Cyclic nucleotide phosphodiesterases in pancreatic islets

Research output: Contribution to journalLiterature review

55 Citations (Scopus)

Abstract

Cyclic nucleotide phosphodiesterases (PDEs) comprise a family of enzymes (PDE1-PDE11) which hydrolyse cyclic AMP and cyclic GMP to their biologically inactive 5' derivatives. Cyclic AMP is an important physiological amplifier of glucose-induced insulin secretion. As PDEs are the only known mechanism for inactivating cyclic nucleotides, it is important to characterise the PDEs present in the pancreatic islet beta cells. Several studies have shown pancreatic islets or beta cells to contain PDE1C, PDE3B and PDE4, with some evidence for PDE10A. Most evidence suggests that PDE3B is the most important in relation to the regulation of insulin release, although PDE1C could have a role. PDE3-selective inhibitors augment glucose-induced insulin secretion. In contrast, activation of beta-cell PDE3B could mediate the inhibitory effect of IGF-1 and leptin on insulin secretion. In vivo, although PDE3 inhibitors augment glucose-induced insulin secretion, concomitant inhibition of PDE3B in liver and adipose tissue induce insulin resistance and PDE3 inhibitors do not induce hypoglycaemia. The development of PDE3 inhibitors as anti-diabetic agents would require differentiation between PDE3B in the beta cell and that in hepatocytes and adipocytes. Through their effects in regulating beta-cell cyclic nucleotide concentrations, PDEs could modulate beta-cell growth, differentiation and survival; some work has shown that selective inhibition of PDE4 prevents diabetes in NOD mice and that selective PDE3 inhibition blocks cytokine-induced nitric oxide production in islet cells. Further work is required to understand the mechanism of regulation and role of the various PDEs in islet-cell function and to validate them as targets for drugs to treat and prevent diabetes.
Original languageEnglish
Pages (from-to)1179-1189
Number of pages11
JournalDiabetologia
Volume46
Issue number9
DOIs
Publication statusPublished - 2003

Fingerprint

Phosphodiesterase 3 Inhibitors
Cyclic Nucleotides
Phosphoric Diester Hydrolases
Islets of Langerhans
Insulin
Glucose
Cyclic AMP
Inbred NOD Mouse
Cyclic GMP
Insulin-Secreting Cells
Leptin
Insulin-Like Growth Factor I
Hypoglycemia
Adipocytes
Insulin Resistance
Adipose Tissue
Cell Differentiation
Hepatocytes
Cell Survival
Nitric Oxide

Keywords

  • 3',5'-Cyclic-AMP Phosphodiesterases
  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Animals
  • Cyclic AMP
  • Cyclic GMP
  • Cyclic Nucleotide Phosphodiesterases, Type 1
  • Humans
  • Islets of Langerhans
  • Isoenzymes

Cite this

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title = "Cyclic nucleotide phosphodiesterases in pancreatic islets",
abstract = "Cyclic nucleotide phosphodiesterases (PDEs) comprise a family of enzymes (PDE1-PDE11) which hydrolyse cyclic AMP and cyclic GMP to their biologically inactive 5' derivatives. Cyclic AMP is an important physiological amplifier of glucose-induced insulin secretion. As PDEs are the only known mechanism for inactivating cyclic nucleotides, it is important to characterise the PDEs present in the pancreatic islet beta cells. Several studies have shown pancreatic islets or beta cells to contain PDE1C, PDE3B and PDE4, with some evidence for PDE10A. Most evidence suggests that PDE3B is the most important in relation to the regulation of insulin release, although PDE1C could have a role. PDE3-selective inhibitors augment glucose-induced insulin secretion. In contrast, activation of beta-cell PDE3B could mediate the inhibitory effect of IGF-1 and leptin on insulin secretion. In vivo, although PDE3 inhibitors augment glucose-induced insulin secretion, concomitant inhibition of PDE3B in liver and adipose tissue induce insulin resistance and PDE3 inhibitors do not induce hypoglycaemia. The development of PDE3 inhibitors as anti-diabetic agents would require differentiation between PDE3B in the beta cell and that in hepatocytes and adipocytes. Through their effects in regulating beta-cell cyclic nucleotide concentrations, PDEs could modulate beta-cell growth, differentiation and survival; some work has shown that selective inhibition of PDE4 prevents diabetes in NOD mice and that selective PDE3 inhibition blocks cytokine-induced nitric oxide production in islet cells. Further work is required to understand the mechanism of regulation and role of the various PDEs in islet-cell function and to validate them as targets for drugs to treat and prevent diabetes.",
keywords = "3',5'-Cyclic-AMP Phosphodiesterases, 3',5'-Cyclic-GMP Phosphodiesterases, Animals, Cyclic AMP, Cyclic GMP, Cyclic Nucleotide Phosphodiesterases, Type 1, Humans, Islets of Langerhans, Isoenzymes",
author = "Pyne, {N J} and Furman, {B L}",
year = "2003",
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language = "English",
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}

Cyclic nucleotide phosphodiesterases in pancreatic islets. / Pyne, N J; Furman, B L.

In: Diabetologia, Vol. 46, No. 9, 2003, p. 1179-1189.

Research output: Contribution to journalLiterature review

TY - JOUR

T1 - Cyclic nucleotide phosphodiesterases in pancreatic islets

AU - Pyne, N J

AU - Furman, B L

PY - 2003

Y1 - 2003

N2 - Cyclic nucleotide phosphodiesterases (PDEs) comprise a family of enzymes (PDE1-PDE11) which hydrolyse cyclic AMP and cyclic GMP to their biologically inactive 5' derivatives. Cyclic AMP is an important physiological amplifier of glucose-induced insulin secretion. As PDEs are the only known mechanism for inactivating cyclic nucleotides, it is important to characterise the PDEs present in the pancreatic islet beta cells. Several studies have shown pancreatic islets or beta cells to contain PDE1C, PDE3B and PDE4, with some evidence for PDE10A. Most evidence suggests that PDE3B is the most important in relation to the regulation of insulin release, although PDE1C could have a role. PDE3-selective inhibitors augment glucose-induced insulin secretion. In contrast, activation of beta-cell PDE3B could mediate the inhibitory effect of IGF-1 and leptin on insulin secretion. In vivo, although PDE3 inhibitors augment glucose-induced insulin secretion, concomitant inhibition of PDE3B in liver and adipose tissue induce insulin resistance and PDE3 inhibitors do not induce hypoglycaemia. The development of PDE3 inhibitors as anti-diabetic agents would require differentiation between PDE3B in the beta cell and that in hepatocytes and adipocytes. Through their effects in regulating beta-cell cyclic nucleotide concentrations, PDEs could modulate beta-cell growth, differentiation and survival; some work has shown that selective inhibition of PDE4 prevents diabetes in NOD mice and that selective PDE3 inhibition blocks cytokine-induced nitric oxide production in islet cells. Further work is required to understand the mechanism of regulation and role of the various PDEs in islet-cell function and to validate them as targets for drugs to treat and prevent diabetes.

AB - Cyclic nucleotide phosphodiesterases (PDEs) comprise a family of enzymes (PDE1-PDE11) which hydrolyse cyclic AMP and cyclic GMP to their biologically inactive 5' derivatives. Cyclic AMP is an important physiological amplifier of glucose-induced insulin secretion. As PDEs are the only known mechanism for inactivating cyclic nucleotides, it is important to characterise the PDEs present in the pancreatic islet beta cells. Several studies have shown pancreatic islets or beta cells to contain PDE1C, PDE3B and PDE4, with some evidence for PDE10A. Most evidence suggests that PDE3B is the most important in relation to the regulation of insulin release, although PDE1C could have a role. PDE3-selective inhibitors augment glucose-induced insulin secretion. In contrast, activation of beta-cell PDE3B could mediate the inhibitory effect of IGF-1 and leptin on insulin secretion. In vivo, although PDE3 inhibitors augment glucose-induced insulin secretion, concomitant inhibition of PDE3B in liver and adipose tissue induce insulin resistance and PDE3 inhibitors do not induce hypoglycaemia. The development of PDE3 inhibitors as anti-diabetic agents would require differentiation between PDE3B in the beta cell and that in hepatocytes and adipocytes. Through their effects in regulating beta-cell cyclic nucleotide concentrations, PDEs could modulate beta-cell growth, differentiation and survival; some work has shown that selective inhibition of PDE4 prevents diabetes in NOD mice and that selective PDE3 inhibition blocks cytokine-induced nitric oxide production in islet cells. Further work is required to understand the mechanism of regulation and role of the various PDEs in islet-cell function and to validate them as targets for drugs to treat and prevent diabetes.

KW - 3',5'-Cyclic-AMP Phosphodiesterases

KW - 3',5'-Cyclic-GMP Phosphodiesterases

KW - Animals

KW - Cyclic AMP

KW - Cyclic GMP

KW - Cyclic Nucleotide Phosphodiesterases, Type 1

KW - Humans

KW - Islets of Langerhans

KW - Isoenzymes

UR - http://link.springer.com/journal/125

U2 - 10.1007/s00125-003-1176-7

DO - 10.1007/s00125-003-1176-7

M3 - Literature review

VL - 46

SP - 1179

EP - 1189

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 9

ER -