Intra-islet PACAP protects pancreatic β-cells against glucotoxicity and lipotoxicity.
Pituitary adenylate cyclase-activating polypeptide (PACAP), a potent insulinotropin, is localized in pancreatic islets. Hyperglycemia and hyperlipidemia impair islet β-cell functions, being recognized as glucotoxicity and lipotoxicity. In this study, we examined whether endogenous PACAP protects islet β-cells against the toxicities. Pancreatic islets were prepared from wild-type and PACAP-null mice, and cultured for 2 days in control conditions containing 5.6 mM glucose, those with elevated 25 mM glucose and those supplemented with 0.4 mM palmitate. After culture in control conditions, a rise in the superfusate glucose concentration from 2.8 mM to a physiologic 8.3 mM increased cytosolic Ca(2+) concentration ([Ca(2+)](i)) in both wild-type and PACAP-null mouse islets. In contrast, after culture with high glucose or palmitate, the glucose-induced first phase [Ca(2+)](i) increases were severely impaired in islets of PACAP-null mice while they were preserved in islets of wild-type mice. Treatment with high glucose or palmitate also impaired glucose-induced insulin secretion in islets and increased mRNA expression of uncoupling protein 2 (UCP2) in islets of PACAP-null, but not wild-type, mice. These data indicate that islet-produced PACAP protects β-cells from deteriorating action of high glucose and palmitate at least partly by blocking the elevation of UCP2, suggesting an anti-diabetic role for PACAP.
Nakata
Masanori
M
Department of Physiology, Division of Integrative Physiology, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Shintani
Norihito
N
Hashimoto
Hitoshi
H
Baba
Akemichi
A
Yada
Toshihiko
T
D000818:Animals; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000378:metabolism; D010168:Palmitates / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000378:metabolism*; D000071246:Uncoupling Protein 2
D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; D010168:Palmitates; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D005947:Glucose
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