ESPE Abstracts (2021) 94 S5.1

ESPE2021 Symposia Novel Therapies in Endocrinology (2 abstracts)

Novel Therapies in the Treatment of Congenital Hyperinsulinism

Diva De Leon-Crutchlow


Children’s Hospital of Philadelphia, Philadelphia, USA. Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA


Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in infants and children. In the past 20+ years there have been tremendous advances in the understanding of the molecular genetics of HI, including the discovery of the mechanisms responsible for a focal form of the disease that can cured surgically. However, treatment options for non-focal HI continue to be limited, with only one drug currently approved for this indication. As a result of delayed diagnosis and inadequate treatment options, up to 50% of children with HI experience neurodevelopmental deficits, thus, there is an urgent need for new effective and safe therapies. Efforts have been directed at repurposing existing drugs and at identifying new therapeutic targets. We have identified the GLP-1 receptor as a potential therapeutic target for HI. GLP-1 is an incretin hormone secreted by the intestinal L-cells that plays a critical role in the regulation of glucose homeostasis, and GLP-1 mimetic therapies are now broadly use in the treatment of diabetes. We have shown that the GLP-1 receptor is constitutively active in islets isolated from a mouse model of K!ATPhyperinsulinism (Sur1-/- mouse), the most common type of HI, and that the GLP-1 receptor antagonist, exendin-(9-39), inhibits insulin secretion in mouse and human islets lacking KATP channels. In preclinical studies, we demonstrated that exendin-(9-39) prevents fasting hypoglycemia in Sur1-/- mice. In clinical studies, we have shown that exendin-(9-39) increases fasting glucose in children, adolescents, and adults with KATPHI and prevents protein-induced hypoglycemia in affected children. In neonates with severe diazoxide-unresponsive HI, exendin-(9-39) reduces the glucose infusion rate required to maintain euglycemia. Other therapies under development include modified glucagon analogues, somatostatin receptor agonists, and inhibitors of the insulin receptor. The ongoing efforts promise to make possible a personalized-approach to treatment of children with HI and to improve their long-term outcomes.

Volume 94

59th Annual ESPE (ESPE 2021 Online)

Online,
22 Sep 2021 - 26 Sep 2021

European Society for Paediatric Endocrinology 

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