Diminished Phosphodiesterase-8B Potentiates Biphasic Insulin Response to Glucose

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.

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Glucagon-like peptide-1(7-36)-amide confers glucose sensitivity to previously glucose-incompetent beta-cells in diabetic rats: in vivo and in vitro studies

Journal of Endocrinology ◽

10.1677/joe.0.1550369 ◽

1997 ◽

Vol 155 (2) ◽

pp. 369-376 ◽

Cited By ~ 28

Author(s):

N Dachicourt ◽

P Serradas ◽

D Bailbe ◽

M Kergoat ◽

L Doare ◽

...

Keyword(s):

Glucose Tolerance ◽

Beta Cells ◽

Insulin Release ◽

Insulin Response ◽

Diabetic Rats ◽

Insulin Response To Glucose ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

The effects of glucagon-like peptide-1(7-36)-amide (GLP-1) on cAMP content and insulin release were studied in islets isolated from diabetic rats (n0-STZ model) which exhibited impaired glucose-induced insulin release. We first examined the possibility of re-activating the insulin response to glucose in the beta-cells of the diabetic rats using GLP-1 in vitro. In static incubation experiments, GLP-1 amplified cAMP accumulation (by 170%) and glucose-induced insulin release (by 140%) in the diabetic islets to the same extent as in control islets. Using a perifusion procedure, GLP-1 amplified the insulin response to 16.7 mM glucose by diabetic islets and generated a clear biphasic pattern of insulin release. The incremental insulin response to glucose in the presence of GLP-1, although lower than corresponding control values (1.56 +/- 0.37 and 4.53 +/- 0.60 pg/min per ng islet DNA in diabetic and control islets respectively), became similar to that of control islets exposed to 16.7 mM glucose alone (1.09 +/- 0.15 pg/min per ng islet DNA). Since in vitro GLP-1 was found to exert positive effects on the glucose competence of the residual beta-cells in the n0-STZ model. we investigated the therapeutic effect of in vivo GLP-1 administration on glucose tolerance and glucose-induced insulin release by n0-STZ rats. An infusion of GLP-1 (10 ng/min per kg; i.v.) in n0-STZ rats enhanced significantly (P < 0.01) basal plasma insulin levels, and, when combined with an i.v. glucose tolerance and insulin secretion test, it was found to improve (P < 0.05) glucose tolerance and the insulinogenic index, as compared with the respective values of these parameters before GLP-1 treatment.

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EFFECT OF BLOCKADE OF THE α-ADRENERGIC RECEPTORS ON INSULIN RESPONSE TO GLUCOSE INFUSION IN PREDIABETIC SUBJECTS

Acta Endocrinologica ◽

10.1530/acta.0.0740542 ◽

1973 ◽

Vol 74 (3) ◽

pp. 542-547 ◽

Cited By ~ 5

Author(s):

S. Efendić ◽

E. Cerasi ◽

R. Luft

Keyword(s):

Insulin Release ◽

Adrenergic Receptors ◽

Insulin Response ◽

Blocking Agent ◽

Glucose Infusion ◽

Β Cells ◽

Pancreatic Β Cells ◽

Experimental Conditions ◽

Insulin Response To Glucose ◽

Adrenergic Blocking

ABSTRACT The α-adrenergic blocking agent phentolamine significantly stimulates, but does not normalise glucose induced insulin release in prediabetic subjects. In earlier studies, under the same experimental conditions, no effect of the drug was observed in non-prediabetic subjects. The present data suggest that the diminished insulin response to glucose in prediabetics may partially be mediated by an enhanced responsiveness of the α-receptors of the pancreatic β-cells.

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Regulation of microRNA-375 by cAMP in Pancreatic β-Cells

Molecular Endocrinology ◽

10.1210/me.2011-1205 ◽

2012 ◽

Vol 26 (6) ◽

pp. 989-999 ◽

Cited By ~ 40

Author(s):

David M. Keller ◽

Elizabeth A. Clark ◽

Richard H. Goodman

Keyword(s):

Rna Polymerase Ii ◽

Insulin Response ◽

Β Cells ◽

Pancreatic Β Cells ◽

Mature Microrna ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Pka Pathway ◽

Kinetics Of ◽

Camp Stimulation

Abstract MicroRNA-375 (miR-375) is necessary for proper formation of pancreatic islets in vertebrates and is necessary for the development of β-cells in mice, but regulation of miR-375 in these cells is poorly understood. Here, we show that miR-375 is transcriptionally repressed by the cAMP-protein kinase A (PKA) pathway and that this repression is mediated through a block in RNA polymerase II binding to the miR-375 promoter. cAMP analogs that are PKA selective repress miR-375, as do cAMP agonists and the glucagon-like peptide-1 receptor agonist, exendin-4. Repression of the miR-375 precursor occurs rapidly in rat insulinoma INS-1 832/13 cells, within 15 min after cAMP stimulation, although the mature microRNA declines more slowly due to the kinetics of RNA processing. Repression of miR-375 in isolated rat islets by exendin-4 also occurs slowly, after several hours of stimulation. Glucose is another reported antagonist of miR-375 expression, although we demonstrate here that glucose does not target the microRNA through the PKA pathway. As reported previously, miR-375 negatively regulates insulin secretion, and attenuation of miR-375 through the cAMP-PKA pathway may boost the insulin response in pancreatic β-cells.

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