Sirolimus in Severe Hyperinsulinemic Hypoglycemia

doi:10.1056/nejmc1404716

Cited by 11 publications

(5 citation statements)

References 8 publications

(6 reference statements)

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“…However, due to a similar mechanism of action as octreotide, long-acting somatostatin analogues show similar side effects (111). Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is an immunosuppressive and anti-proliferative agent that has been used in patients with diffuse CHI, unresponsive to diazoxide and octreotide therapy (22,112). It suppresses insulin release by different mechanisms, which have not been fully elucidated (30).…”

Section: Possible K Atp Channel-independent Strategies To Treat Chimentioning

confidence: 99%

“…Additionally, diazoxide is only effective when K ATP channels are functional (10). Alternatives to the therapy with diazoxide and novel medications include glucagon, somatostatin analogues, nifedipine, GLP1-receptor antagonists [exendin- ], and sirolimus [ (17)(18)(19)(20)(21)(22), reviewed in (3)]. Many of these drugs act by lowering the Ca 2+ influx into b-cells (23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

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Possible New Strategies for the Treatment of Congenital Hyperinsulinism

et al. 2020

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Objective: Congenital hyperinsulinism (CHI) is a rare disease characterized by persistent hypoglycemia as a result of inappropriate insulin secretion, which can lead to irreversible neurological defects in infants. Poor efficacy and strong adverse effects of the current medications impede successful treatment. The aim of the study was to investigate new approaches to silence b-cells and thus attenuate insulin secretion. Research Design and Methods: In the scope of our research, we tested substances more selective and more potent than the gold standard diazoxide that also interact with neuroendocrine ATP-sensitive K + (K ATP) channels. Additionally, K ATP channel-independent targets as Ca 2+-activated K + channels of intermediate conductance (K Ca 3.1) and L-type Ca 2+ channels were investigated. Experiments were performed using human islet cell clusters isolated from tissue of CHI patients (histologically classified as pathological) and islet cell clusters obtained from C57BL/6N (WT) or SUR1 knockout (SUR1-/-) mice. The cytosolic Ca 2+ concentration ([Ca 2+ ] c) was used as a parameter for the pathway regulated by electrical activity and was determined by fura-2 fluorescence. The mitochondrial membrane potential (DY) was determined by rhodamine 123 fluorescence and single channel currents were measured by the patch-clamp technique. Results: The selective K ATP channel opener NN414 (5 µM) diminished [Ca 2+ ] c in isolated human CHI islet cell clusters and WT mouse islet cell clusters stimulated with 10 mM glucose. In islet cell clusters lacking functional K ATP channels (SUR1-/-) the drug was without effect. VU0071063 (30 µM), another K ATP channel opener considered to be selective, lowered [Ca 2+ ] c in human CHI islet cell clusters. The compound was also effective in islet cell clusters from SUR1-/mice, showing that [Ca 2+ ] c is influenced by additional effects besides K ATP channels. Contrasting to NN414, the drug depolarized DY in murine islet cell clusters pointing to severe interference with mitochondrial metabolism. An opener of K Ca 3.1 channels, DCEBIO (100 µM), significantly decreased [Ca 2+ ] c in SUR1-/and human CHI islet cell clusters. To target L-type Ca 2+ channels we tested two

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Section: Possible K Atp Channel-independent Strategies To Treat Chimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Possible New Strategies for the Treatment of Congenital Hyperinsulinism

et al. 2020

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“…This condition is also called non-thyroidal illness syndrome (NTIS) (1,2) or euthyroid sick syndrome (ESS) (3). NTIS consists of a low level of circulating values of triiodothyronine (T3) and normal or low levels of thyroxine (T4) and thyroid-stimulating hormone (TSH) (4). This phenomenon was first reported in patients admitted to intensive care units, and it was also observed in various critical conditions, such as acute myocardial infarction (5), heart failure (6), and in the postoperative period of cardiac surgery (7).…”

Section: Introductionmentioning

confidence: 99%

“…Low levels of T3 were observed in 15-30% of patients with heart failure (6,8) and in 15-20% of patients with acute myocardial infarction (5,9). Critical illness-induced NTIS is characterized by decreases in T3, circulating T4, and TSH (4). Severe illness induces dramatic changes in thyroid metabolism, resulting in a downregulation of the hypothalamic-pituitary-thyroid axis at both the hypothalamic and pituitary levels, with related decreases in circulating thyroid hormone concentrations (10).…”

Section: Introductionmentioning

confidence: 99%

Thyroid Hormone Is Related to Postoperative AKI in Acute Type A Aortic Dissection

et al. 2020

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“…Despite early concerns about the use of this drug in the neonatal population [3], several case studies have subsequently appeared in the literature reporting the success of Sirolimus therapy in CHI with no reports of adverse outcomes [4–7]. The original paper by Senniappan and colleagues (2014) is not without weakness.…”

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confidence: 99%

Extreme caution on the use of sirolimus for the congenital hyperinsulinism in infancy patient

Banerjee

León

Dunne

2017

Orphanet J Rare Dis

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We have recently published on the limited effectiveness of sirolimus as a treatment option for hypoglycaemia as a consequence of hyperinsulinism. Our data oppose the view that mTOR inhibitors provide new opportunities for the treatment of patients with hyperinsulinism. We are not convinced by the argument that any benefit for some patients outweighs the potential and later long-term problems that accompany mTOR inhibition in the neonate. We also express the opinion that caution must be taken when repurposing/repositioning therapies in the field of rare disease.

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Sirolimus in Severe Hyperinsulinemic Hypoglycemia

Cited by 11 publications

References 8 publications

Possible New Strategies for the Treatment of Congenital Hyperinsulinism

Possible New Strategies for the Treatment of Congenital Hyperinsulinism

Thyroid Hormone Is Related to Postoperative AKI in Acute Type A Aortic Dissection

Extreme caution on the use of sirolimus for the congenital hyperinsulinism in infancy patient

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