Effect of exogenously administered glucagon versus spontaneous endogenous counter-regulation on glycaemic recovery from insulin-induced hypoglycaemia in patients with type 2 diabetes treated with a novel glucokinase activator, AZD1656, and metformin

Aims To study the effect of exogenous i.m. glucagon on recovery from controlled insulin‐induced hypoglycaemia in patients with type 2 diabetes treated with the novel glucokinase activator AZD1656, in combination with metformin. Methods This was a single‐centre randomized, open, two‐way crossover pha...

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Published in:Diabetes, obesity & metabolism obesity & metabolism, 2014-11, Vol.16 (11), p.1096-1101
Main Authors: Krentz, A. J., Morrow, L., Petersson, M., Norjavaara, E., Hompesch, M.
Format: Article
Language:English
Subjects:
antidiabetic drug
Antidiabetics
Azetidines - administration & dosage
Azetidines - pharmacology
Blood Glucose - drug effects
Blood Glucose - metabolism
Body Mass Index
Catecholamines
Catecholamines - blood
Cross-Over Studies
Diabetes
Diabetes mellitus (non-insulin dependent)
Diabetes Mellitus, Type 2 - blood
Diabetes Mellitus, Type 2 - drug therapy
Drug Therapy, Combination
Enzyme Activators - administration & dosage
Enzyme Activators - pharmacology
Fasting - blood
Female
Glucagon
Glucagon - blood
Glucokinase
Glucokinase - drug effects
Glucokinase - metabolism
Glucose
Glucose Clamp Technique
Growth hormone
Growth hormones
Human Growth Hormone - blood
Human Growth Hormone - drug effects
Humans
Hydrocortisone - blood
Hypoglycemia
Hypoglycemia - chemically induced
Hypoglycemic Agents - administration & dosage
Insulin
Male
Metformin
Metformin - administration & dosage
Middle Aged
phase I-II study
Pyrazines - administration & dosage
Pyrazines - pharmacology
Titration
type 2 diabetes
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Summary:Aims To study the effect of exogenous i.m. glucagon on recovery from controlled insulin‐induced hypoglycaemia in patients with type 2 diabetes treated with the novel glucokinase activator AZD1656, in combination with metformin. Methods This was a single‐centre randomized, open, two‐way crossover phase I, automated glucose clamp (Biostator®; Life Science Instruments, Elkhart, MD, USA) study (NCT00817271) in eight patients (seven men and one woman, mean age 58.6 years, body mass index 28.1 kg/m2). All patients received a stable dose of metformin twice daily, ranging from 1000 to 2250 mg. A 2‐day titration phase commenced with 40 mg AZD1656 twice daily, escalating to 80 mg twice daily if tolerated. This was followed by a single dose of 80 or 160 mg AZD1656, administered on days 5 and 8 when metabolic studies were performed. After an overnight fast on days 5 and 8, controlled hypoglycaemia was induced using an exogenous i.v. infusion of insulin. Plasma glucose was lowered in a stepwise fashion over 3 h to attain a target nadir of 2.7 mmol/l. This was sustained for 30 min, at the end of which the hypoglycaemic clamp was released. In random sequence, patients either received an i.m. injection of 1 mg glucagon or were allowed to recover from hypoglycaemia by endogenous counter‐regulation. To avoid prolonged hypoglycaemia, a reverse glucose clamp was applied from 4 to 6 h post‐dose. Results Three patients received 40 mg AZD1656 twice daily and five patients 80 mg twice daily. Mean plasma glucose at 20 min after release of the hypoglycaemic clamp was significantly lower (3.1 ± 0.3 mmol/l) for AZD1656 alone than for AZD1656 + glucagon (4.9 ± 0.8 mmol/l; p 
ISSN:1462-8902
1463-1326
DOI:10.1111/dom.12323