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Endocrine Abstracts (2010) 24 OC3.1

BSPED2010 Oral Communications Oral Communications 3 (3 abstracts)

Altered Expression of HCN Channels in Patients with Congenital Hyperinsulinism of Infancy (CHI)

L Adams 1 , M Skae 1 , I Banerjee 1 , C Hall 1 , S Ellard 3 , P Clayton 2 , P Kippet-Drews 4 , G Drews 4 , K Cosgrove 1 & M Dunne 1

1University of Manchester, Manchester, UK; 2Royal Manchester Children’s Hospital, Manchester, UK; 3Royal Devon and Exeter Foundation NHS, Exeter, UK; 4University of Tubingen, Tubingen, Germany.

Hyperpolarisation-activated cyclic nucleotide-gated channels (HCNCs). are selective for Na+/Ca2+ under physiological conditions and are responsible for the rhythmical electrical behaviour of pacemakers in the heart and brain. Their role in human pancreas has not been reported previously. Congenital hyperinsulinism of infancy (CHI) is an inherited disorder of inappropriate insulin secretion often caused by gene defects in the subunits of KATP channels (ABCC8, KCNJ11). We aimed to investigate the expression and function of HCNCs in pancreatic tissue and assess their relationship to CHI. Tissue was isolated from adult control human pancreas and from six patients following pancreatectomy for CHI to examine HCNC gene and protein expression by RT-PCR and immuno-fluorescence, respectively. HCNC expression was also assessed in pancreatic tissue from ABCC8-knockout mice. The role of HCNCs in glucose-stimulated insulin secretion (GSIS) from control mouse islets was assessed by ELISA. HCNC1-4 mRNA was detected in islets isolated from both adult control and CHI patient pancreatic tissue. Co-expression of HCNC isoforms with insulin confirmed that HCNC1, −2 and −4 were β-cell specific in control human and rodent islets. By contrast, in all patient tissues expression of HCNCs was altered, and in 5 out of 6 cases, HCNC was not expressed in β-cells. We found similar data in islets of ABCC8-knockout mice, but not their litter-mate controls (n=3). The HCNC agonist lamotrigine had no effect on GSIS (n=3), but GSIS was significantly inhibited by the HCNC blocker zatebradine (n=3) thereby confirming that HCNCs may play a role in glucose homeostasis. These studies provide the first data on expression of HCNCs in the human pancreas and we also found that HCNC expression in β-cells is altered in CHI patients and we speculate that this is as a consequence of physiological remodelling.

Volume 24

38th Meeting of the British Society for Paediatric Endocrinology and Diabetes

British Society for Paediatric Endocrinology and Diabetes 

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