Beyond insulin-like growth factor-1 (IGF-1) normalization: portal insulin and hepatic growth hormone (GH) sensitivity across metabolic disease.

Clinical management of growth hormone (GH) deficiency, acromegaly, and diabetes mellitus is dominated by single-analyte targets: serum insulin-like growth factor-1 (IGF-1) in the GH disorders and glycated hemoglobin in diabetes. This reductive framework obscures a central regulatory fact: GH does not autonomously dictate hepatic IGF-1 output. Whether GH is translated into IGF-1 by the hepatocyte is gated by the concentration of insulin reaching the liver through the portal vein. We propose liver sensitivity to GH (LSG), operationally defined as portal-insulin-determined hepatic GH receptor (GHR) availability, as a unifying variable that places type 1 and type 2 diabetes, obesity, liver failure, and acromegaly on a single continuum rather than treating them as separate phenomena. We develop the molecular basis of insulin-dependent GHR regulation, distinguish the divergent roles of portal versus systemic insulin, and argue that this distinction explains why subcutaneous insulin therapy in type 1 diabetes corrects glycemia while leaving the hepatic GH-resistant state intact. We then re-examine the weight-gain liability of insulinotropic antidiabetic agents, the discordant GH/IGF-1 signatures produced by GLP-1 receptor agonists, the prognostic and potentially therapeutic role of IGF-1 in cirrhosis, and the metabolic limitations of current acromegaly treatment targets when viewed through the LSG framework. The aim is to give the treating physician a mechanistic, rather than purely biochemical, account of how metabolism behaves in these states.