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Sirolimus therapy in a child with partially diazoxide-responsive hyperinsulinaemic hypoglycaemia
Kah-Yin Loke1, Andrew Sng Anjian2, Yvonne Lim Yijuan2
1Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore.
Insights
Sirolimus offers a potential treatment for hyperinsulinaemic hypoglycaemia (HH) when diazoxide is insufficient. This mTOR inhibitor effectively managed breakthrough hypoglycaemia and resolved diazoxide side effects in a patient with a novel ABCC8 mutation.
Area of Science:
- Pediatric Endocrinology
- Metabolic Disorders
- Genetics
Background:
- Hyperinsulinaemic hypoglycaemia (HH) is a challenging condition causing persistent neonatal hypoglycaemia, potentially leading to neurological damage.
- Diazoxide is the standard first-line treatment, but efficacy is limited in some patients and it can cause adverse effects.
- Sirolimus, an mTOR inhibitor, has shown promise in severe diffuse HH cases, potentially avoiding pancreatectomy.
Purpose of the Study:
- To report the case of a patient with HH and a novel ABCC8 mutation treated with sirolimus.
- To evaluate the efficacy and safety of sirolimus in managing breakthrough hypoglycaemia in a partially diazoxide-responsive HH patient.
- To assess the resolution of diazoxide-associated side effects with sirolimus treatment.
Main Methods:
- Case report of a girl with HH and a novel heterozygous ABCC8 missense mutation (c.4154A>T/p.Lys1385Thr).
- Initial treatment with diazoxide, followed by the introduction of sirolimus due to breakthrough hypoglycaemia and adverse effects.
- Gradual weaning of diazoxide as sirolimus was initiated and titrated.
Main Results:
- The patient initially responded to diazoxide but developed breakthrough hypoglycaemia, hypertrichosis, and weight gain.
- Sirolimus treatment led to a significant reduction and eventual abolition of hypoglycaemic episodes.
- Hypertrichosis resolved, and weight gain decreased with sirolimus, which was well-tolerated.
- Normoglycaemia was maintained after sirolimus discontinuation, even after a 10-hour fast.
Conclusions:
- Conventional diazoxide treatment for diffuse HH may be ineffective and associated with side effects.
- Sirolimus successfully controlled recurrent hypoglycaemia in a partially diazoxide-responsive HH case, resolving adverse effects.
- Sirolimus demonstrated good tolerability with no significant side effects in this patient.
- Capillary glucose levels remained normal after sirolimus cessation.
Abstract:
Hyperinsulinaemic hypoglycaemia (HH), which causes persistent neonatal hypoglycaemia, can result in neurological damage and it's management is challenging. Diazoxide is the first-line treatment, albeit not all patients will fully respond to it, as episodes of hypoglycaemia may persist and it entails unpleasant adverse effects. Sirolimus, an mTOR inhibitor, has reportedly been successful in treating children with severe diffuse HH, thus obviating the need for pancreatectomy. We report a girl with HH, with a novel heterozygous ABCC8 gene missense mutation (c.4154A>T/ p.Lys1385Thr), who was initially responsive to diazoxide therapy. After 11 months of diazoxide treatment, she developed intermittent, unpredictable breakthrough episodes of hypoglycaemia, in addition to generalized hypertrichosis and weight gain from enforced feeding to avoid hypoglycaemia. Sirolimus, which was commenced at 15 months of age, gradually replaced diazoxide, with significant reduction and abolition of hypoglycaemia. The hypertrichosis resolved and there was less weight gain given the reduced need for enforced feeding. Sirolimus, which was administered over the next 15 months, was well tolerated with no significant side effects and was gradually weaned off. After stopping sirolimus, apart from hypoglycaemia developing during an episode of severe viral gastroenteritis, the capillary glucose concentrations were maintained >3.5 mmol/L, even after a 10 h fast. Sirolimus may have a role in the treatment of partially diazoxide-responsive forms of HH who experience breakthrough hypoglycaemia, but the long-term safety and efficacy of sirolimus are not established.
Learning Points:
Conventional treatment of diffuse HH with diazoxide is not always effective in controlling hypoglycaemia and can be associated with unpleasant side effects.Sirolimus was successfully used to abolish recurrent hypoglycaemia in partially diazoxide-responsive HH, with resolution of unacceptable diazoxide-associated side effects.Sirolimus was well tolerated with no clinically significant side effects.Shortly after stopping sirolimus, the capillary glucose levels remained normoglycemic.
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