Inhibition of protein-tyrosine phosphatases stimulates insulin secretion in pancreatic islets of diabetic Goto-Kakizaki rats.
OBJECTIVE
Because increased expression of protein tyrosine phosphatases in the pancreatic islets may contribute to impaired insulin secretion in diabetes, we studied the effects of the phosphatase inhibitor peroxovanadate (pV) in islets of spontaneously diabetic Goto-Kakizaki (GK) and control Wistar rats.


METHODS
Insulin release and glucose use were studied in isolated islets of GK and control rats.


RESULTS
Insulin release from isolated GK rat islets at 3.3 and 16.7 mmol/L glucose was enhanced by pV in a dose-dependent manner (0.1-1 mmol/L). This was partly in contrast to the effect of pV in Wistar rat islets, where insulin response to 16.7 mmol/L glucose was inhibited by 0.01-0.1 mmol/L of the compound. In GK rat islets, pV was a strong initiator of insulin release and also had some potentiating effect on glucose-stimulated insulin secretion, whereas in Wistar rat islets, pV only had an initiating, and lacked potentiating, effect. The PI3K inhibitor wortmannin suppressed pV-induced insulin release at 3.3 mmol/L but not at 16.7 mmol/L glucose in both GK and Wistar rat islets. The modulatory effects by pV on insulin release were not related to effects by the compound on islet glucose metabolism.


CONCLUSIONS
Our findings suggest that impaired insulin secretion in GK rat islets is accounted for, at least partly, by increased protein-tyrosine phosphatase activity in B cells.
Chen
Jie
J
Department of Molecular Medicine, Endocrine and Diabetes Unit, Karolinska Hospital, Stockholm, Sweden.
Ostenson
Claes-Göran
CG
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D014638:Vanadates / Q000494:pharmacology*; D000077191:Wortmannin
D000730:Androstadienes; D004791:Enzyme Inhibitors; D005947:Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D017027:Protein Tyrosine Phosphatases; D014638:Vanadates; D000077191:Wortmannin; C069276:peroxovanadate