Effects of palmitate on insulin secretion and exocytotic proteins in islets of diabetic Goto-Kakizaki rats

• Published in: Pancreas Vol. 34; no. 3; p. 359
• Main Authors: Ostenson, Claes-Göran, Chen, Jie, Sheu, Laura, Gaisano, Herbert Y
• Format: Journal Article
• Language: English
• Published: United States 01.04.2007
• Subjects: Animals; Exocytosis - drug effects; Glucose - pharmacology; Insulin - metabolism; Insulin Secretion; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Palmitic Acid - pharmacology; Proteins - metabolism; Rats; Rats, Mutant Strains
• ISSN: 1536-4828
• DOI: 10.1097/mpa.0b013e3180304825

We examined how lipotoxicity contributes to pancreatic beta-cell secretory dysfunction. Effects of palmitate (0.2 mmol/L) were assessed on insulin secretion and soluble N-ethylmaleimide-sensitive factor attachment protein receptor exocytotic machinery in isolated pancreatic islets of type 2 diabetic Goto-Kakizaki (GK) rats and control Wistar (W) rats. One-day palmitate treatment enhanced basal glucose (3.3 mmol/L)-mediated insulin release 5-fold in W and 3.3-fold in GK islets, but had no effect at high glucose (16.7 mmol/L) on W islets while enhancing GK islet insulin release 2-fold. After 3-day palmitate treatment, high-glucose-induced insulin release in W islets was reduced (by 69%), whereas in GK islets, it increased 2-fold. Insulin response to arginine was reduced in both islet types, but more so in GK islets. Exocytotic proteins (syntaxin 1A, VAMP-2, SNAP-25, nSec1) were reduced in GK islets by 56% to 69% compared with W islets. In W islets, palmitate treatment caused no changes in the levels of these proteins but increased actin levels. In GK islets, whereas 1-day palmitate treatment had no effect, 3-day treatment further reduced SNAP-25 and nSec1 levels. Lipotoxic-induced secretory insufficiency in normal islets may be attributed to lack of compensatory increase in levels of exocytotic proteins and/or excess actin. However, in GK islets, palmitate treatment moderately enhanced insulin secretion, likely by acting on proximal metabolic pathways capable of compensating for the defective soluble N-ethylmaleimide-sensitive factor attachment protein receptor exocytotic machinery. These results were different from prolonged glucose treatment we previously reported, indicating differences between glucotoxic and lipotoxic actions on the insulin secretory machinery.