Pancreatic β-cell dysfunction, expression of iNOS and the effect of phosphodiesterase inhibitors in human pancreatic islets of type 2 diabetes.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Abstract

AIMS:
Induction of iNOS in pancreatic islets leads to exaggerated NO production associated with dysfunctional β-cells. We examined insulin secretion, iNOS expression and its relation to the cAMP system in islets from human type 2 diabetes.

METHODS:
Insulin, glucagon and cAMP were analyzed by RIA; iNOS or PDE expression by qPCR, Western blot and confocal microscopy; cell viability by MTS.

RESULTS: Diabetic islets displayed impaired insulin and glucagon responses to glucose, disturbed cAMP generation, and high iNOS mRNA and protein expression. Confocal microscopy showed iNOS protein expression in diabetic islets being confined to insulin, glucagon and somatostatin cells. Culture of diabetic islets at 5.5 mmol/l glucose with dibutyryl-cAMP (Bt(2) -cAMP) for 24 h was accompanied by marked suppression of iNOS mRNA, reduced nitrite production and increased insulin secretion. Diabetic islets displayed marked increase in PDE3A and PDE3B mRNA expression. Short-time incubation of diabetic islets showed, among the PDE inhibitors tested, cilostazol being most favourable to increase insulin secretion. Diabetic islets were most susceptible to long-term (72 h) culture at high glucose (20 mmol/l) reacting with increased apoptosis. Bt(2) -cAMP and the PDE inhibitors cilostazol, milrinone and IBMX efficiently increased cell viability at high glucose during culture. Defective glucose-stimulated insulin release upon induction of iNOS was restored by iNOS inhibitor aminoguanidine.

CONCLUSION:
Our results suggest that in islets from type 2 diabetes, stimulatory effects in certain cAMP-compartments induced by PDE inhibitors might play a central role in the suppression of iNOS, resulting in increased β-cell viability and improved secretory response to glucose.

Detaljer

Författare
Enheter & grupper
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Endokrinologi och diabetes

Nyckelord

Originalspråkengelska
Sidor (från-till)1010-1019
TidskriftDiabetes, Obesity and Metabolism
Volym14
Utgivningsnummer11
StatusPublished - 2012
PublikationskategoriForskning
Peer review utfördJa

Relaterad forskningsoutput

Jabar Muhammed, S., 2012, Diabetes Centre, Lund University. 174 s.

Forskningsoutput: AvhandlingDoktorsavhandling (sammanläggning)

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