Early insulin release effectively improves glucose tolerance: studies in two rodent models of type 2 diabetes mellitus.
OBJECTIVE
Islet dysfunction, characterized by the loss of an acute insulin secretory response (AIR) to glucose is a well-established pathology of type 2 diabetes mellitus. Using oral insulin secreting agents with very different pharmacodynamic profiles, the present study was undertaken to test the hypothesis that, within the setting of an underlying insulin resistance, changes in the insulin response profile can differentially affect glycaemic control.


METHODS
The mildly insulin resistant high-fat fed Sprague Dawley (HF) rat and the very insulin resistant Zucker fatty (fa/fa) rat, chronically fitted with indwelling jugular cannula were subjected to an oral glucose load. Compounds were administered 5 min before the oral glucose load. Nateglinide (Nateg) was administered to elicit only an early insulin secretory response and glipizide (Glip) to elicit a later but greater insulin secretory response. Acetaminophen was used as a marker to assess for potential effects of these compounds on gastric emptying rates.


RESULTS
Nateg rapidly increased early insulin release (from -5 to 0) while the effects on total insulin release were similar to those in the controls and glucose excursions were eliminated in both diabetic models with no evidence of sustained hypoglycaemia. Conversely, Glip did not affect early insulin release but increased total insulin release (- 15 to 120 min), but only after the oral glucose load. Glip partially curbed glucose excursions in the mildly insulin resistant HF rodent and was totally ineffective in the very insulin resistant Zucker rat. The differential effects could not be attributed to effects on gastric emptying rates.


CONCLUSIONS
These data support the importance of early insulin release in type 2 diabetes mellitus and indicate that, independent of the level of insulin resistance, stimulating insulin release early and briefly provides for more effective and tighter glycaemic control than increasing insulin exposure to a greater magnitude later.
de Souza
C J
CJ
Metabolic and Cardiovascular Pharmacology, Novartis Institute for Biomedical Research, Summit, NJ 07901, USA. christopher.desouza@pharma.novartis.com
Gagen
K
K
Chen
W
W
Dragonas
N
N
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003510:Cyclohexanes / Q000494:pharmacology* / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D004041:Dietary Fats / Q000008:administration & dosage; D005746:Gastric Emptying / Q000187:drug effects; D005913:Glipizide / Q000494:pharmacology* / Q000627:therapeutic use; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008297:Male; D000077715:Nateglinide; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker
D001786:Blood Glucose; D003510:Cyclohexanes; D004041:Dietary Fats; D007004:Hypoglycemic Agents; D007328:Insulin; D000077715:Nateglinide; D010649:Phenylalanine; D005913:Glipizide