jade M
JM
Stobbe
Department of Medicine, Division of Endocrinology, Harold Schnitzer Diabetes Health Center Oregon Health & Science University, Portland, OR.
Deborah
D
Branigan
Oregon Clinical and Translational Research Institute Biostatistics & Design Program, Oregon Health & Science University, Portland, OR.
Katrina
K
Ramsey
Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR.
Peter
P
Jacobs
Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR.
Ravi
R
Reddy
Advanced Imaging Research Center, Oregon Health & Science University, Portland, OR Portland State University, Portland, OR.
Mark
M
Woods
Department of Medicine, Division of Endocrinology, Harold Schnitzer Diabetes Health Center Oregon Health & Science University, Portland, OR.
W Kenneth
WK
Ward
D000328:Adult; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy*; D025461:Feedback, Physiological; D005260:Female; D005934:Glucagon / Q000008:administration & dosage / Q000627:therapeutic use*; D006728:Hormones / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D007003:Hypoglycemia / Q000517:prevention & control / Q000628:therapy*; D007328:Insulin / Q000008:administration & dosage / Q000627:therapeutic use; D008112:Liver Glycogen / Q000172:deficiency / Q000378:metabolism*; D008297:Male
D001786:Blood Glucose; D006728:Hormones; D007328:Insulin; D008112:Liver Glycogen; D005934:Glucagon