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

Research output: Contribution to journalArticle

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.

Details

Authors
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes

Keywords

  • PKA system, cAMP, iNOS expression, insulin secretion, phosphodiesterase, type 2 diabetic islets
Original languageEnglish
Pages (from-to)1010-1019
JournalDiabetes, Obesity and Metabolism
Volume14
Issue number11
Publication statusPublished - 2012
Publication categoryResearch
Peer-reviewedYes

Related research output

Sarheed Jabar Muhammed, 2012, Diabetes Centre, Lund University. 174 p.

Research output: ThesisDoctoral Thesis (compilation)

View all (1)