Changes in Circulating Pancreatic Islet-Specific MicroRNA-375 Levels and Improvements in Insulin Sensitivity and Glucose Metabolism in Response to Weight-Loss Diets with Different Compositions of Macronutrients-The POUNDS Lost Trial

Pancreatic islet-specific microRNA-375 (miR-375) regulates insulin secretion and has an essential role in β-cell compensation when escalating insulin demand. We recently reported that changes in circulating miR-375 were associated with improved diabetogenic fat depots. Here, we investigated whether changes in circulating miR-375 induced by weight-loss diet interventions with different macronutrient intakes (fat, carbohydrate (carb), and protein) were related to improved insulin sensitivity and glucose metabolism. This study included participants from the POUNDS Lost trial with available data on circulating miR-375-3p at baseline (n=520) and its changes from baseline to 6 months after weight-loss diet interventions (n=508). At baseline, higher levels of miR-375 were related to lower degrees of BMI, total adipose tissue mass, and whole-body fat content (P <0.05 for all). There was a significant increase in miR-375 levels from baseline to 6 months (P by paired t-test <0.001). We found that associations of changes in miR-375 with changes in fasting insulin, glucose, and insulin resistance (HOMA-IR) were significantly modified by carb and fat intakes (P interaction <0.05 for all). In response to a low-fat and high-carb diet, a greater increase in miR-375 was significantly associated with larger reductions of fasting insulin and HOMA-IR at 6 months, regardless of baseline miR-375 levels. On the other hand, in response to a high-fat and low-carb diet intervention, there were significant positive associations between miR-375 changes and changes in glucose, insulin, and HOMA-IR. These results suggest that changes in the pancreatic islet-specific miRNA expression are associated with weight-loss diet intervention outcomes on insulin sensitivity and glucose metabolism. Different macronutrient intakes may modify these associations. Disclosure Y.Heianza: None. Q.Xue: None. H.Ma: None. G.Bray: Advisory Panel; Medifast, Inc., Herbalife International of America, Inc. F.Sacks: None. L.Qi: None. Funding National Institutes of Health (DK091718, DK100383, DK115679)