905-P: Increased GDF15 Levels Are Unrelated to Anterior Pituitary Hormone Shifts in Metformin Use

Metformin is a widely used medication in the management of type 2 diabetes, and its weight-lowering effects involve the central nervous system. Growth differentiation factor 15 (GDF15) acts on the mid-brain, is increased with metformin, and is positively correlated with weight loss. Pituitary hormones can also be altered by metformin and in states of stress. We sought to understand the relationship between GDF15 and pituitary function with metformin use. Data was collected from a randomized, double-blinded, cross-over study of 9 adult patients with prediabetes who received metformin or placebo for two weeks. GDF15, thyroid stimulating hormone (TSH), and adrenocorticotropic hormone (ACTH), cortisol, free T3, total T3, and total T4 were collected at baseline and following metformin. In this small study, GDF15 levels were significantly increased with metformin, however there was no association between the blood level of metformin and the degree of GDF15 increase (R²=0.339, P=0.1). Metformin was associated with an isolated TSH increase (p=0.024) without a significant change in thyroid hormones. TSH was negatively correlated with free T3 values (R²=0.558, P=0.021). A similar correlation was noted with the change in total T3 and total T4 which did not reach significance (R²=0.374, P=0.08; R²=0.389, P=0.073). Metformin was associated with an isolated increase in cortisol (P=0.012) without a significant change in ACTH (P=0.664). There was no correlation between ACTH and cortisol (R²=0.064, P=0.511). There was no relationship identified between GDF15 and TSH (R²=0.171, P=0.17) or GDF15 and cortisol (R²=0.201, P=0.226). Short-term metformin use is associated with isolated increases in TSH, which is likely physiologic, and cortisol, which is unrelated to ACTH. It remains to be determined whether metformin's effect on cortisol is due to altered adrenal steroidogenesis. Our findings suggest that the changes in TSH and cortisol with metformin are not due to GDF15 or a direct effect on the pituitary.