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Prince Henry’s Institute of Medical Research, PO Box 5152, Clayton, Victoria, 3168, Australia
¹ Department of Physiology, Fourth Military Medical University, Xi’an, People’s Republic of China

(Requests for offprints should be addressed to C Chen; Email: chen.chen{at}phimr.monash.edu.au)

Current address of Y-F Zhao: Department of Physiology, Fourth Military Medical University, Xi’an, People’s Republic of China

^* Yu-Feng Zhao and D J Keating contributed equally to this work

Dysfunction of pancreatic ß-cells is a fundamental feature in the pathogenesis of type 2 diabetes. As insulin receptor signaling occurs via protein tyrosine kinase (PTK), we investigated the role of PTK activity in the etiology of ß-cell dysfunction by inhibiting PTK activity in primary cultured mouse pancreatic ß-cells and INS-1 cells with genistein treatment over 24 h. Electrophysiologic recordings showed genistein treatment significantly attenuated ATP-sensitive K⁺ (K_ATP) and voltage-dependent Ca²⁺ currents, and depolarized the resting membrane potential in primary ß-cells. When stimulated by high glucose, genistein-treated ß-cells exhibited a time delay of both depolarization and Ca²⁺ influx, and were unable to fire action potentials, as well as displaying a reduced level of Ca²⁺ influx and a loss of Ca²⁺ oscillations. Semiquantitative PCR analysis revealed decreased expression of K_ATP and L-type Ca²⁺ channel mRNA in genistein-treated islets. PTK inhibition also significantly reduced the rapid component of secretory vesicle exocytosis, as indicated by membrane capacitance measurements, and this is likely to be due to the reduced Ca²⁺ current amplitude in these cells. These results illustrate that compromised PTK activity contributes to pancreatic ß-cell dysfunction and may be involved in the etiology of type 2 diabetes.

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