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2000
Volume 5, Issue 1
  • ISSN: 0250-6882
  • E-ISSN: 0250-6882

Abstract

Phosphodiesterase inhibitors (PDEIs) have emerged as potential agents in managing diabetes, offering novel avenues for therapeutic intervention. This comprehensive review explores the diverse mechanisms, clinical applications, and the evolving landscape of phosphodiesterase inhibitors in the context of diabetes mellitus. The molecular mechanisms underlying the impact of PDEIs on diabetes form a cornerstone of this review. PDEs, a family of enzymes that regulate cyclic nucleotide levels, play a crucial role in intracellular signaling cascades. Understanding these intricate mechanisms is essential for unraveling the therapeutic potential of PDEIs in diabetes. Clinical applications of PDEIs in diabetes management are explored, highlighting their multifaceted roles. The review discusses pivotal preclinical and clinical studies that showcase the efficacy of PDEIs in lowering hyperglycemia, enhancing lipid profiles, and averting diabetic sequelae such as neuropathy and nephropathy. Moreover, synergistic effects have been shown in combination therapy, including PDEIs and already available antidiabetic drugs, improving overall therapeutic effectiveness. Recent studies have unveiled new PDE targets and refined inhibitor designs, contributing to the continuous evolution of this therapeutic approach. Despite these advancements, issues with patient-specific responses, dose optimization, and long-term safety still exist. The necessity of further study into PDEIs, particularly their role in customized medicine for the treatment of diabetes, is emphasized in the review's conclusion. The creation of next-generation PDE inhibitors with higher metabolic benefits, fewer side effects, and better selectivity is one of the future goals.

Furthermore, the review delves into the prospects of PDEIs in diabetes management. It explores emerging technologies, such as targeted drug delivery systems and precision medicine, that aim to enhance the therapeutic efficacy of PDEIs while minimizing adverse effects. The potential role of PDEIs in addressing specific diabetes subtypes and complications, including diabetic neuropathy and cardiovascular complications, is also contemplated.

© 2024 The Author(s). Published by Bentham Science Publishers. This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
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2025-09-30
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References

  1. MezilS.A. AbedB.A. Complication of diabetes mellitus.Ann. Rom. Soc. Cell Biol.202115461556
    [Google Scholar]
  2. ZhangY. LazzariniP.A. McPhailS.M. van NettenJ.J. ArmstrongD.G. PacellaR.E. Global disability burdens of diabetes-related lower-extremity complications in 1990 and 2016.Diabetes Care202043596497410.2337/dc19‑161432139380
    [Google Scholar]
  3. JohnS. Complication in diabetic nephropathy.Diabetes Metab. Syndr.201610424724910.1016/j.dsx.2016.06.00527389078
    [Google Scholar]
  4. MouradN.I. NenquinM. HenquinJ.C. cAMP-mediated and metabolic amplification of insulin secretion are distinct pathways sharing independence of β-cell microfilaments.Endocrinology2012153104644465410.1210/en.2012‑145022948217
    [Google Scholar]
  5. StraubS.G. SharpG.W.G. Hypothesis: One rate-limiting step controls the magnitude of both phases of glucose-stimulated insulin secretion.Am. J. Physiol. Cell Physiol.20042873C565C57110.1152/ajpcell.00079.200415308461
    [Google Scholar]
  6. HenquinJ.C. Regulation of insulin secretion: A matter of phase control and amplitude modulation.Diabetologia200952573975110.1007/s00125‑009‑1314‑y19288076
    [Google Scholar]
  7. TengholmA. Cyclic AMP dynamics in the pancreatic β-cell.Ups. J. Med. Sci.2012117435536910.3109/03009734.2012.72473222970724
    [Google Scholar]
  8. HellmanB. Pulsatility of insulin release – A clinically important phenomenon.Ups. J. Med. Sci.2009114419320510.3109/0300973090336607519961265
    [Google Scholar]
  9. RenströmE. EliassonL. RorsmanP. Protein kinase A-dependent and -Independent stimulation of exocytosis by cAMP in mouse pancreatic B-cells.J. Physiol.1997502110511810.1111/j.1469‑7793.1997.105bl.x9234200
    [Google Scholar]
  10. HärndahlL. JingX.J. IvarssonR. DegermanE. AhrénB. ManganielloV.C. RenströmE. HolstL.S. Important role of phosphodiesterase 3B for the stimulatory action of cAMP on pancreatic β-cell exocytosis and release of insulin.J. Biol. Chem.200227740374463745510.1074/jbc.M20540120012169692
    [Google Scholar]
  11. OwenD.R. PanditJ. DaroutE. Menhaji-KlotzE. ChappieT.A. VerhoestP. PollastriM.P. BellA.S. LirasS. Phosphodiesterases and Their Inhibitors.Wiley-VCH2014
    [Google Scholar]
  12. AmsallemE. KasparianC. HaddourG. BoisselJ.P. NonyP. Phosphodiesterase III inhibitors for heart failure.Cochrane Database Syst. Rev.200520051CD00223015674893
    [Google Scholar]
  13. DohertyA.M. Phosphodiesterase 4 inhibitors as novel anti-inflammatory agents.Curr. Opin. Chem. Biol.19993446647310.1016/S1367‑5931(99)80068‑410419856
    [Google Scholar]
  14. HuangZ. DucharmeY. MacdonaldD. RobichaudA. The next generation of PDE4 inhibitors.Curr. Opin. Chem. Biol.20015443243810.1016/S1367‑5931(00)00224‑611470607
    [Google Scholar]
  15. MilaniE. NikfarS. KhorasaniR. ZamaniM.J. AbdollahiM. Reduction of diabetes-induced oxidative stress by phosphodiesterase inhibitors in rats.Comp. Biochem. Physiol. C Toxicol. Pharmacol.2005140225125510.1016/j.cca.2005.02.01015907769
    [Google Scholar]
  16. ThapaK. SinghT.G. KaurA. Cyclic nucleotide phosphodiesterase inhibition as a potential therapeutic target in renal ischemia reperfusion injury.Life Sci.202128211984310.1016/j.lfs.2021.11984334298037
    [Google Scholar]
  17. Rahnama’iM.S. ÜckertS. HohnenR. van KoeveringeG.A. The role of phosphodiesterases in bladder pathophysiology.Nat. Rev. Urol.201310741442410.1038/nrurol.2013.10123670184
    [Google Scholar]
  18. DumanR. S. NestlerE. J. Cyclic Nucleotides.Basic Neurochemistry: Molecular, Cellular and Medical AspectsLippincott-RavenPhiladelphia1999
    [Google Scholar]
  19. AroraK. SinhaC. ZhangW. RenA. MoonC.S. YarlagaddaS. NarenA.P. Compartmentalization of cyclic nucleotide signaling: A question of when, where, and why?Pflugers Arch.2013465101397140710.1007/s00424‑013‑1280‑623604972
    [Google Scholar]
  20. PyneN.J. FurmanB.L. Cyclic nucleotide phosphodiesterases in pancreatic islets.Diabetologia20034691179118910.1007/s00125‑003‑1176‑712904862
    [Google Scholar]
  21. WaddletonD. WuW. FengY. ThompsonC. WuM. ZhouY.P. HowardA. ThornberryN. LiJ. ManciniJ.A. Phosphodiesterase 3 and 4 comprise the major cAMP metabolizing enzymes responsible for insulin secretion in INS-1 (832/13) cells and rat islets.Biochem. Pharmacol.200876788489310.1016/j.bcp.2008.07.02518706893
    [Google Scholar]
  22. XieT. ChenM. ZhangQ.H. MaZ. WeinsteinL.S. β cell-specific deficiency of the stimulatory G protein α-subunit G s α leads to reduced β cell mass and insulin-deficient diabetes.Proc. Natl. Acad. Sci. USA200710449196011960610.1073/pnas.070479610418029451
    [Google Scholar]
  23. SchwenkgrubJ. ZarembaM. Joniec-MaciejakI. CudnaA. Mirowska-GuzelD. Kurkowska-JastrzębskaI. The phosphodiesterase inhibitor, ibudilast, attenuates neuroinflammation in the MPTP model of parkinson’s disease.PLoS One2017127e018201910.1371/journal.pone.018201928753652
    [Google Scholar]
  24. PatraC. FosterK. CorleyJ. E. DimriM. BradyM. F. Biochemistry, Cyclic GMP.StatPearlsTreasure Island (FL)2018
    [Google Scholar]
  25. PasmanterN. IheanachoF. HashmiM.F. Biochemistry.Cyclic GMP2019
    [Google Scholar]
  26. OokawaraM. NioY. Phosphodiesterase 4 inhibitors in diabetic nephropathy.Cell. Signal.20229011018510.1016/j.cellsig.2021.11018534785349
    [Google Scholar]
  27. DhaliwalA. GuptaM. PDE5 inhibitors.StatPearls Publishing2023
    [Google Scholar]
  28. SinghV. A comprehensive study on the impact of yoga on diabetes.2022
    [Google Scholar]
  29. MZBanday Pathophysiology of diabetes: An overview.Avicenna J Med2020104174188
    [Google Scholar]
  30. PihokerC. GilliamL.K. HampeC.S. LernmarkÅ. Autoantibodies in diabetes.Diabetes200554Suppl. 2S52S6110.2337/diabetes.54.suppl_2.S5216306341
    [Google Scholar]
  31. AtkinsonM.A. EisenbarthG.S. Type 1 diabetes: New perspectives on disease pathogenesis and treatment.Lancet2001358927722122910.1016/S0140‑6736(01)05415‑011476858
    [Google Scholar]
  32. SkylerJ.S. BakrisG.L. BonifacioE. DarsowT. EckelR.H. GroopL. GroopP.H. HandelsmanY. InselR.A. MathieuC. McElvaineA.T. PalmerJ.P. PuglieseA. SchatzD.A. SosenkoJ.M. WildingJ.P.H. RatnerR.E. Differentiation of diabetes by pathophysiology, natural history, and prognosis.Diabetes201766224125510.2337/db16‑080627980006
    [Google Scholar]
  33. DeFronzoR.A. The triumvirate: β-cell, muscle, liver. A collusion responsible for NIDDM.Diabetes198837666768710.2337/diab.37.6.6673289989
    [Google Scholar]
  34. DEFRONZO Pathogenesis of type2 daiabetes: Metabolic and molecular implications for identhfying diabetes genes.Diabetes Rev.19975177269
    [Google Scholar]
  35. DeFronzoR.A. Pathogenesis of type 2 diabetes mellitus.Med. Clin. North Am.2004884787835, ix10.1016/j.mcna.2004.04.01315308380
    [Google Scholar]
  36. Abdul-GhaniM.A. DeFronzoR.A. Mitochondrial dysfunction, insulin resistance, and type 2 diabetes mellitus.Curr. Diab. Rep.20088317317810.1007/s11892‑008‑0030‑118625112
    [Google Scholar]
  37. BanerjiM.A. LebovitzH.E. Insulin action in black Americans with NIDDM.Diabetes Care199215101295130210.2337/diacare.15.10.12951425092
    [Google Scholar]
  38. MiyazakiY. MahankaliA. MatsudaM. MahankaliS. HardiesJ. CusiK. MandarinoL.J. DeFronzoR.A. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients.J. Clin. Endocrinol. Metab.20028762784279110.1210/jcem.87.6.856712050251
    [Google Scholar]
  39. CersosimoE. DeFronzoR.A. Insulin resistance and endothelial dysfunction: The road map to cardiovascular diseases.Diabetes Metab. Res. Rev.200622642343610.1002/dmrr.63416506274
    [Google Scholar]
  40. ReavenG.M. Banting lecture 1988. Role of insulin resistance in human disease.Diabetes198837121595160710.2337/diab.37.12.15953056758
    [Google Scholar]
  41. DeFronzoR.A. FerranniniE. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease.Diabetes Care199114317319410.2337/diacare.14.3.1732044434
    [Google Scholar]
  42. DeSistoC. L. KimS. Y. SharmaA. J. Prevalence estimates of gestational diabetes mellitus in the United States, pregnancy risk assessment monitoring system (PRAMS), 2007-2010.Prev Chronic Dis201411E104
    [Google Scholar]
  43. BhattamisraS.K. SiangT.C. RongC.Y. AnnanN.C. SeanE.H.Y. XiL.W. LynO.S. ShanL.H. ChoudhuryH. PandeyM. GorainB. Type-3c diabetes mellitus, diabetes of exocrine pancreas-an update.Curr. Diabetes Rev.201915538239410.2174/157339981566619011514570230648511
    [Google Scholar]
  44. NaikR.G. PalmerJ.P. Latent autoimmune diabetes in adults (LADA).Rev. Endocr. Metab. Disord.20034323324110.1023/A:102514821158714501174
    [Google Scholar]
  45. Aguilar-BryanL. BryanJ. Neonatal diabetes mellitus.Endocr. Rev.200829326529110.1210/er.2007‑002918436707
    [Google Scholar]
  46. TattersallR. Brittle diabetes.BMJ1985291649555555710.1136/bmj.291.6495.5553929870
    [Google Scholar]
  47. HaakT. GölzS. FritscheA. FüchtenbuschM. SiegmundT. SchnellbächerE. DroßelD. Therapy of type 1 diabetes.Exp. Clin. Endocrinol. Diabetes2019127S 01S27S38
    [Google Scholar]
  48. RojasJ. BermudezV. PalmarJ. MartínezM.S. OlivarL.C. NavaM. TomeyD. RojasM. SalazarJ. GaricanoC. VelascoM. Pancreatic beta cell death: Novel potential mechanisms in diabetes therapy.J. Diabetes Res.2018201811910.1155/2018/960180129670917
    [Google Scholar]
  49. MalikA. MoryaR.K. BhadadaS.K. RanaS. Type 1 diabetes mellitus: Complex interplay of oxidative stress, cytokines, gastrointestinal motility and small intestinal bacterial overgrowth.Eur. J. Clin. Invest.20184811e1302110.1111/eci.1302130155878
    [Google Scholar]
  50. CnopM. WelshN. JonasJ.C. JörnsA. LenzenS. EizirikD.L. Mechanisms of pancreatic β-cell death in type 1 and type 2 diabetes: Many differences, few similarities.Diabetes200554Suppl. 2S97S10710.2337/diabetes.54.suppl_2.S9716306347
    [Google Scholar]
  51. SounessJ.E. AldousD. SargentC. Immunosuppressive and anti-inflammatory effects of cyclic AMP phosphodiesterase (PDE) type 4 inhibitors.Immunopharmacology2000472-312716210.1016/S0162‑3109(00)00185‑510878287
    [Google Scholar]
  52. AgrawalN. MaitiR. DashD. PandeyB. Cilostazol reduces inflammatory burden and oxidative stress in hypertensive type 2 diabetes mellitus patients.Pharmacol. Res.200756211812310.1016/j.phrs.2007.04.00717548203
    [Google Scholar]
  53. MillerM. Phosphodiesterase inhibition in the treatment of autoimmune and inflammatory diseases: Current status and potential.J. Receptor Ligand Channel Res.2014193010.2147/JRLCR.S50401
    [Google Scholar]
  54. ByunH.R. ChoiJ.A. KohJ.Y. The role of metallothionein-3 in streptozotocin-induced beta-islet cell death and diabetes in mice.Metallomics2014691748175710.1039/C4MT00143E25054451
    [Google Scholar]
  55. BeshayE. Prud’hommeG.J. Inhibitors of phosphodiesterase isoforms III or IV suppress islet-cell nitric oxide production.Lab. Invest.20018181109111710.1038/labinvest.378032311502862
    [Google Scholar]
  56. PetersenM.C. ShulmanG.I. Mechanisms of insulin action and insulin resistance.Physiol. Rev.20189842133222310.1152/physrev.00063.201730067154
    [Google Scholar]
  57. KahnS.E. HullR.L. UtzschneiderK.M. Mechanisms linking obesity to insulin resistance and type 2 diabetes.Nature2006444712184084610.1038/nature0548217167471
    [Google Scholar]
  58. HillK.D. EckhauserA.W. MarneyA. BrownN.J. Phosphodiesterase 5 inhibition improves β-cell function in metabolic syndrome.Diabetes Care200932585785910.2337/dc08‑186219196886
    [Google Scholar]
  59. AamodtK.I. AramandlaR. BrownJ.J. Fiaschi-TaeschN. WangP. StewartA.F. BrissovaM. PowersA.C. Development of a reliable automated screening system to identify small molecules and biologics that promote human β-cell regeneration.Am. J. Physiol. Endocrinol. Metab.20163115E859E86810.1152/ajpendo.00515.201527624103
    [Google Scholar]
  60. ErukainureO.L. IjomoneO.M. OyebodeO.A. ChukwumaC.I. AschnerM. IslamM.S. Hyperglycemia-induced oxidative brain injury: Therapeutic effects of Cola nitida infusion against redox imbalance, cerebellar neuronal insults, and upregulated Nrf2 expression in type 2 diabetic rats.Food Chem. Toxicol.201912720621710.1016/j.fct.2019.03.04430914353
    [Google Scholar]
  61. WangJ. WangH. Oxidative stress in pancreatic beta cell regeneration.Oxid. Med. Cell. Longev.201720171193026110.1155/2017/193026128845211
    [Google Scholar]
  62. MuhammedS.J. LundquistI. SalehiA. Pancreatic β-cell dysfunction, expression of iNOS and the effect of phosphodiesterase inhibitors in human pancreatic islets of type 2 diabetes.Diabetes Obes. Metab.201214111010101910.1111/j.1463‑1326.2012.01632.x22687049
    [Google Scholar]
  63. Boswell-SmithV. SpinaD. PageC.P. Phosphodiesterase inhibitors.Br. J. Pharmacol.2006147Suppl 1Suppl. 1S252S25716402111
    [Google Scholar]
  64. AversaA. Systemic and metabolic effects of PDE5-inhibitor drugs.World J. Diabetes2010113710.4239/wjd.v1.i1.321537421
    [Google Scholar]
  65. SandnerP. From molecules to patients: Exploring the therapeutic role of soluble guanylate cyclase stimulators.Biol. Chem.2018399767969010.1515/hsz‑2018‑015529604206
    [Google Scholar]
  66. MaramponF. AntinozziC. CorinaldesiC. VannelliG.B. SarchielliE. MigliaccioS. Di LuigiL. LenziA. CrescioliC. The phosphodiesterase 5 inhibitor tadalafil regulates lipidic homeostasis in human skeletal muscle cell metabolism.Endocrine201859360261310.1007/s12020‑017‑1378‑228786077
    [Google Scholar]
  67. AversaA. FittipaldiS. FrancomanoD. BimonteV.M. GrecoE.A. CrescioliC. Di LuigiL. LenziA. MigliaccioS. Tadalafil improves lean mass and endothelial function in nonobese men with mild ED/LUTS: in vivo and in vitro characterization.Endocrine201756363964810.1007/s12020‑016‑1208‑y28133708
    [Google Scholar]
  68. SantiD. LocasoM. GranataA.R. TrentiT. RoliL. PacchioniC. RochiraV. CaraniC. SimoniM. Could chronic Vardenafil administration influence the cardiovascular risk in men with type 2 diabetes mellitus?PLoS One2018136e019929910.1371/journal.pone.019929929953477
    [Google Scholar]
  69. AntinozziC. SgròP. Di LuigiL. Advantages of phosphodiesterase type 5 inhibitors in the management of glucose metabolism disorders: A clinical and translational issue.Int. J. Endocrinol.202020201810.1155/2020/707810832774364
    [Google Scholar]
  70. HoJ.E. AroraP. WalfordG.A. GhorbaniA. GuanagaD.P. DhakalB.P. NathanD.I. BuysE.S. FlorezJ.C. Newton-ChehC. LewisG.D. WangT.J. Effect of phosphodiesterase inhibition on insulin resistance in obese individuals.J. Am. Heart Assoc.201435e00100110.1161/JAHA.114.00100125213566
    [Google Scholar]
  71. NyströmT. OrtsäterH. HuangZ. ZhangF. LarsenF.J. WeitzbergE. LundbergJ.O. SjöholmÅ. Inorganic nitrite stimulates pancreatic islet blood flow and insulin secretion.Free Radic. Biol. Med.20125351017102310.1016/j.freeradbiomed.2012.06.03122750508
    [Google Scholar]
  72. BergandiL. SilvagnoF. RussoI. RigantiC. AnfossiG. AldieriE. GhigoD. TrovatiM. BosiaA. Insulin stimulates glucose transport via nitric muscle cells.Arter. Thromb. Vasc Biol.2003232215222110.1161/01.ATV.0000107028.20478.8e14615391
    [Google Scholar]
  73. JohannK. ReisM.C. HarderL. HerrmannB. GachkarS. MittagJ. OelkrugR. Effects of sildenafil treatment on thermogenesis and glucose homeostasis in diet-induced obese mice.Nutr. Diabetes201881910.1038/s41387‑018‑0026‑029549244
    [Google Scholar]
  74. HolstJ.J. GromadaJ. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans.Am. J. Physiol. Endocrinol. Metab.20042872E199E20610.1152/ajpendo.00545.200315271645
    [Google Scholar]
  75. NichollsD.G. The pancreatic β-cell: A bioenergetic perspective.Physiol. Rev.20169641385144710.1152/physrev.00009.201627582250
    [Google Scholar]
  76. FrancisS.H. BlountM.A. CorbinJ.D. Mammalian cyclic nucleotide phosphodiesterases: Molecular mechanisms and physiological functions.Physiol. Rev.201191265169010.1152/physrev.00030.201021527734
    [Google Scholar]
  77. XieW. YeY. FengY. XuT. HuangS. ShenJ. LengY. Linderane suppresses hepatic gluconeogenesis by inhibiting the cAMP/PKA/CREB pathway through indirect activation of PDE 3 via ERK/STAT3.Front. Pharmacol.2018947610.3389/fphar.2018.0047629867482
    [Google Scholar]
  78. JohannsM. LaiY.C. HsuM.F. JacobsR. VertommenD. Van SandeJ. DumontJ.E. WoodsA. CarlingD. HueL. ViolletB. ForetzM. RiderM.H. AMPK antagonizes hepatic glucagon-stimulated cyclic AMP signalling via phosphorylation-induced activation of cyclic nucleotide phosphodiesterase 4B.Nat. Commun.2016711085610.1038/ncomms1085626952277
    [Google Scholar]
  79. MengS. CaoJ. HeQ. XiongL. ChangE. RadovickS. WondisfordF.E. HeL. Metformin activates AMP-activated protein kinase by promoting formation of the αβγ heterotrimeric complex.J. Biol. Chem.201529063793380210.1074/jbc.M114.60442125538235
    [Google Scholar]
  80. MillerR.A. ChuQ. XieJ. ForetzM. ViolletB. BirnbaumM.J. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP.Nature2013494743625626010.1038/nature1180823292513
    [Google Scholar]
  81. MurdoloG. SjöstrandM. StrindbergL. LönnrothP. JanssonP.A. The selective phosphodiesterase-5 inhibitor tadalafil induces microvascular and metabolic effects in type 2 diabetic postmenopausal females.J. Clin. Endocrinol. Metab.201398124525410.1210/jc.2012‑183023118430
    [Google Scholar]
  82. JanssonP.A. MurdoloG. SjögrenL. NyströmB. SjöstrandM. StrindbergL. LönnrothP. Tadalafil increases muscle capillary recruitment and forearm glucose uptake in women with type 2 diabetes.Diabetologia201053102205220810.1007/s00125‑010‑1819‑420535445
    [Google Scholar]
  83. MammiC. PastoreD. LombardoM.F. FerrelliF. CaprioM. ConsoliC. TesauroM. GattaL. FiniM. FedericiM. SbracciaP. DonadelG. BelliaA. RosanoG.M. FabbriA. LauroD. Sildenafil reduces insulin-resistance in human endothelial cells.PLoS One201161e1454210.1371/journal.pone.001454221297971
    [Google Scholar]
  84. ArmaniA. MarzollaV. RosanoG.M.C. FabbriA. CaprioM. Phosphodiesterase type 5 (PDE5) in the adipocyte: A novel player in fat metabolism?Trends Endocrinol. Metab.2011221040441110.1016/j.tem.2011.05.00421741267
    [Google Scholar]
  85. AyalaJ.E. BracyD.P. JulienB.M. RottmanJ.N. FuegerP.T. WassermanD.H. Chronic treatment with sildenafil improves energy balance and insulin action in high fat-fed conscious mice.Diabetes20075641025103310.2337/db06‑088317229936
    [Google Scholar]
  86. RamirezC.E. NianH. YuC. GamboaJ.L. LutherJ.M. BrownN.J. ShibaoC.A. Treatment with sildenafil improves insulin sensitivity in prediabetes: A randomized, controlled trial.J. Clin. Endocrinol. Metab.2015100124533454010.1210/jc.2015‑341526580240
    [Google Scholar]
  87. SantiD. GiannettaE. IsidoriA.M. VitaleC. AversaA. SimoniM. Therapy of endocrine disease: Effects of chronic use of phosphodiesterase inhibitors on endothelial markers in type 2 diabetes mellitus: A meta-analysis.Eur. J. Endocrinol.20151723R103R11410.1530/EJE‑14‑070025277671
    [Google Scholar]
  88. Phosphodiesterase inhibitors.2021Available from: https://my.clevelandclinic.org/health/treatments/23211-phosphodiesterase-inhibitors
  89. RabeK.F. WatzH. Chronic obstructive pulmonary disease.Lancet2017389100821931194010.1016/S0140‑6736(17)31222‑928513453
    [Google Scholar]
  90. PapiA. BrightlingC. PedersenS.E. ReddelH.K. Asthma.Lancet20183911012278380010.1016/S0140‑6736(17)33311‑129273246
    [Google Scholar]
  91. SpinaD. PageC. P. Xanthines and phosphodiesterase inhibitors.Handb Exp Pharmacol20172376391
    [Google Scholar]
  92. Cardiovascular diseases (CVDs).2022Available from: https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)
  93. SunB. LiH. ShakurY. HensleyJ. HockmanS. KambayashiJ. ManganielloV. LiuY. Role of phosphodiesterase type 3A and 3B in regulating platelet and cardiac function using subtype-selective knockout mice.Cell. Signal.20071981765177110.1016/j.cellsig.2007.03.01217482796
    [Google Scholar]
  94. BoehnckeW.H. SchönM.P. Psoriasis.Lancet2015386999798399410.1016/S0140‑6736(14)61909‑726025581
    [Google Scholar]
  95. TollefsonM.M. BrucknerA.L. CohenB.A. AntayaR. BrucknerA. HoriiK. SilverbergN.B. WrightT. Atopic dermatitis: Skin-directed management.Pediatrics20141346e1735e174410.1542/peds.2014‑281225422009
    [Google Scholar]
  96. LiH. ZuoJ. TangW. Phosphodiesterase-4 inhibitors for the treatment of inflammatory diseases.Front. Pharmacol.20189104810.3389/fphar.2018.0104830386231
    [Google Scholar]
  97. PataiZ. GuttmanA. MikusE.G. Potential L-type voltage–operated calcium channel blocking effect of drotaverine on functional models.J. Pharmacol. Exp. Ther.2016359344245110.1124/jpet.116.23727127738091
    [Google Scholar]
  98. AtikA. HardingR. De MatteoR. Kondos-DevcicD. CheongJ. DoyleL.W. TolcosM. Caffeine for apnea of prematurity: Effects on the developing brain.Neurotoxicology2017589410210.1016/j.neuro.2016.11.01227899304
    [Google Scholar]
  99. RundfeldtC. SocałaK. WlaźP. The atypical anxiolytic drug, tofisopam, selectively blocks phosphodiesterase isoenzymes and is active in the mouse model of negative symptoms of psychosis.J. Neural Transm.2010117111319132510.1007/s00702‑010‑0507‑320967473
    [Google Scholar]
  100. VardiM. NiniA. Phosphodiesterase inhibitors for erectile dysfunction in patients with diabetes mellitus.Cochrane Libr.200720091CD00218710.1002/14651858.CD002187.pub317253475
    [Google Scholar]
  101. KlonerR.A. Novel phosphodiesterase type 5 inhibitors: Assessing hemodynamic effects and safety parameters.Clin. Cardiol.200427S1Suppl. 1202510.1002/clc.496027130615115192
    [Google Scholar]
  102. SnyderG. L. VanoverK. E. PDE inhibitors for the treatment of schizophrenia.Adv Neurobiol201717385409
    [Google Scholar]
  103. ChenY. LiS. ZhongX. KangZ. ChenR. PDE-7 inhibitor BRL-50481 reduces neurodegeneration and long-term memory deficits in mice following sevoflurane exposure.ACS Chem. Neurosci.20201191353135810.1021/acschemneuro.0c0010632271540
    [Google Scholar]
  104. KimH.J. SongJ.Y. ParkT.I. ChoiW.S. KimJ.H. KwonO.S. LeeJ.Y. The effects of BRL-50481 on ovalbumin-induced asthmatic lung inflammation exacerbated by co-exposure to Asian sand dust in the murine model.Arch. Pharm. Res.2022451516210.1007/s12272‑021‑01367‑x34984603
    [Google Scholar]
  105. BaillieG.S. TejedaG.S. KellyM.P. Therapeutic targeting of 3′,5′-cyclic nucleotide phosphodiesterases: Inhibition and beyond.Nat. Rev. Drug Discov.2019181077079610.1038/s41573‑019‑0033‑431388135
    [Google Scholar]
  106. HalimiS. SchweizerA. MinicB. FoleyJ. DejagerS. Combination treatment in the management of type 2 diabetes: Focus on vildagliptin and metformin as a single tablet.Vasc. Health Risk Manag.20084348149218827867
    [Google Scholar]
  107. ZeynalooE. StoneL.D. DikiciE. RicordiC. DeoS.K. BachasL.G. DaunertS. LanzoniG. Delivery of therapeutic agents and cells to pancreatic islets: Towards a new era in the treatment of diabetes.Mol. Aspects Med.20228310106310.1016/j.mam.2021.10106334961627
    [Google Scholar]
  108. What is personalized medicine?.2023Available from: https://www.jax.org/personalized-medicine/precision-medicine-and-you/what-is-precision-medicine
  109. ShiY. LuA. WangX. BelhadjZ. WangJ. ZhangQ. A review of existing strategies for designing long-acting parenteral formulations: Focus on underlying mechanisms, and future perspectives.Acta Pharm. Sin. B20211182396241510.1016/j.apsb.2021.05.00234522592
    [Google Scholar]
  110. Ortiz-MartínezM. González-GonzálezM. MartagónA.J. HlavinkaV. WillsonR.C. Rito-PalomaresM. Recent developments in biomarkers for diagnosis and screening of Type 2 diabetes mellitus.Curr. Diab. Rep.20222239511510.1007/s11892‑022‑01453‑435267140
    [Google Scholar]
  111. HuangS. A. LieJ. D. Phosphodiesterase-5 (PDE5) inhibitors in the management of erectile dysfunction.P T2013387407419
    [Google Scholar]
  112. PoolsupN. SuksomboonN. AungN. Effect of phosphodiesterase-5 inhibitors on glycemic control in person with type 2 diabetes mellitus: A systematic review and meta-analysis.J. Clin. Transl. Endocrinol.20166505510.1016/j.jcte.2016.11.00329067241
    [Google Scholar]
  113. YanagawaH. NishiyaM. MiyamotoT. ShikishimaM. ImuraM. NakanishiR. AriuchiK. AkaishiA. TakaiS. AbeS. KisyukuM. KageyamaC. SatoC. YamagamiM. UrakawaN. SoneS. IraharaM. Clinical trials for drug approval: A pilot study of the view of doctors at Tokushima University hospital.J. Med. Invest.2006533-429229610.2152/jmi.53.29216953067
    [Google Scholar]
  114. PaterickT.E. PatelN. TajikA.J. ChandrasekaranK. Improving health outcomes through patient education and partnerships with patients.Proc. Bayl. Univ. Med. Cent.201730111211310.1080/08998280.2017.1192955228152110
    [Google Scholar]
  115. TiwariP. Recent trends in therapeutic approaches for diabetes management: A comprehensive update.J. Diabetes Res.2015201511110.1155/2015/34083826273667
    [Google Scholar]
  116. What are they, how do they work, what are they used for, and more.2020Available from: https://www.osmosis.org/answers/phosphodiesterase-inhibitors
  117. ThakurJ.S. ThakurS. SharmaD.R. MohindrooN.K. ThakurA. NegiP.C. Hearing loss with phosphodiesterase-5 inhibitors.Laryngoscope201312361527153010.1002/lary.2386523553123
    [Google Scholar]
  118. TsalamandrisS. AntonopoulosA.S. OikonomouE. PapamikroulisG.A. VogiatziG. PapaioannouS. DeftereosS. TousoulisD. The role of inflammation in diabetes: Current concepts and future perspectives.Eur. Cardiol.2019141505910.15420/ecr.2018.33.131131037
    [Google Scholar]
  119. RodenD.M. WilkeR.A. KroemerH.K. SteinC.M. Pharmacogenomics.Circulation2011123151661167010.1161/CIRCULATIONAHA.109.91482021502584
    [Google Scholar]
  120. AliT. RobertsD.N. TierneyW.M. Long-term safety concerns with proton pump inhibitors.Am. J. Med.20091221089690310.1016/j.amjmed.2009.04.01419786155
    [Google Scholar]
  121. DorcelyB. KatzK. JagannathanR. ChiangS.S. OluwadareB. GoldbergI.J. BergmanM. Novel biomarkers for prediabetes, diabetes, and associated complications.Diabetes Metab. Syndr. Obes.20171034536110.2147/DMSO.S10007428860833
    [Google Scholar]
  122. Standards of medical care in diabetes--2012Diabetes Care201235Suppl 1S11S63
    [Google Scholar]
  123. SankarV. SaaedY. JosephR. AziziH. ThomasP. Serious drug-drug interactions in the prescriptions of diabetic patients.Med. Sci. (Basel)2015349310310.3390/medsci304009329083394
    [Google Scholar]
  124. LaxminarayanR. ChowJ. Shahid-SallesS.A. Intervention cost-effectiveness: Overview of main messages.Disease Control Priorities in Developing Countries2nd ed2006
    [Google Scholar]
  125. KnottE. AssiM. RaoS. GhoshM. PearseD. Phosphodiesterase inhibitors as a therapeutic approach to neuroprotection and repair.Int. J. Mol. Sci.201718469610.3390/ijms1804069628338622
    [Google Scholar]
  126. KilanowskaA. ZiółkowskaA. Role of phosphodiesterase in the biology and pathology of diabetes.Int. J. Mol. Sci.20202121824410.3390/ijms2121824433153226
    [Google Scholar]
  127. NaithaniN. SinhaS. MisraP. VasudevanB. SahuR. Precision medicine: Concept and tools.Med J Armed Forces India2021773249257
    [Google Scholar]
  128. MateraM.G. OraJ. CavalliF. RoglianiP. CazzolaM. New avenues for phosphodiesterase inhibitors in asthma.J. Exp. Pharmacol.20211329130210.2147/JEP.S24296133758554
    [Google Scholar]
  129. LieblA. KhuntiK. Orozco-BeltranD. YaleJ.F. Health economic evaluation of type 2 diabetes mellitus: A clinical practice focused review.Clin. Med. Insights Endocrinol. Diabetes20158CMED.S2090610.4137/CMED.S2090625861233
    [Google Scholar]
  130. LosiS. BerraC.C.F. FornengoR. PitoccoD. BiricoltiG. Orsini FedericiM. The role of patient preferences in adherence to treatment in chronic disease: A narrative review.Drug Target Insights202115132010.33393/dti.2021.234234785884
    [Google Scholar]
  131. BhattJ. BathijaP. Ensuring access to quality health care in vulnerable communities.Acad. Med.20189391271127510.1097/ACM.000000000000225429697433
    [Google Scholar]
  132. ChatterjeeS. DaviesM.J. Current management of diabetes mellitus and future directions in care.Postgrad. Med. J.201591108161262110.1136/postgradmedj‑2014‑13320026453594
    [Google Scholar]
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