title: Effect of phosphodiesterase inhibition on insulin resistance in obese individuals.
abstract: BACKGROUND
  Obesity is associated with cardiometabolic disease, including insulin resistance (IR) and diabetes. Cyclic guanosine monophosphate (cGMP) signaling affects energy balance, IR, and glucose metabolism in experimental models. We sought to examine effects of phosphodiesterase-5 inhibition with tadalafil on IR in a pilot study of obese nondiabetic individuals.
  
  
  RESULTS
  We conducted a randomized, double-blinded, placebo-controlled trial of adults age 18 to 50 years with obesity and elevated fasting insulin levels (≥10 μU/mL). Participants were randomized to tadalafil 20 mg daily or placebo for 3 months. Oral glucose tolerance tests were performed, and the effect of tadalafil on IR was examined. A total of 53 participants (mean age, 33 years; body mass index [BMI], 38 kg/m(2)) were analyzed, 25 randomized to tadalafil and 28 to placebo. In the overall sample, measures of IR did not differ between tadalafil and placebo groups at 3 months. However, in individuals with severe obesity (BMI ≥36.2 kg/m(2)), tadalafil use was associated with improved IR (homeostatic model assessment for IR), compared to placebo (P=0.02, respectively). Furthermore, one measure of β-cell compensation for IR (oral disposition index) improved with tadalafil in the overall sample (P=0.009) and in the subgroup with severe obesity (P=0.01).
  
  
  CONCLUSIONS
  Results of this pilot study did not show improvements in IR with tadalafil, compared to placebo. However, tadalafil may have favorable effects on β-cell compensation, particularly in individuals with severe obesity. Future studies evaluating the potential metabolic benefits of cGMP modulation in obesity are warranted.
  
  
  BACKGROUND
  ClinicalTrials.gov. Unique Identifier: NCT01444651.
authors.affiliation: Cardiovascular Medicine Section, Department of Medicine, Boston University School of Medicine, Boston, MA (J.E.H.).
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Ho
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL (P.A.).
authors.forename: Pankaj
authors.initials: P
authors.lastname: Arora
authors.affiliation: Diabetes Center, Massachusetts General Hospital, Boston, MA (G.A.W., J.C.F.).
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Walford
authors.affiliation: Department of Medicine, Mount Auburn Hospital, Cambridge, MA (A.G.).
authors.forename: Anahita
authors.initials: A
authors.lastname: Ghorbani
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Boston, MA (D.P.G.).
authors.forename: Derek P
authors.initials: DP
authors.lastname: Guanaga
authors.affiliation: Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA (B.P.D., C.N.C., G.D.L.).
authors.forename: Bishnu P
authors.initials: BP
authors.lastname: Dhakal
authors.affiliation: Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA (D.I.N., E.S.B.).
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Nathan
authors.affiliation: Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA (D.I.N., E.S.B.).
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Buys
authors.affiliation: Diabetes Center, Massachusetts General Hospital, Boston, MA (G.A.W., J.C.F.) Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA (J.C.F.).
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
authors.affiliation: Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA (B.P.D., C.N.C., G.D.L.) Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA (C.N.C.) Broad Institute of Harvard and MIT, Cambridge, MA (C.N.C.).
authors.forename: Christopher
authors.initials: C
authors.lastname: Newton-Cheh
authors.affiliation: Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA (B.P.D., C.N.C., G.D.L.).
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Lewis
authors.affiliation: Cardiovascular Medicine Division, Department of Medicine, Vanderbilt University, Nashville, TN (T.J.W.).
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wang
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D015992:Body Mass Index; D001900:Boston; D002243:Carbolines / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000097:blood / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology; D058986:Phosphodiesterase 5 Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D010865:Pilot Projects; D012720:Severity of Illness Index; D000068581:Tadalafil; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D002243:Carbolines; D007328:Insulin; D058986:Phosphodiesterase 5 Inhibitors; D000068581:Tadalafil
keywords: cGMP; insulin resistance; obesity; phosphodiesterase type 5 inhibition