title: Systemic administration of pituitary adenylate cyclase-activating polypeptide maintains beta-cell mass and retards onset of hyperglycaemia in beta-cell-specific calmodulin-overexpressing transgenic mice.
abstract: OBJECTIVE
  Pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to play an important role in the regulation of islet function. We investigated its effects in beta-cell-specific calmodulin-overexpressing diabetic (CaMTg) mice, in which we consider that apoptosis of beta cells is the primary defect leading to basal hyperglycaemia.
  
  
  METHODS
  CaMTg mice were treated with continuous s.c. infusions of PACAP from 2 to 4 weeks after birth, and were evaluated against littermate non-transgenic (nTg) and saline-treated CaMTg mice as to plasma glucose levels, insulin content, islet function and morphological features.
  
  
  RESULTS
  Remarkable and progressive hyperglycaemia was observed in CaMTg mice, and PACAP treatment blunted this elevation. Insulin secretion from isolated islets demonstrated an impaired response to glucose in CaMTg mice, and PACAP treatment did not cause any improvement. The total pancreatic insulin content in CaMTg mice decreased significantly to 19.1% of that in nTg mice. PACAP treatment of CaMTg mice increased the content to 158% of the value in saline-treated CaMTg mice. The insulin content in isolated islets from CaMTg mice also decreased to 15.9% of that in nTg mice, while PACAP treatment caused a doubling of the value. Immunohistochemical investigation revealed that the insulin-positive islet area was markedly smaller in CaMTg mice and that PACAP treatment significantly expanded the insulin-positive islet area.
  
  
  CONCLUSIONS
  These findings indicate that PACAP treatment retards the onset of hyperglycaemia in CaMTg mice by maintaining beta-cell mass and PACAP treatment may potentially be a therapeutic measure for preventing beta-cell exhaustion during hyperglycaemia.
authors.affiliation: Department of Endocrinology and Diabetology, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Tsunekawa
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Miura
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Yuji
authors.initials: Y
authors.lastname: Itoh
authors.forename: Yoh
authors.initials: Y
authors.lastname: Ariyoshi
authors.forename: Takao
authors.initials: T
authors.lastname: Senda
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Oiso
authors.forename: Ichiro
authors.initials: I
authors.lastname: Niki
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002147:Calmodulin / Q000235:genetics*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000517:prevention & control*; D015870:Gene Expression; D006943:Hyperglycemia / Q000235:genetics / Q000517:prevention & control*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009479:Neuropeptides / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide
chemical_list: C495402:Adcyap1 protein, mouse; D001786:Blood Glucose; D002147:Calmodulin; D007328:Insulin; D009414:Nerve Growth Factors; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide