Glucokinase activators AZD6370 and AZD1656 do not affect the central counterregulatory response to hypoglycemia in healthy males.
BACKGROUND
Glucokinase is expressed in the hypothalamus, but effects of glucokinase activators (GKAs) on counterregulatory responses to hypoglycemia are unknown.


OBJECTIVE
Two separate studies assessed the counterregulatory hormone responses to hypoglycemia induced by the GKAs, AZD6370 and AZD1656, compared with insulin infusion.


METHODS
Both studies were randomized, open, two-way crossover studies, conducted in separate clinical research centers.


METHODS
Both studies involved 12 healthy adult male volunteers.


METHODS
Each subject received two treatments in randomized order, separated by a washout. In the AZD6370 study, overnight-fasted subjects received either a single oral AZD6370 dose (300 mg) or insulin infusion (0.8 mU/kg · min). In the AZD1656 study, overnight-fasted subjects received either a single oral dose of AZD1656 (80 mg) plus supporting insulin (1 mU/kg · min) or insulin alone (1 mU/kg · min). Insulin was added to support AZD1656 because AZD1656 alone did not produce the desired hypoglycemia. Plasma glucose was lowered during a stepwise hypoglycemic clamp with a glycemic nadir of 2.7 mmol/liter for 30 min.


METHODS
Epinephrine, norepinephrine, GH, cortisol, and glucagon plasma levels were assessed.


RESULTS
No safety issues were raised. AZD6370 and AZD1656 had no effect on counterregulatory responses for norepinephrine, GH, or cortisol, but epinephrine increased slightly with AZD1656. Glucagon responses were reduced by approximately 30% with both GKAs vs. insulin.


CONCLUSIONS
These data suggest the central nervous system-mediated counterregulatory response during GKA-induced hypoglycemia was preserved, whereas the glucagon response was attenuated; the latter was possibly mediated by a local pancreatic effect (intraislet hyperinsulinemia) rather than by impairment of the central nervous system-mediated response.
Division of Research and Development, AstraZeneca, 431 83 Mölndal, Sweden. ensio.norjavaara@astrazeneca.com
Ensio
E
Norjavaara
Hans
H
Ericsson
Folke
F
Sjöberg
Maria
M
Leonsson-Zachrisson
Mikaela
M
Sjöstrand
Linda A
LA
Morrow
Marcus
M
Hompesch
D000328:Adult; D001384:Azetidines / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D015992:Body Mass Index; D002096:C-Peptide / Q000097:blood; D018592:Cross-Over Studies; D020536:Enzyme Activators / Q000494:pharmacology*; D004837:Epinephrine / Q000097:blood; D005934:Glucagon / Q000097:blood; D005941:Glucokinase / Q000187:drug effects* / Q000378:metabolism*; D019382:Human Growth Hormone / Q000097:blood; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007003:Hypoglycemia / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000097:blood; D011719:Pyrazines / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology*; D055815:Young Adult
C576406:3-(2-hydroxy-1-methylethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-5-(4-(methylsulfonyl)phenoxy)benzamide; C576407:AZD1656; D001384:Azetidines; D001549:Benzamides; D002096:C-Peptide; D020536:Enzyme Activators; D007004:Hypoglycemic Agents; D007328:Insulin; D011719:Pyrazines; D013450:Sulfones; D019382:Human Growth Hormone; D005934:Glucagon; D005941:Glucokinase; D006854:Hydrocortisone; D009638:Norepinephrine; D004837:Epinephrine