Introduction: Obstructive sleep apnea (OSA) is a prevalent sleep disorder linked to high type 2 diabetes risk. Positive airway pressure (PAP) therapy is the standard of care for OSA, but it inconsistently improves glucose homeostasis. Senescent cells are common in adipose tissue (AT) of patients with OSA and may impair insulin signaling. However, the effects of PAP therapy on AT senescence are not known. Addition of metformin, an insulin-sensitizer with anti-senescent effects, may be a good adjuvant therapeutic strategy to improve glycemic control in patients with OSA. Methods: We randomly assigned 16 nondiabetic participants with OSA (Mean± SD; age: 50.9 ± 6.7 y, BMI: 36.5 ± 2.9 kg/m2) in a 1:1 ratio to receive either 2g metformin or placebo daily along with PAP therapy for 3 months in a double-blind pilot study. Whole body and AT insulin sensitivity was determined by 2h oral glucose tolerance test (OGTT). AT biopsy was obtained to estimate tissue insulin signaling and senescence. Results: The metformin and placebo groups had comparable age, BMI and OSA severity at baseline. PAP compliance was 38% and 75% in the metformin and placebo groups, respectively. Matsuda Index, glucose area under the curve (2h AUC), and free-fatty acid suppression at baseline and follow-up were not different in metformin or placebo treated groups. Compared to baseline, insulin AUC and insulin to glucose AUC ratio during OGTT was unchanged in the metformin but increased in the placebo group. Metformin, but not placebo, was associated with increased insulin mediated AKT phosphorylation and decreased senescence biomarkers (p21 and MCP1) in AT during the follow-up visit. Conclusion: Metformin, as adjunct to PAP therapy, attenuated insulin rises during OGTT, improved AT insulin signaling, and lowered senescence biomarkers in OSA patients. Larger trials of longer treatment duration are needed to determine if metformin can prevent diabetes in OSA patients. Disclosure S. Rodrigues: None. W.S. Dantas: None. R.A. Beyl: None. R.C. Hebert: None. I. Griffith: None. M. Tanksley: None. E.C. Mader: None. J.P. Kirwan: None. C.L. Axelrod: None. E. Ravussin: Research Support; Eli Lilly and Company, Novartis AG. Advisory Panel; Novartis. P. Singh: None. Funding National Institutes of Health (P30DK072476, U54GM104940); CAPES (88887.470405/2019-00 to S.R.)
Introduction: Obstructive sleep apnea (OSA) is a prevalent sleep disorder with high type 2 diabetes (T2D) risk. OSA therapy includes positive airway pressure (PAP) treatment, which resolves breathing events but modestly improves metabolic health. Metformin is recommended for T2D prevention but is not advocated in patients with OSA. Our pilot study evaluated the effects of metformin on glucose metabolism and mitochondrial function in OSA patients. Methods: Sixteen adults (50.5±1.6 years, BMI: 36.4±0.8 kg/m2) with OSA (apnea hypopnea index: 53.2±21.1 events/hour) were randomized to receive placebo (n=8) or metformin (n=8) treatment along with PAP for 3 months in a double-blind parallel-group design. Whole body and adipose tissue-specific insulin sensitivity (IS) was determined by oral glucose tolerance test (OGTT) . Skeletal muscle mitochondrial function was determined by high-resolution respirometry using biopsies obtained at baseline and after 3 months of treatment. Results: Change in whole body IS (Matsuda index) was not different in metformin or placebo treated groups (p=0.46) . However, improved acute phase responses during OGTT - glucose uptake (p=0.02) , insulin release (p=0.03) , and suppressed lipolysis (p=0.03) were observed with metformin treatment relative to control. Increased skeletal muscle mitochondrial function was evident with metformin relative to control. Specifically, metformin increased complex I phosphorylation and complex IV electron transfer capacity. Conclusion: Metformin treatment improves acute phase IS and insulin suppression of lipolysis in OSA patients. Strikingly, metformin improved skeletal muscle mitochondrial function independent of changes in second phase glucose disposal and BMI, indicating improved tissue metabolic function. These data suggest that in patients with OSA, improvement in tissue level metabolic function may precede changes in whole-body IS and metformin may improve metabolism. Disclosure E.R.M.Zunica: None. E.C.Heintz: None. R.C.Hebert: None. M.C.Tanksley: None. E.C.Mader: None. J.P.Kirwan: None. C.L.Axelrod: None. P.Singh: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DK123456789) ;National Institute of General Medical Sciences (GM123456789)
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