mTOR Inhibitors for the Treatment of Severe Congenital Hyperinsulinism: Perspectives on Limited Therapeutic Success

Szymanowski, Marie; Estebanez, Maria Salomon; Padidela, Raja; Han, Bing; Mosinska, Karolina; Stevens, Adam; Damaj, Léna; Bars, Florence Pihan-Le; Lascouts, Emilie; Reynaud, Rachel; Ferreira, Catherine; Bansept, Claire; Lonlay, Pascale de; Saint‐Martin, Cécile; Dunne, Mark J.; Banerjee, Indraneel; Arnoux, Jean‐Baptiste

doi:10.1210/jc.2016-2711

Cited by 50 publications

(53 citation statements)

References 35 publications

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“…First line medical treatment after iv glucose and/or glucagon rescue is the K ATP agonist diazoxide with the somatostatin analog octreotide as second line (15). Rapamycin, an mTOR inhibitor, has more recently been used with variable effect (16, 17). …”

Section: Introductionmentioning

confidence: 99%

Both Low Blood Glucose and Insufficient Treatment Confer Risk of Neurodevelopmental Impairment in Congenital Hyperinsulinism: A Multinational Cohort Study

Helleskov¹,

Melikyan

Globa³

et al. 2017

Front. Endocrinol.

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Background/aimsCongenital hyperinsulinism (CHI) is a heterogeneous disease most frequently caused by KATP-channel (ABCC8 and KCNJ11) mutations, with neonatal or later onset, variable severity, and with focal or diffuse pancreatic involvement as the two major histological types. CHI confers a high risk of neurological impairment; however, sparsely studied in larger patient series. We assessed the neurodevelopmental outcome in children with CHI at follow-up in a mixed international cohort.MethodsIn two hyperinsulinism expert centers, 75 CHI patients were included (Russian, n = 33, referred non-Scandinavian, treated in Denmark n = 27, Scandinavian, n = 15). Hospital files were reviewed. At follow-up, neurodevelopmental impairment and neurodevelopmental, cognitive and motor function scores were assessed.ResultsMedian (range) age at follow-up was 3.7 years (3.3 months–18.2 years). Neurodevelopmental impairment was seen in 35 (47%). Impairment was associated with abnormal brain magnetic resonance imaging (MRI); odds ratio (OR) (95% CI) 15.0 (3.0–74.3), p = 0.001; lowest recorded blood glucose ≤1 mmol/L; OR 3.8 (1.3–11.3), p = 0.015, being non-Scandinavian patient, OR 3.8 (1.2–11.9), p = 0.023; and treatment delay from first symptom to expert center >5 days; OR 4.0 (1.0–16.6), trend p = 0.05. In multivariate analysis (n = 31) for early predictors with exclusion of brain MRI, treatment delay from first symptom to expert center >5 days conferred a significantly increased risk of neurodevelopment impairment, adjusted OR (aOR) 15.6 (1.6–146.7), p = 0.016, while lowest blood glucose ≤1 mmol/L had a trend toward increased risk, aOR 3.5 (1.1–14.3), p = 0.058. No associations for early vs. late disease onset, KATP-channel mutations, disease severity, focal vs. diffuse disease, or age at follow-up were seen in uni- or multivariate analysis.ConclusionNot only very low blood glucose, but also insufficient treatment as expressed by delay until expert center hospitalization, increased the risk of neurodevelopmental impairment. This novel finding calls for improvements in spread of knowledge about CHI among health-care personnel and rapid contact with an expert CHI center on suspicion of CHI.

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Section: Introductionmentioning

confidence: 99%

Both Low Blood Glucose and Insufficient Treatment Confer Risk of Neurodevelopmental Impairment in Congenital Hyperinsulinism: A Multinational Cohort Study

Helleskov¹,

Melikyan

Globa³

et al. 2017

Front. Endocrinol.

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“…Up to now, there are insufficient long-term safety data regarding, for example, pituitary dysfunction and the development of insulin resistance. Off -label use of sirolimus might be an alternative to LAN-ATG in infancy, with a completely different and substantial risk profile and variable results in children with CHI and persistent hypoglycaemia [36, 37]. …”

Section: Discussionmentioning

confidence: 99%

Treatment with long-acting lanreotide autogel in early infancy in patients with severe neonatal hyperinsulinism

Corda

Kummer

Welters

et al. 2017

Orphanet J Rare Dis

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BackgroundTreatment of severe diffuse congenital hyperinsulinism (CHI) without sufficient response to diazoxide is complicated by the lack of approved drugs. Therefore, patients are often hospitalized long-term or have to undergo pancreatic surgery if episodes of severe hypoglycaemia cannot be prevented. A long-acting somatostatin analogue, octreotide, has been reported to be an effective treatment option that prevents severe hypoglycaemia in children with CHI, and its off-label use is common in CHI. However, octreotide requires continuous i.v. or s.c. infusion or multiple daily injections. Here, we report our experiences with the use of a monthly application of a long-acting somatostatin analogue, lanreotide autogel® (LAN-ATG), in early infancy.ResultsThe mean blood glucose concentration within 7 days before the first LAN-ATG administration were compared to 7 days after the first LAN-ATG administration and increased by 0.75 mmol/L (range 0.39–1.19 mmol/L). In the following weeks intravenous glucose infusions, octreotide, and glucagon treatment could be successfully stopped in all patients 3–20 days after the first LAN-ATG injection without substantial worsening of the hypoglycaemia rate. Increased carbohydrate requirements could be normalized with an average reduction in the carbohydrate-intake of 7 g/kg body weight/d (range 1.75–12.8 g/kg body weight/d). Over a total of 52 treatment months, no serious adverse effects occurred.ConclusionLong-term LAN-ATG treatment improved blood glucose concentrations, lowered the frequency of hypoglycaemia or allowed for normalization of oral carbohydrate intake in infants with CHI younger than 6 months of age. No severe side effects were observed. LAN-ATG might be an alternative treatment option in infants with severe CHI who lack risk factors for necrotizing enterocolitis and are not responding to current treatment regimens as an alternative to surgery after careful individual evaluation.

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“…Despite limited clinical experience in CHI, mTOR inhibitors are thought to be a good option for selected patients who do not respond to diazoxide or octreotide. However, in a recent report evaluating the efficacy of sirolimus in 10 patients with diazoxide unresponsive congenital HH, mTOR inhibition has shown to achieve euglycemia, improve fasting tolerance, and reduced requirement for medical therapy in only three patients (30%) with certain side effects [151]. In addition, pancreatic tissue from two patients who did not respond to sirolimus showed no reduction in cell proliferation, further suggesting that mTOR signaling did not down-regulate proliferation in the pancreas of patients with congenital HH [151].…”

Section: New and Potential Future Therapiesmentioning

confidence: 99%

Diagnosis and treatment of hyperinsulinaemic hypoglycaemia and its implications for paediatric endocrinology

Demirbilek

Rahman

Büyükyılmaz

et al. 2017

Int J Pediatr Endocrinol

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Glucose homeostasis requires appropriate and synchronous coordination of metabolic events and hormonal activities to keep plasma glucose concentrations in a narrow range of 3.5–5.5 mmol/L. Insulin, the only glucose lowering hormone secreted from pancreatic β-cells, plays the key role in glucose homeostasis. Insulin release from pancreatic β-cells is mainly regulated by intracellular ATP-generating metabolic pathways. Hyperinsulinaemic hypoglycaemia (HH), the most common cause of severe and persistent hypoglycaemia in neonates and children, is the inappropriate secretion of insulin which occurs despite low plasma glucose levels leading to severe and persistent hypoketotic hypoglycaemia. Mutations in 12 different key genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1 and PMM2) constitute the underlying molecular mechanisms of congenital HH. Since insulin supressess ketogenesis, the alternative energy source to the brain, a prompt diagnosis and immediate management of HH is essential to avoid irreversible hypoglycaemic brain damage in children. Advances in molecular genetics, imaging methods (18F–DOPA PET-CT), medical therapy and surgical approach (laparoscopic and open pancreatectomy) have changed the management and improved the outcome of patients with HH. This up to date review article provides a background to the diagnosis, molecular genetics, recent advances and therapeutic options in the field of HH in children.

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mTOR Inhibitors for the Treatment of Severe Congenital Hyperinsulinism: Perspectives on Limited Therapeutic Success

Abstract: mTOR inhibitor treatment is associated with very limited success and must be used with caution in children with severe CHI.

Cited by 50 publications

References 35 publications

Both Low Blood Glucose and Insufficient Treatment Confer Risk of Neurodevelopmental Impairment in Congenital Hyperinsulinism: A Multinational Cohort Study

Both Low Blood Glucose and Insufficient Treatment Confer Risk of Neurodevelopmental Impairment in Congenital Hyperinsulinism: A Multinational Cohort Study

Treatment with long-acting lanreotide autogel in early infancy in patients with severe neonatal hyperinsulinism

Diagnosis and treatment of hyperinsulinaemic hypoglycaemia and its implications for paediatric endocrinology

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