This study investigated how fatty liver worsens hyperglycemia via a liver-to-gut signaling axis — specifically, how hepatocyte-derived alkaline phosphatase (ALP) communicates remotely with intestinal stem cells (ISCs) to impair L-cell differentiation and reduce hypoglycemic hormone secretion, independent of intrahepatic gluconeogenesis.
Hepatocyte-derived ALP activates α2δ-1 on ISCs → promotes Cav1.2 membrane translocation → raises intracellular calcium → activates calcineurin/NFATC2 → suppresses SOX21 → reduces BMP7 → fewer L-cells and lower GLP-1/PYY secretion → hyperglycemia. Inhibiting ALP in fatty liver independently lowered blood glucose and synergistically enhanced metformin's hypoglycemic effect.
Preclinical mechanistic study — translational relevance to humans is not yet established. No clinical or human-tissue validation cohort is described. Long-term safety and specificity of ALP inhibition as a therapeutic target are not assessed.
This is a mechanistic study and not yet ready for clinical application, but it identifies hepatic ALP as a potential drug target in fatty liver–associated hyperglycemia. Clinicians should watch for future trials exploring ALP inhibition as an adjunct to metformin in metabolic dysfunction–associated steatotic liver disease (MASLD) with type 2 diabetes.
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