Hyperinsulinaemic hypoglycaemia in children and adults

Shah, Pratik; Rahman, Sofia; Demirbilek, Hüseyin; Güemes, María; Hussain, Khalid

doi:10.1016/s2213-8587(16)30323-0

Cited by 102 publications

(125 citation statements)

References 112 publications

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“…CHI is the commonest cause of persistent hypoglycemia in infancy and childhood, and results from dysregulated insulin secretion . The phenotype of CHI is variable and, although in many cases the genetic cause is unclear, a number of gene mutations have been identified, including many associated with MODY ( HNF1A , HNF4A , GCK , KCNJ11 , and ABCC8 ), in addition to non‐MODY‐associated genes ( GLUD1, HADH, UCP2, HK1 and SLC16A1 ). Furthermore, the same variants may cause both MODY and CHI, both within the same pedigree and even within the same individual at different times .…”

Section: Introductionmentioning

confidence: 99%

Whole-exome sequencing for mutation detection in pediatric disorders of insulin secretion: Maturity onset diabetes of the young and congenital hyperinsulinism

et al. 2018

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Section: Introductionmentioning

confidence: 99%

Whole-exome sequencing for mutation detection in pediatric disorders of insulin secretion: Maturity onset diabetes of the young and congenital hyperinsulinism

et al. 2018

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“…Regarding the type of mutation reported in ABCC8 which caused neonatal HH and diabetes later in life only few cases had a homozygous mutation (18), whilst the majority had heterozygous or compound heterozygous mutations (7,11,15,17,19,20). Biallelic (either homozygous or compound heterozygous) ABCC8 mutations usually cause severe, diazoxide unresponsive HH which often requires surgical management (3). Therefore, the number of medically managed cases, particularly those with long-term follow-up is very few.…”

Section: Treatment and Follow Upmentioning

confidence: 99%

“…Increased metabolism, resulting in an increased adenosine triphosphate (ATP)/adenosine diphosphate (ADP) ratio, leads to closure of the K ATP channel, depolarisation of the beta cell membrane and subsequent calcium influx through voltage-gated calcium channels. This in turn leads to insulin secretion via the exocytosis of secretory granules (2,3). Dysfunction of the K ATP channel can cause either congenital hyperinsulinism (CHI) or diabetes (neonatal or adult onset) (1,4,5,6,7,8,9).…”

mentioning

confidence: 99%

Congenital hyperinsulinism and evolution to sulfonylurea-responsive diabetes later in life due to a novel homozygous p.L171F ABCC8 mutation

Isik¹,

Demirbilek²,

Houghton³

et al. 2018

Jcrpe

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What is already known on this topic?Homozygous ABCC8 mutations cause severe persistent diffuse hyperinsulinemic hypoglycaemia (HH) which is usually diazoxide unresponsive and requires surgical therapy. In medically managed patients with congenital hyperinsulinism (CHI), disease symptoms become milder overtime. Hyperinsulinemic hypoglycemia at neonatal period and later diabetes have been reported in heterozygous mutation of HNF4A and HNF1A as well as heterozygous ABCC8 mutations What this study adds? We describe the first homozygous ABCC8 mutation with HH at neonatal period and evolution to complete insulin deficient, sulphonylurea responsive diabetes mellitus. Findings from present work which show a broad range of clinical spectrum from asymptomatic, mild symptomatic hypoglycemia, severe hypoglycemia as well as insulin deficient diabetes mellitus in family members with identical mutation confirms the phenotypical variations in ABCC8 mutations Present case report emphasizes the need for long-term follow up of patients with HH at neonatal period due to ABCC8 mutations, particularly those managed with medical therapy for risk of developing diabetes in later life. Abstract:Background: Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infants and children. Recessive inactivating mutations in the ABCC8 and KCNJ11 genes account for approximately 50 % of all CHI cases. Hyperinsulinaemic hypoglycaemia (HH) in infancy and diabetes in later life have been reported in subjects with HNF1A, HNF4A and ABCC8 mutations. Case report: Herein, we present a child who was diagnosed with CHI at birth, then developed diabetes mellitus at the age of 9 years due to a novel homozygous missense, p.L171F (c.511C>T) mutation in the exon 4 of ABCC8. The parents and one sibling were heterozygous carriers, whilst a younger sibling who had transient neonatal hypoglycemia was homozygous for the mutation. The mother and (maternal) uncle, who was also heterozygous for the mutation, developed diabetes within their third decade of life. The preliminary results of sulphonylurea (SU) treatment was suggestive for SU responsiveness. Patients with homozygous ABCC8 mutations can present with CHI in the newborn period, the hyperinsulinism can show variability in terms of clinical severity and age at presentation and can cause diabetes later in life. Patients with homozygous ABCC8 mutations who are managed medically should be followed as they may be at increased risk of developing diabetes.

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“…Impaired insulin secretion and insulin resistance are suggested to mediate those effects. Recently, it was also discussed the therapeutic potential of mTOR inhibitors to treat hypoglycemia and hyperinsulinemia (for review see Shah et al , 2016). Interestingly, it has been widely known that both, insulin and glucose, play pivotal roles during spermatogenesis (Martins et al , 2016; Meneses et al , 2016).…”

Section: Introductionmentioning

confidence: 99%

Mammalian target of rapamycin (mTOR): a central regulator of male fertility?

Jesus

Oliveira

Sousa

et al. 2017

Critical Reviews in Biochemistry and Molecular Biology

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Mammalian target of rapamycin (mTOR) is a central regulator of cellular metabolic phenotype and is involved in virtually all aspects of cellular function. It integrates not only nutrient and energy-sensing pathways but also actin cytoskeleton organization, in response to environmental cues including growth factors and cellular energy levels. These events are pivotal for spermato-genesis and determine the reproductive potential of males. Yet, the molecular mechanisms by which mTOR signaling acts in male reproductive system remain a matter of debate. Here, we review the current knowledge on physiological and molecular events mediated by mTOR in testis and testicular cells. In recent years, mTOR inhibition has been explored as a prime strategy to develop novel therapeutic approaches to treat cancer, cardiovascular disease, autoimmunity, and metabolic disorders. However, the physiological consequences of mTOR dysregulation and inhibition to male reproductive potential are still not fully understood. Compelling evidence suggests that mTOR is an arising regulator of male fertility and better understanding of this atypical protein kinase coordinated action in testis will provide insightful information concerning its biological significance in other tissues/organs. We also discuss why a new generation of mTOR inhibitors aiming to be used in clinical practice may also need to include an integrative view on the effects in male reproductive system.

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Hyperinsulinaemic hypoglycaemia in children and adults

Cited by 102 publications

References 112 publications

Whole-exome sequencing for mutation detection in pediatric disorders of insulin secretion: Maturity onset diabetes of the young and congenital hyperinsulinism

Whole-exome sequencing for mutation detection in pediatric disorders of insulin secretion: Maturity onset diabetes of the young and congenital hyperinsulinism

Congenital hyperinsulinism and evolution to sulfonylurea-responsive diabetes later in life due to a novel homozygous p.L171F ABCC8 mutation

Mammalian target of rapamycin (mTOR): a central regulator of male fertility?

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