Effects of palmitate on insulin secretion and exocytotic proteins in islets of diabetic Goto-Kakizaki rats.
OBJECTIVE
We examined how lipotoxicity contributes to pancreatic beta-cell secretory dysfunction.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Ostenson
Claes-Göran
CG
Department of Molecular Medicine and Surgery, Endocrine and Diabetes Unit, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden. claes-goran.ostenson@karolinska.se
Chen
Jie
J
Sheu
Laura
L
Gaisano
Herbert Y
HY
D000818:Animals; D005089:Exocytosis / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D019308:Palmitic Acid / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D011922:Rats, Mutant Strains
D007328:Insulin; D011506:Proteins; D019308:Palmitic Acid; D005947:Glucose