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Increased KATP channel current in pancreatic beta cells over expressing fatty acyl CoA synthetase I
Author(s) -
Webster Nicola Jane,
Dyck Jason R.B.,
Light Peter E.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a299-b
Subject(s) - medicine , endocrinology , intracellular , beta cell , secretion , beta (programming language) , patch clamp , biology , cytosol , cell , insulin , chemistry , biochemistry , enzyme , electrophysiology , computer science , programming language , islet
Closure of KATP channels links glucose metabolism to enhanced electrical activity and insulin secretion in the pancreatic beta cell. Long chain acyl CoAs can potently activate KATP when perfused directly across excised membrane patches, which could account for impaired glucose‐stimulated insulin secretion in obese and type II diabetic individuals via reduced beta cell excitability. However, the effects of chronic elevation of acyl CoAs within beta cells have not been documented. We have enhanced endogenous acyl CoA levels within intact primary mouse beta cells using virally delivered over expression of fatty acyl CoA synthetase‐1 (FACS‐1), and assessed the effects of this manipulation on beta cell excitability using the perforated whole‐cell patch‐clamp technique. Infection with AdFACS‐1 produced a large increase in FACS‐1 protein expression compared to controls (AdGFP‐treated), as confirmed by Western blot. Patch‐clamp data indicated a significant enhancement (p<0.05, n=7) of basal KATP current measured at low glucose in AdFACS‐1 infected cells compared to controls. Furthermore, membrane potential recordings showed a decreased spiking frequency in response to high glucose in AdFACS‐1 infected cells. We provide direct evidence for reduced beta cell excitability by a FACS‐1 driven cytosolic accumulation of acyl CoAs. These observations suggest a strong and direct link between intracellular fatty esters and KATP activity and may have major implications for our current understanding of the involvement of diet and obesity in the development of type II diabetes. Work is sponsored by CIHR and AHFMR.