Identification of myokines susceptible to improve glucose homeostasis after bariatric surgery

Abstract

Abstract Importance and Objective The identification of myokines susceptible to improve glucose homeostasis following bariatric surgery could lead to new therapeutic approaches for type 2 diabetes. Methods Changes in the homeostasis model assessment (HOMA) test were assessed in patients before and 3 months after bariatric surgery. Changes in myokines expression and circulating levels were assessed using real-time quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA). Myokines known to regulate glucose homeostasis were identified using literature (targeted study) and putative myokines using RNA-sequencing (untargeted study). A linear regression analysis adjusted for age and sex was used to search for associations between changes in the HOMA test and changes in myokines. Results In the targeted study, brain-derived neurotrophic factor (BDNF) expression was upregulated (+30%, P = .006) while BDNF circulating levels were decreased (−12%, P = .001). Upregulated BDNF expression was associated with decreased HOMA of insulin resistance (HOMA-IR) (adjusted estimate [95% confidence interval {CI}]: −0.51 [−0.88 to −0.13], P = .010). Decreased BDNF serum levels were associated with decreased HOMA of beta-cell function (HOMA-B) (adjusted estimate [95% CI] = 0.002 [0.00002-0.0031], P = .046). In the untargeted study, upregulated putative myokines included XYLT1 (+64%, P < .001), LGR5 (+57, P< .001), and SPINK5 (+46%, P < .001). Upregulated LGR5 was associated with decreased HOMA-IR (adjusted estimate [95% CI] = −0.50 [−0.86 to −0.13], P = .009). Upregulated XYLT1 and SPINK5 were associated with increased HOMA of insulin sensitivity (HOMA-S) (respectively, adjusted estimate [95% CI] = 109.1 [28.5-189.8], P = .009 and 16.5 [0.87-32.19], P = .039). Conclusions Improved glucose homeostasis following bariatric surgery is associated with changes in myokines expression and circulating levels. In particular, upregulation of BDNF, XYLT1, SPINK5, and LGR5 is associated with improved insulin sensitivity. These results suggest that these myokines could contribute to improved glucose homeostasis following bariatric surgery. Study registration NCT03341793 on ClinicalTrials.gov (https://clinicaltrials.gov/).