Early effects of roflumilast on insulin sensitivity in adults with prediabetes and overweight/obesity involve age-associated fat mass loss – results of an exploratory study
Ijeoma M Muo,1 Sandra D MacDonald,2 Ritu Madan,3 Sung-Jun Park,1 Ahmed M Gharib,4 Pedro E. Martinez,5 Mary F Walter,3 Shanna B Yang,6 Justin A Rodante,7 Amber B Courville,6 Peter J Walter,8 Hongyi Cai,8 Michael Glicksman,3 Gioia M Guerrieri,5 Rivka R Ben-Dor,9 Ronald Ouwerkerk,4 Stephanie Mao,1 Jay...
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Dove Medical Press
2019
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AMPK Incretins inflammation adiposity Specialties of internal medicine RC581-951 |
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AMPK Incretins inflammation adiposity Specialties of internal medicine RC581-951 Muo IM MacDonald SD Madan R Park SJ Gharib AM Martinez PE Walter MF Yang SB Rodante JA Courville AB Walter PJ Cai H Glicksman M Guerrieri GM Ben-Dor RR Ouwerkerk R Mao S Chung JH Early effects of roflumilast on insulin sensitivity in adults with prediabetes and overweight/obesity involve age-associated fat mass loss – results of an exploratory study |
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Ijeoma M Muo,1 Sandra D MacDonald,2 Ritu Madan,3 Sung-Jun Park,1 Ahmed M Gharib,4 Pedro E. Martinez,5 Mary F Walter,3 Shanna B Yang,6 Justin A Rodante,7 Amber B Courville,6 Peter J Walter,8 Hongyi Cai,8 Michael Glicksman,3 Gioia M Guerrieri,5 Rivka R Ben-Dor,9 Ronald Ouwerkerk,4 Stephanie Mao,1 Jay H Chung1 1Laboratory of Obesity and Aging Research NHLBI, National Institutes of Health, Bethesda, MD 20892, USA; 2NHLBI Pulmonary Branch, Laboratory of Chronic Airway Infections, National Institutes of Health, Bethesda, MD 20892, USA; 3Diabetes Endocrinology and Obesity Branch, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA; 4Biomedical and Metabolic Imaging Branch NIDDK, National Institutes of Health, Bethesda, MD 20892, USA; 5Section on Behavioral Endocrinology, NIMH, National Institutes of Health, Bethesda, MD 20892, USA; 6Clinical Center Nutrition Department, National Institutes of Health, Bethesda, MD 20892, USA; 7Laboratory of Inflammation and Cardiometabolic Diseases, NHLBI, National Institutes of Health, Bethesda, MD 20892, USA; 8Mass Spectrometry Clinical Core, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA; 9NIMH, National Institutes of Health, Bethesda, MD 20892, USA Purpose: Roflumilast (Daliresp, Daxas) is a FDA-approved phosphodiesterase 4 (PDE4) inhibitor for the treatment of moderate-to-severe chronic obstructive pulmonary disease. In mice and in limited human studies, this oral medication can cause weight loss and improve insulin sensitivity. We set out to determine the mechanism of its effect on insulin sensitivity. Patients and methods: Eight adults with overweight/obesity and prediabetes received roflumilast for 6 weeks. Before and after roflumilast, subjects underwent tests of insulin sensitivity, mixed meal test, body composition, markers of inflammation, and mitochondria function. Dietary intake and physical activity were also assessed. Our primary outcome was the change in peripheral insulin sensitivity, as assessed by the hyper-insulinemic euglycemic clamp. Results: This study was underpowered for the primary outcome. Pre- and post-roflumilast mean peripheral insulin sensitivity were 48.7 and 70.0 mg/g fat free mass/minute, respectively, (P-value=0.18), respectively. Among the mixed meal variables, roflumilast altered glucagon-like peptide 1 (GLP-1) hormone the most, although the average effect was not statistically significant (P=0.18). Roflumilast induced a trend toward significance in 1) decreased energy intake (from 11,095 KJ to 8,4555 KJ, P=0.07), 2) decreased fat mass (from 34.53 to 32.97 kg, P=0.06), 3) decreased total and LDL cholesterol (P=0.06 for both variables), and 4) increased plasma free fatty acids (from 0.40 to 0.50 mEq/L, P=0.09) The interval changes in adiposity and free fatty acid were significantly associated with the subject’s age (P-value range=<0.001 to 0.02 for the correlations). Inflammatory and adhesion markers, though unchanged, significantly correlated with one another and with incretin hormones only after roflumilast. Conclusion: We demonstrate, for the first time in humans, increasing percentage of fat mass loss from roflumilast with increasing age in adults with prediabetes and overweight/obesity. We also demonstrate novel associations among roflumilast-induced changes in incretin hormones, inflammatory markers, peripheral insulin sensitivity, and adiposity. We conclude that roflumilast’s early effects on insulin sensitivity is indirect and likely mediated through roflumilast’s prioritization of lipid over glucose handling.Clinical trials registration: NCT01862029. Keywords: phosphodiesterase 4, obesity, diabetes, inflammation, incretins, aging |
| format |
article |
| author |
Muo IM MacDonald SD Madan R Park SJ Gharib AM Martinez PE Walter MF Yang SB Rodante JA Courville AB Walter PJ Cai H Glicksman M Guerrieri GM Ben-Dor RR Ouwerkerk R Mao S Chung JH |
| author_facet |
Muo IM MacDonald SD Madan R Park SJ Gharib AM Martinez PE Walter MF Yang SB Rodante JA Courville AB Walter PJ Cai H Glicksman M Guerrieri GM Ben-Dor RR Ouwerkerk R Mao S Chung JH |
| author_sort |
Muo IM |
| title |
Early effects of roflumilast on insulin sensitivity in adults with prediabetes and overweight/obesity involve age-associated fat mass loss – results of an exploratory study |
| title_short |
Early effects of roflumilast on insulin sensitivity in adults with prediabetes and overweight/obesity involve age-associated fat mass loss – results of an exploratory study |
| title_full |
Early effects of roflumilast on insulin sensitivity in adults with prediabetes and overweight/obesity involve age-associated fat mass loss – results of an exploratory study |
| title_fullStr |
Early effects of roflumilast on insulin sensitivity in adults with prediabetes and overweight/obesity involve age-associated fat mass loss – results of an exploratory study |
| title_full_unstemmed |
Early effects of roflumilast on insulin sensitivity in adults with prediabetes and overweight/obesity involve age-associated fat mass loss – results of an exploratory study |
| title_sort |
early effects of roflumilast on insulin sensitivity in adults with prediabetes and overweight/obesity involve age-associated fat mass loss – results of an exploratory study |
| publisher |
Dove Medical Press |
| publishDate |
2019 |
| url |
https://doaj.org/article/66e00c0787514230833a8d16f1920e6a |
| work_keys_str_mv |
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oai:doaj.org-article:66e00c0787514230833a8d16f1920e6a2021-12-02T07:31:50ZEarly effects of roflumilast on insulin sensitivity in adults with prediabetes and overweight/obesity involve age-associated fat mass loss – results of an exploratory study1178-7007https://doaj.org/article/66e00c0787514230833a8d16f1920e6a2019-05-01T00:00:00Zhttps://www.dovepress.com/early-effects-of-roflumilast-on-insulin-sensitivity-in-adults-with-pre-peer-reviewed-article-DMSOhttps://doaj.org/toc/1178-7007Ijeoma M Muo,1 Sandra D MacDonald,2 Ritu Madan,3 Sung-Jun Park,1 Ahmed M Gharib,4 Pedro E. Martinez,5 Mary F Walter,3 Shanna B Yang,6 Justin A Rodante,7 Amber B Courville,6 Peter J Walter,8 Hongyi Cai,8 Michael Glicksman,3 Gioia M Guerrieri,5 Rivka R Ben-Dor,9 Ronald Ouwerkerk,4 Stephanie Mao,1 Jay H Chung1 1Laboratory of Obesity and Aging Research NHLBI, National Institutes of Health, Bethesda, MD 20892, USA; 2NHLBI Pulmonary Branch, Laboratory of Chronic Airway Infections, National Institutes of Health, Bethesda, MD 20892, USA; 3Diabetes Endocrinology and Obesity Branch, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA; 4Biomedical and Metabolic Imaging Branch NIDDK, National Institutes of Health, Bethesda, MD 20892, USA; 5Section on Behavioral Endocrinology, NIMH, National Institutes of Health, Bethesda, MD 20892, USA; 6Clinical Center Nutrition Department, National Institutes of Health, Bethesda, MD 20892, USA; 7Laboratory of Inflammation and Cardiometabolic Diseases, NHLBI, National Institutes of Health, Bethesda, MD 20892, USA; 8Mass Spectrometry Clinical Core, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA; 9NIMH, National Institutes of Health, Bethesda, MD 20892, USA Purpose: Roflumilast (Daliresp, Daxas) is a FDA-approved phosphodiesterase 4 (PDE4) inhibitor for the treatment of moderate-to-severe chronic obstructive pulmonary disease. In mice and in limited human studies, this oral medication can cause weight loss and improve insulin sensitivity. We set out to determine the mechanism of its effect on insulin sensitivity. Patients and methods: Eight adults with overweight/obesity and prediabetes received roflumilast for 6 weeks. Before and after roflumilast, subjects underwent tests of insulin sensitivity, mixed meal test, body composition, markers of inflammation, and mitochondria function. Dietary intake and physical activity were also assessed. Our primary outcome was the change in peripheral insulin sensitivity, as assessed by the hyper-insulinemic euglycemic clamp. Results: This study was underpowered for the primary outcome. Pre- and post-roflumilast mean peripheral insulin sensitivity were 48.7 and 70.0 mg/g fat free mass/minute, respectively, (P-value=0.18), respectively. Among the mixed meal variables, roflumilast altered glucagon-like peptide 1 (GLP-1) hormone the most, although the average effect was not statistically significant (P=0.18). Roflumilast induced a trend toward significance in 1) decreased energy intake (from 11,095 KJ to 8,4555 KJ, P=0.07), 2) decreased fat mass (from 34.53 to 32.97 kg, P=0.06), 3) decreased total and LDL cholesterol (P=0.06 for both variables), and 4) increased plasma free fatty acids (from 0.40 to 0.50 mEq/L, P=0.09) The interval changes in adiposity and free fatty acid were significantly associated with the subject’s age (P-value range=<0.001 to 0.02 for the correlations). Inflammatory and adhesion markers, though unchanged, significantly correlated with one another and with incretin hormones only after roflumilast. Conclusion: We demonstrate, for the first time in humans, increasing percentage of fat mass loss from roflumilast with increasing age in adults with prediabetes and overweight/obesity. We also demonstrate novel associations among roflumilast-induced changes in incretin hormones, inflammatory markers, peripheral insulin sensitivity, and adiposity. We conclude that roflumilast’s early effects on insulin sensitivity is indirect and likely mediated through roflumilast’s prioritization of lipid over glucose handling.Clinical trials registration: NCT01862029. Keywords: phosphodiesterase 4, obesity, diabetes, inflammation, incretins, aging Muo IMMacDonald SDMadan RPark SJGharib AMMartinez PEWalter MFYang SBRodante JACourville ABWalter PJCai HGlicksman MGuerrieri GMBen-Dor RROuwerkerk RMao SChung JHDove Medical PressarticleAMPKIncretinsinflammationadipositySpecialties of internal medicineRC581-951ENDiabetes, Metabolic Syndrome and Obesity: Targets and Therapy, Vol Volume 12, Pp 743-759 (2019) |