Circulating selenoprotein P levels predict glucose‐lowering and insulinotropic effects of metformin, but not alogliptin: A post‐hoc analysis

AIMS/INTRODUCTION: Selenoprotein P (SeP; encoded by SEPP1 in humans) is a hepatokine that causes impaired insulin secretion and insulin resistance. Metformin downregulates SELENOP promoter activity through an adenosine monophosphate‐activated kinase–forkhead box protein O3a pathway in hepatocytes. This study aimed to test our hypothesis that circulating SeP levels are associated with the glucose‐lowering effect of metformin in humans. MATERIALS AND METHODS: A total of 84 participants with poorly controlled type 2 diabetes were randomly assigned to receive metformin (1,000 mg, twice daily) or a dipeptidyl peptidase‐4 inhibitor, alogliptin (25 mg, once daily) for 12 weeks. We tested metformin and alogliptin on SeP levels and factors associated therewith as a post‐hoc analysis. RESULTS: Both metformin and aloglipitin did not change the SeP levels. Although metformin significantly increased the insulin secretory index secretory units of islets in transplantation only in participants with higher baseline SeP (>3.87), both agents similarly reduced fasting plasma glucose and glycated hemoglobin. SeP levels at baseline were correlated negatively with changes in SeP (r = −0.484, P = 0.004) and fasting plasma glucose (r = −0.433, P = 0.011), and positively with changes in C‐peptide immunoreactivity (r = 0.420, P = 0.017) and secretory units of islets in transplantation (r = 0.388, P = 0.028) in the metformin, but not alogliptin, group. CONCLUSIONS: Higher baseline levels of SeP significantly predicted metformin‐mediated, but not alogliptin‐mediated, glucose‐lowering and insulinotropic effects. Serum SeP levels might be a novel biomarker for predicting the outcomes of metformin therapy, which might be helpful in tailoring diabetes medication.