Melatonin improved glucose homeostasis is associated with  the reprogrammed gut microbiota and reduced fecal levels of  short-chain fatty acids in db/db mice

Accumulated evidence shows that melatonin possesses the potential to improve  lipid metabolism by modifying gut microbiota and glucose metabolism via regulating  the melatonin receptor signaling pathway. However, the contribution of melatonin  consumption on glucose homeostasis by affecting gut microbiota has not been investigated in diabetes. In the current work, we investigated the effect of melatonin  administration on gut microbiota and glucose homeostasis in db/db mice, a type 2  diabetes model with leptin receptor deficiency. Administration of melatonin through  drinking water (at 0.25% and 0.50%) for 12 weeks decreased diabetic polydipsia and  polyuria, increased insulin sensitivity and impeded glycemia. The accumulated fecal  levels of total short-chain fatty acids (SCFAs) and acetic acid are positively correlated  with diabetes-related parameters—homeostasis model assessment of insulin resistance (HOMA-IR) index and fasting blood glucose (FBG) level. The reprogramming of  gut microbiota structure and abundance and the reduction of fecal levels of SCFAs,  including acetic acid, butyric acid, isovaleric acid, caproic acid, and isobutyric acid,  by melatonin may be beneficial for enhancing insulin sensitivity and lowering FBG,  which were verified by the results of correlation analysis between acetic acid or total  SCFAs and HOMA-IR and FBG. In addition, the melatonin downregulated hepatic  genes, including fructose-1,6-bisphosphatase 1, forkhead box O1 alpha, thioredoxin interacting protein, phosphoenolpyruvate carboxy-kinase (PEPCK), PEPCK1 a  glucose-6-phosphatase catalytic subunit, that responsible for gluconeogenesis support the result that melatonin improved glucose metabolism. Overall, results showed  that the melatonin supplementation reduced fecal SCFAs level via reprogramming of  gut microbiota, and the reduction of fecal SCFAs level is associated with improved  glucose homeostasis in db/db mice.