Effect of phosphodiesterase inhibition on insulin resistance in obese individuals

Jennifer E Ho, Pankaj Arora, Geoffrey A Walford, Anahita Ghorbani, Derek P Guanaga, Bishnu P Dhakal, Daniel I Nathan, Emmanuel S Buys, Jose C Florez, Christopher Newton-Cheh, Gregory D Lewis, Thomas J Wang, Jennifer E Ho, Pankaj Arora, Geoffrey A Walford, Anahita Ghorbani, Derek P Guanaga, Bishnu P Dhakal, Daniel I Nathan, Emmanuel S Buys, Jose C Florez, Christopher Newton-Cheh, Gregory D Lewis, Thomas J Wang

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.

Methods and 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).

Conclusion: 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.

Clinical trial registration url: ClinicalTrials.gov. Unique Identifier: NCT01444651.

Keywords: cGMP; insulin resistance; obesity; phosphodiesterase type 5 inhibition.

© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1.
Figure 1.
Participant recruitment, screening, and randomization chart.
Figure 2.
Figure 2.
Change in HOMA‐IR and oral disposition index after 3 months of treatment with tadalafil vs placebo groups. Data represent means±standard deviations. HOMA‐IR indicates homeostatic model of insulin resistance, ODI indicates oral disposition index..

References

    1. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Magid D, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER, Moy CS, Mussolino ME, Nichol G, Paynter NP, Schreiner PJ, Sorlie PD, Stein J, Turan TN, Virani SS, Wong ND, Woo D, Turner MB. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation. 2013; 127:e6-e245.
    1. Fox CS, Pencina MJ, Meigs JB, Vasan RS, Levitzky YS, D'Agostino RB., Sr Trends in the incidence of type 2 diabetes mellitus from the 1970s to the 1990s: the Framingham Heart Study. Circulation. 2006; 113:2914-2918.
    1. Wang TJ, Larson MG, Keyes MJ, Levy D, Benjamin EJ, Vasan RS. Association of plasma natriuretic peptide levels with metabolic risk factors in ambulatory individuals. Circulation. 2007; 115:1345-1353.
    1. Sengenes C, Berlan M, De Glisezinski I, Lafontan M, Galitzky J. Natriuretic peptides: a new lipolytic pathway in human adipocytes. FASEB J. 2000; 14:1345-1351.
    1. Cheng S, Fox CS, Larson MG, Massaro JM, McCabe EL, Khan AM, Levy D, Hoffmann U, O'Donnell CJ, Miller KK, Newton‐Cheh C, Coviello AD, Bhasin S, Vasan RS, Wang TJ. Relation of visceral adiposity to circulating natriuretic peptides in ambulatory individuals. Am J Cardiol. 2011; 108:979-984.
    1. Miyashita K, Itoh H, Tsujimoto H, Tamura N, Fukunaga Y, Sone M, Yamahara K, Taura D, Inuzuka M, Sonoyama T, Nakao K. Natriuretic peptides/cGMP/cGMP‐dependent protein kinase cascades promote muscle mitochondrial biogenesis and prevent obesity. Diabetes. 2009; 58:2880-2892.
    1. Duplain H, Burcelin R, Sartori C, Cook S, Egli M, Lepori M, Vollenweider P, Pedrazzini T, Nicod P, Thorens B, Scherrer U. Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase. Circulation. 2001; 104:342-345.
    1. Young ME, Leighton B. Evidence for altered sensitivity of the nitric oxide/cGMP signalling cascade in insulin‐resistant skeletal muscle. Biochem J. 1998; 329Pt 1:73-79.
    1. Ayala JE, Bracy DP, Julien BM, Rottman JN, Fueger PT, Wasserman DH. Chronic treatment with sildenafil improves energy balance and insulin action in high fat‐fed conscious mice. Diabetes. 2007; 56:1025-1033.
    1. Hill KD, Eckhauser AW, Marney A, Brown NJ. Phosphodiesterase 5 inhibition improves beta‐cell function in metabolic syndrome. Diabetes Care. 2009; 32:857-859.
    1. Forgue ST, Patterson BE, Bedding AW, Payne CD, Phillips DL, Wrishko RE, Mitchell MI. Tadalafil pharmacokinetics in healthy subjects. Br J Clin Pharmacol. 2006; 61:280-288.
    1. Manley SE, Stratton IM, Clark PM, Luzio SD. Comparison of 11 human insulin assays: implications for clinical investigation and research. Clin Chem. 2007; 53:922-932.
    1. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta‐cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985; 28:412-419.
    1. Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999; 22:1462-1470.
    1. Yoneda H, Ikegami H, Yamamoto Y, Yamato E, Cha T, Kawaguchi Y, Tahara Y, Ogihara T. Analysis of early‐phase insulin responses in nonobese subjects with mild glucose intolerance. Diabetes Care. 1992; 15:1517-1521.
    1. Utzschneider KM, Prigeon RL, Faulenbach MV, Tong J, Carr DB, Boyko EJ, Leonetti DL, McNeely MJ, Fujimoto WY, Kahn SE. Oral disposition index predicts the development of future diabetes above and beyond fasting and 2‐h glucose levels. Diabetes Care. 2009; 32:335-341.
    1. Kim JY, Coletta DK, Mandarino LJ, Shaibi GQ. Glucose response curve and type 2 diabetes risk in Latino adolescents. Diabetes Care. 2012; 35:1925-1930.
    1. Bonetti PO, Pumper GM, Higano ST, Holmes DR, Kuvin JT, Lerman A. Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol. 2004; 44:2137-2141.
    1. Wilkinson IB, MacCallum H, Flint L, Cockcroft JR, Newby DE, Webb DJ. The influence of heart rate on augmentation index and central arterial pressure in humans. J Physiol. 2000; 525Pt 1:263-270.
    1. Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, Schwartz MW, Neifing JL, Ward WK, Beard JC, Palmer JP, Porte D Jr. Quantification of the relationship between insulin sensitivity and beta‐cell function in human subjects. Evidence for a hyperbolic function. Diabetes. 1993; 42:1663-1672.
    1. Xiang AH, Wang C, Peters RK, Trigo E, Kjos SL, Buchanan TA. Coordinate changes in plasma glucose and pancreatic beta‐cell function in Latino women at high risk for type 2 diabetes. Diabetes. 2006; 55:1074-1079.
    1. Rizzo NO, Maloney E, Pham M, Luttrell I, Wessells H, Tateya S, Daum G, Handa P, Schwartz MW, Kim F. Reduced NO‐cGMP signaling contributes to vascular inflammation and insulin resistance induced by high‐fat feeding. Arterioscler Thromb Vasc Biol. 2010; 30:758-765.
    1. Baron AD, Zhu JS, Marshall S, Irsula O, Brechtel G, Keech C. Insulin resistance after hypertension induced by the nitric oxide synthesis inhibitor L‐NMMA in rats. Am J Physiol. 1995; 269:E709-E715.
    1. Smukler SR, Tang L, Wheeler MB, Salapatek AM. Exogenous nitric oxide and endogenous glucose‐stimulated beta‐cell nitric oxide augment insulin release. Diabetes. 2002; 51:3450-3460.
    1. Laakso M, Edelman SV, Brechtel G, Baron AD. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance. J Clin Invest. 1990; 85:1844-1852.
    1. Baron AD, Tarshoby M, Hook G, Lazaridis EN, Cronin J, Johnson A, Steinberg HO. Interaction between insulin sensitivity and muscle perfusion on glucose uptake in human skeletal muscle: evidence for capillary recruitment. Diabetes. 2000; 49:768-774.
    1. Kapur S, Bedard S, Marcotte B, Cote CH, Marette A. Expression of nitric oxide synthase in skeletal muscle: a novel role for nitric oxide as a modulator of insulin action. Diabetes. 1997; 46:1691-1700.
    1. Stumvoll M, Van Haeften T, Fritsche A, Gerich J. Oral glucose tolerance test indexes for insulin sensitivity and secretion based on various availabilities of sampling times. Diabetes Care. 2001; 24:796-797.

Source: PubMed

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