The antilipolytic agent 3,5-dimethylpyrazole inhibits insulin release in response to both nutrient secretagogues and cyclic adenosine monophosphate agonists in isolated rat islets.
This study intended to test the hypothesis that intracellular lipolysis in the pancreatic beta cells is implicated in the regulation of insulin secretion stimulated by nutrient secretagogues or cyclic adenosine monophosphate (cAMP) agonists. Indeed, although lipid signaling molecules were repeatedly reported to influence beta-cell function, the contribution of intracellular triglycerides to the generation of these molecules has remained elusive. Thus, we have studied insulin secretion of isolated rat pancreatic islets in response to various secretagogues in the presence or absence of 3,5-dimethylpyrazole (DMP), a water-soluble and highly effective antilipolytic agent, as previously shown in vivo. In vitro exposure of islets to DMP resulted in an inhibition (by approximately 50%) of the insulin release stimulated not only by high glucose, but also by another nutrient secretagogue, 2-ketoisocaproate, as well as the cAMP agonists 3-isobutyl-1-methylxanthine and glucagon. The inhibitory effect of DMP, which was not due to alteration of islet glucose oxidation, could be reversed upon addition of sn-1,2-dioctanoylglycerol, a synthetic diglyceride, which activates protein kinase C. The results provide direct pharmacologic evidence supporting the concept that endogenous beta-cell lipolysis plays an important role in the generation of lipid signaling molecules involved in the control of insulin secretion in response to both fuel stimuli and cAMP agonists.
Masiello
P
P
Dipartimento di Patologia Sperimentale, University of Pisa, Pisa, Italy.
Novelli
M
M
Bombara
M
M
Fierabracci
V
V
Vittorini
S
S
Prentki
M
M
Bergamini
E
E
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000819:agonists*; D004075:Diglycerides / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007651:Keto Acids / Q000494:pharmacology; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D009747:Nutritional Physiological Phenomena; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004075:Diglycerides; D007328:Insulin; D007651:Keto Acids; D011720:Pyrazoles; C044295:1,2-dioctanoylglycerol; C013082:alpha-ketoisocaproic acid; D005934:Glucagon; D000242:Cyclic AMP; C027635:3,5-dimethylpyrazole; D005947:Glucose; D015056:1-Methyl-3-isobutylxanthine