The influence of anterior pituitary hormones such as growth hormone (GH) and ACTH on sugar metabolism was unclear at the time. Houssay surgically removed the pituitary from dogs and measured blood sugar and insulin sensitivity in detail. Animals without the pituitary showed lower glucose and higher insulin responsiveness, whereas injection of pituitary extracts raised blood sugar. He concluded that anterior lobe hormones antagonize insulin, proposing that GH stimulates gluconeogenesis and lipolysis. The discovery expanded endocrine feedback theory and reshaped the understanding of diabetes types.

Houssay placed the hypothalamic-pituitary axis at the center of metabolic regulation, using selective anterior lobe ablation and insulin tolerance tests. He devised statistical standardization of crude hormone extract activity and quantified changes in glucose curves. Growth hormone, ACTH and cortisol were shown to induce transcription of gluconeogenic enzymes and promote insulin resistance. The work aided diagnostic criteria for pituitary insufficiency and Cushing’s disease, laying groundwork for hormone replacement therapy. It also propelled endocrine research in Latin America and trained many new investigators.

Using pan-hypophysectomized dogs, Houssay showed in perfused liver systems that GH extracts enhance hepatic glucose output and kinetically modeled GH–insulin antagonism. He demonstrated that ACTH can raise glucose without adrenal cortical mediation, proposing hierarchical control. GH-driven lipolysis elevates free fatty acids, inhibits insulin signaling and amplifies hepatic glucose release, a lipid–glucose crosstalk mechanism he described. He matched these findings with impaired glucose tolerance in acromegaly patients, providing translational validation. His insights paved the way for systems-biology descriptions of the brain–liver–pancreas network.