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Diminished Phosphodiesterase-8B Potentiates Biphasic Insulin Response to Glucose

Endocrinology and Metabolism Service, Department of Medicine, Hadassah, the Hebrew University Medical Center, 91120 Jerusalem, Israel

Address all correspondence and requests for reprints to: Dr. R. Nesher, Endocrinology and Metabolism Service, Department of Medicine, Hadassah, the Hebrew University Medical Center, P.O. Box 12000, 91120 Jerusalem, Israel. E-mail: rafael.nesher{at}huji.ac.il.

cAMP activates multiple signal pathways, crucial for the pancreatic β-cells function and survival and is a major potentiator of insulin release. A family of phosphodiesterases (PDEs) terminate the cAMP signals. We examined the expression of PDEs in rat β-cells and their role in the regulation of insulin response. Using RT-PCR and Western blot analyses, we identified PDE3A, PDE3B, PDE4B, PDE4D, and PDE8B in rat islets and in INS-1E cells and several possible splice variants of these PDEs. Specific depletion of PDE3A with small interfering (si) RNA (siPDE3A) led to a small (67%) increase in the insulin response to glucose in INS-1E cells but not rat islets. siPDE3A had no effect on the glucagon-like peptide-1 (10 nmol/liter) potentiated insulin response in rat islets. Depletion in PDE8B levels in rat islets using similar technology (siPDE8B) increased insulin response to glucose by 70%, the potentiation being of similar magnitude during the first and second phase insulin release. The siPDE8B-potentiated insulin response was further increased by 23% when glucagon-like peptide-1 was included during the glucose stimulus. In conclusion, PDE8B is expressed in a small number of tissues unrelated to glucose or fat metabolism. We propose that PDE8B, an 3-isobutyl-1-methylxanthine-insensitive cAMP-specific phosphodiesterase, could prove a novel target for enhanced insulin response, affecting a specific pool of cAMP involved in the control of insulin granule trafficking and exocytosis. Finally, we discuss evidence for functional compartmentation of cAMP in pancreatic β-cells.