Stem Cells Transl Med. 2026 Jul 20. pii: szag055. [Epub ahead of print]15(8):
INTRODUCTION: KATP-channel-related hyperinsulinism (KATPHI) is a rare genetic disorder of the pancreatic beta cells, manifesting as life-threatening hypoglycemia in neonates due to excessive insulin secretion. Management of the severe diffuse form of KATPHI currently lacks treatment options, as the first-line therapy octreotide is often insufficiently effective, necessitating radical pancreatectomy in many patients.
METHODS: In this study, we differentiated stem cells carrying the KATPHI-causing mutation KCNJ11-/- to stem cell-derived islets (SC-islets) to develop new pharmaceutical therapies for KATPHI. We tested seven candidate molecules in vitro and the most effective ones in vivo in immunocompromised mice that were transplanted with the human KCNJ11-/- SC-islets.
RESULTS: KCNJ11 -/- SC-islets inappropriately secreted 3.9 times more insulin in low glucose than KCNJ11+/+ controls. Transplanted KCNJ11-/- SC-islets caused persistent hyperinsulinemia and hypoglycemia to the recipient mice. We tested acyl-ghrelin identified in our in vitro experiments and its long-acting analogue relamorelin in these mice. Acyl-ghrelin and relamorelin alone increased fasting blood glucose. Combining relamorelin with octreotide increased blood glucose synergistically, ie, more than the sum of each drug alone, reverting hypoglycemia to normoglycemia while reducing the excessive insulin secretion.
CONCLUSIONS: We show that ghrelin-receptor agonists have acute anti-hypoglycemic effects in a humanized mouse model of KATPHI, especially when combined with octreotide. Relamorelin has been tested in >650 diabetic adults with little side effects, leading us to propose relamorelin-octreotide combination for further development as a therapeutic candidate for severe KATPHI patients.
Keywords: congenital hyperinsulinism; disease modeling; ghrelin; hypoglycemia; stem cell-derived islets