PDE-10A inhibitors as insulin secretagogues

Cantin, Louis‐David; Magnuson, Steven; Gunn, David; Barucci, Nicole; Breuhaus, Marina; Bullock, William H.; Burke, Jeanmarie R.; Claus, Thomas H.; Daly, Michelle; DeCarr, Lynn B.; Gore-Willse, Ann; Hoover-Litty, Helana; Kumarasinghe, E. Sathyajith; Li, Yaxin; Liang, Steve H. L.; Livingston, James N.; Lowinger, Timothy B.; MacDougall, Margit; Ogutu, Herbert; Olague, Alan; Ott-Morgan, Ronda; Schoenleber, Robert; Tersteegen, Adrian; Wickens, Philip L.; Zhang, Zhonghua; Zhu, Jian; Zhu, Lei; Sweet, Laurel J.

doi:10.1016/j.bmcl.2007.02.061

Cited by 32 publications

(18 citation statements)

References 8 publications

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“…Selective PDE10A inhibitors, such as SEP-39, are unlikely to produce the metabolic side effects seen with current antipsychotics, which are due to, in part, H1 antagonism. Furthermore, data in the literature suggest that PDE10A inhibitors protect against the effects of a high fat diet (Nawrocki et al, 2014) and may be insulinogenic (Cantin et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological evaluation of a novel phosphodiesterase 10A inhibitor in models of antipsychotic activity and cognition

Jones¹,

Hewitt²,

Campbell³

et al. 2015

Pharmacology Biochemistry and Behavior

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Section: Discussionmentioning

confidence: 99%

Pharmacological evaluation of a novel phosphodiesterase 10A inhibitor in models of antipsychotic activity and cognition

Jones¹,

Hewitt²,

Campbell³

et al. 2015

Pharmacology Biochemistry and Behavior

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“…However, whether PDE10A activity directly impacts metabolic parameters independently of CNS-mediated effects remains to be examined. PDE10A mRNA is expressed in pancreatic islet cells, and researchers have reported that small-molecule PDE10A inhibitors function as insulin secretagogues in vitro (31,32). Furthermore, Cantin et al (31) demonstrated that PDE10A inhibitors improved glucose tolerance and reduced insulin secretion in Wistar rats after a glucose challenge, suggesting that the effects of THPP-6 in DIO and HFD studies may be partly related to altered insulin secretion.…”

Section: Discussionmentioning

confidence: 99%

“…PDE10A mRNA is expressed in pancreatic islet cells, and researchers have reported that small-molecule PDE10A inhibitors function as insulin secretagogues in vitro (31,32). Furthermore, Cantin et al (31) demonstrated that PDE10A inhibitors improved glucose tolerance and reduced insulin secretion in Wistar rats after a glucose challenge, suggesting that the effects of THPP-6 in DIO and HFD studies may be partly related to altered insulin secretion. In this study, we examined the effects of THPP-6 on glucose-stimulated insulin release and showed that THPP-6 did not significantly affect glucosestimulated insulin release in isolated mouse islets (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Genetic Deletion and Pharmacological Inhibition of Phosphodiesterase 10A Protects Mice From Diet-Induced Obesity and Insulin Resistance

et al. 2013

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Phosphodiesterase 10A (PDE10A) is a novel therapeutic target for the treatment of schizophrenia. Here we report a novel role of PDE10A in the regulation of caloric intake and energy homeostasis. PDE10A-deficient mice are resistant to diet-induced obesity (DIO) and associated metabolic disturbances. Inhibition of weight gain is due to hypophagia after mice are fed a highly palatable diet rich in fats and sugar but not a standard diet. PDE10A deficiency produces a decrease in caloric intake without affecting meal frequency, daytime versus nighttime feeding behavior, or locomotor activity. We tested THPP-6, a small molecule PDE10A inhibitor, in DIO mice. THPP-6 treatment resulted in decreased food intake, body weight loss, and reduced adiposity at doses that produced antipsychotic efficacy in behavioral models. We show that PDE10A inhibition increased whole-body energy expenditure in DIO mice fed a Western-style diet, achieving weight loss and reducing adiposity beyond the extent seen with food restriction alone. Therefore, chronic THPP-6 treatment conferred improved insulin sensitivity and reversed hyperinsulinemia. These data demonstrate that PDE10A inhibition represents a novel antipsychotic target that may have additional metabolic benefits over current medications for schizophrenia by suppressing food intake, alleviating weight gain, and reducing the risk for the development of diabetes.

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“…More recently mRNAs for PDE1B-C, PDE2A, PDE3A-B, PDE4A-D, PDE5A, PDE8A-B, PDE9A, PDE10A and PDE11A as well as the proteins PDE3A-B, PDE4B and PDE8A have been detected in rodent pancreatic islets and β-cell lines [8], [10], [11], [13]. Of these PDEs, PDE8B and PDE10A have potential in the context of β-cell function, since diminished activity of PDE8B [13] as well as PDE10A inhibition [14] potentiated insulin secretion in response to glucose in rat pancreatic islets.…”

Section: Introductionmentioning

confidence: 99%

Expression and Regulation of Cyclic Nucleotide Phosphodiesterases in Human and Rat Pancreatic Islets

et al. 2010

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As shown by transgenic mouse models and by using phosphodiesterase 3 (PDE3) inhibitors, PDE3B has an important role in the regulation of insulin secretion in pancreatic β-cells. However, very little is known about the regulation of the enzyme. Here, we show that PDE3B is activated in response to high glucose, insulin and cAMP elevation in rat pancreatic islets and INS-1 (832/13) cells. Activation by glucose was not affected by the presence of diazoxide. PDE3B activation was coupled to an increase as well as a decrease in total phosphorylation of the enzyme. In addition to PDE3B, several other PDEs were detected in human pancreatic islets: PDE1, PDE3, PDE4C, PDE7A, PDE8A and PDE10A. We conclude that PDE3B is activated in response to agents relevant for β-cell function and that activation is linked to increased as well as decreased phosphorylation of the enzyme. Moreover, we conclude that several PDEs are present in human pancreatic islets.

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PDE-10A inhibitors as insulin secretagogues

Cited by 32 publications

References 8 publications

Pharmacological evaluation of a novel phosphodiesterase 10A inhibitor in models of antipsychotic activity and cognition

Pharmacological evaluation of a novel phosphodiesterase 10A inhibitor in models of antipsychotic activity and cognition

Genetic Deletion and Pharmacological Inhibition of Phosphodiesterase 10A Protects Mice From Diet-Induced Obesity and Insulin Resistance

Expression and Regulation of Cyclic Nucleotide Phosphodiesterases in Human and Rat Pancreatic Islets

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