Differential effects of short and long duration insulinotropic agents on meal-related glucose excursions.
OBJECTIVE
Abnormal beta-cell function, characterized as the inability of the beta-cell to mount a rapid secretory response to glucose, is a well-established pathology of type 2 diabetes mellitus. These studies were designed to demonstrate the importance of early insulin release on the control of meal-induced glucose excursions by capitalizing on the significant pharmacodynamic differences between several oral insulin secreting agents.


METHODS
Male Sprague Dawley fitted with indwelling jugular cannulas were used to compare the pharmacodynamic profiles of nateglinide (Nateg), glipizide (Glip) and repaglinide (Repag) through frequent blood samples following the administration of these compounds via oral gavage. In similar animals which were pretrained to consume their daily food intake in two discrete 45-min meals, the effects of compound induced changes in pre-meal, meal and post-meal insulin profiles on glycaemic control were assessed through frequent blood sampling following the administration of these compounds 10 min prior to a 30-min meal.


RESULTS
There were significant pharmacodynamics differences between the three oral agents tested and the time to elicit peak insulin secretory responses increased from Nateg (4 min) to Repag (10 min) to Glip (45 min). During the meal tolerance test, glibenclamide did not increase pre-meal insulin levels and glucose excursions paralleled those in the control. Conversely, the other three agents, at doses that produced hypoglycaemic responses of similar magnitude, all increased early insulin release (Delta AUC(-15 to 3 min) = 0.5 +/- 0.01, 1.6 +/- 0.4, 3.6 +/- 0.0, 1.2 +/- 0.1 and 1.73 +/- 0.4 nmol/min, for control, Nateg at 60 and 120 mg/kg, Glip and Repag, respectively) and curbed glucose excursions during the meal at varying rates and degrees (Delta AUC(0--30 min) = 39 +/- 6, 8 +/- 7, 5 +/- 7, - 1 +/- 8 and - 3 +/- 8 mmol/min for control, Nateg at 60 and 120 mg/kg, Glip and Repag, respectively). However, unlike Nateg, the longer duration of action of Repag and Glip elicited sustained post-meal relative hypoglycaemia.


CONCLUSIONS
These data support the impact of early and rapid insulin release in the control of prandial and post-meal glycaemia and demonstrate that a short anticipatory burst of insulin, restricted to the beginning of a meal, provides a clear metabolic advantage and prevents post-meal hypoglycaemic episodes when compared to a greater but reactive insulin exposure that follows a meal-induced increase in glucose excursion.
de Souza
C J
CJ
Metabolic and Cardiovascular Pharmacology, Novartis Institute for Biomedical Research, Summit, NJ 07901, USA. christopher.desouza@pharma.novartis.com
Russo
P
P
Lozito
R
R
Dunning
B E
BE
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002219:Carbamates / Q000494:pharmacology; D003510:Cyclohexanes / Q000494:pharmacology; D005502:Food; D005913:Glipizide / Q000494:pharmacology; D005934:Glucagon / Q000097:blood; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D000077715:Nateglinide; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D001786:Blood Glucose; D002219:Carbamates; D003510:Cyclohexanes; D007328:Insulin; D010880:Piperidines; D000077715:Nateglinide; D010649:Phenylalanine; C072379:repaglinide; D005934:Glucagon; D005913:Glipizide