The Pituitary Gland is a Novel Major Site of Action of Metformin in Non-Human Primates: a Potential Path to Expand and Integrate Its Metabolic Actions

Abstract

Background/Aims: Biguanides are anti-hyperglycaemic agents used to treat diabetes by acting primarily on the liver, inhibiting hepatic gluconeogenesis. However, biguanides may target other key metabolic tissues to exert beneficial actions. As the “master endocrine gland”, the pituitary is a true homeostatic sensor that controls whole body homeostasis and metabolism by integrating central and peripheral signals. However, whether the pituitary is a primary site of biguanides action in normal adult humans/primates remains unknown. Therefore, we aimed to elucidate the direct effects of two biguanides (metformin/phenformin) on the expression and secretion of all anterior pituitary hormones in two non-human primate species (Papio anubis and Macaca fascicularis), and the molecular/signalling-mechanisms behind these actions. Methods: Primary pituitary cell cultures from baboons and macaques were used to determine the direct impact of metformin/phenformin (alone and combined with primary regulators) on the functioning of all pituitary cell-types (i.e. expression/secretion/signaling-pathways, etc). Results: Metformin/phenformin inhibited basal, but not GHRH/ghrelin-stimulated GH/ACTH/ FSH-secretion and GH/POMC-expression, without altering secretion or expression of other pituitary hormones (PRL/LH/TSH), FSH-expression or cell viability in both primate models. These biguanide actions are likely mediated through modulation of: 1) common (mTOR/PI3K/intracellular-Ca2+mobilization) and distinct (MAPK) signaling pathways; and 2) gene expression of key receptors regulating somatotrope/corticotrope/gonadotrope function (i.e. upregulation of SSTR2/SSTR5/INSR/IGF1R/LEPR). Conclusion: The pituitary gland is a primary target of biguanide actions wherein they modulate somatotrope/corticotrope/gonadotrope-function through multiple molecular/signaling pathways in non-human primate-models. This suggests that the well-known metabolic effects of biguanides might be, at least in part, influenced by their actions at the pituitary level.