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      Reduced Glycemic Variability in Diazoxide-Responsive Children with Congenital Hyperinsulinism Using Supplemental Omega-3-Polyunsaturated Fatty Acids; A Pilot Trial with MaxEPA R

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          Abstract

          Objective: Congenital hyperinsulinism (CHI) is a rare condition of hypoglycemia where therapeutic options are limited and often complicated by side-effects. Omega-3-polyunsaturated fatty acids (PUFA), which can suppress cardiac myocyte electrical activity, may also reduce ion channel activity in insulin-secreting cells. PUFA supplements in combination with standard medical treatment may improve glucose profile and may reduce glycemic variability in diazoxide-responsive CHI.

          Design: Open label pilot trial with MaxEPA R liquid (eicosapentaenoic and docosahexaenoic acid) PUFA (3 ml/day for 21 days) in diazoxide-responsive CHI patients ( https://eudract.ema.europa.eu/, EudraCT number 201100363333).

          Methods: Glucose levels were monitored pre-treatment, end of treatment, and at follow-up by subcutaneous continuous glucose monitoring systems (CGMS) in 13 patients (7 girls) who received PUFA. Outcome measures were an improved glucose profile, reduced glycemic variability quantified by a reduction in the frequency of glucose levels <4 and >10 mmol/l, and safety of PUFA. All children were analyzed either as intention to treat ( n = 13) or as per protocol ( n = 7).

          Results: Mean (%) CGMS glucose levels increased by 0.1 mmol/l (2%) in intention to treat and by 0.4 mmol/l (8%) in per protocol analysis ( n = 7). The frequency of CGMS <4 mmol/l was significantly less at the end of treatment than in the pre-treatment period [556 (7%) vs. 749 (10%)]. Similarly, the frequency of CGMS >10 mmol/l, was also less at the end of treatment [27 (0.3%) vs. 49 (0.7%)]. Except for one child with increased LDL cholesterol, all safety parameters were normal.

          Conclusion: MaxEPA R was safe and reduced glycemic variability, but did not increase glucose profiles significantly in diazoxide-responsive CHI. The supplemental value of PUFA should be evaluated in a comprehensive clinical trial.

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          Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism

          Ritika R Kapoor, Sarah Flanagan, Ved Arya … (2013)
          Background Congenital hyperinsulinism (CHI) is a clinically heterogeneous condition. Mutations in eight genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A and HNF1A) are known to cause CHI. Aim To characterise the clinical and molecular aspects of a large cohort of patients with CHI. Methodology Three hundred patients were recruited and clinical information was collected before genotyping. ABCC8 and KCNJ11 genes were analysed in all patients. Mutations in GLUD1, HADH, GCK and HNF4A genes were sought in patients with diazoxide-responsive CHI with hyperammonaemia (GLUD1), raised 3-hydroxybutyrylcarnitine and/or consanguinity (HADH), positive family history (GCK) or when CHI was diagnosed within the first week of life (HNF4A). Results Mutations were identified in 136/300 patients (45.3%). Mutations in ABCC8/KCNJ11 were the commonest genetic cause identified (n=109, 36.3%). Among diazoxide-unresponsive patients (n=105), mutations in ABCC8/KCNJ11 were identified in 92 (87.6%) patients, of whom 63 patients had recessively inherited mutations while four patients had dominantly inherited mutations. A paternal mutation in the ABCC8/KCNJ11 genes was identified in 23 diazoxide-unresponsive patients, of whom six had diffuse disease. Among the diazoxide-responsive patients (n=183), mutations were identified in 41 patients (22.4%). These include mutations in ABCC8/KCNJ11 (n=15), HNF4A (n=7), GLUD1 (n=16) and HADH (n=3). Conclusions A genetic diagnosis was made for 45.3% of patients in this large series. Mutations in the ABCC8 gene were the commonest identifiable cause. The vast majority of patients with diazoxide-responsive CHI (77.6%) had no identifiable mutations, suggesting other genetic and/or environmental mechanisms.
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            Congenital hyperinsulinism: current trends in diagnosis and therapy

            Jean-Baptiste Arnoux, Virginie Verkarre, Cécile Saint-Martin … (2011)
            Congenital hyperinsulinism (HI) is an inappropriate insulin secretion by the pancreatic β-cells secondary to various genetic disorders. The incidence is estimated at 1/50, 000 live births, but it may be as high as 1/2, 500 in countries with substantial consanguinity. Recurrent episodes of hyperinsulinemic hypoglycemia may expose to high risk of brain damage. Hypoglycemias are diagnosed because of seizures, a faint, or any other neurological symptom, in the neonatal period or later, usually within the first two years of life. After the neonatal period, the patient can present the typical clinical features of a hypoglycemia: pallor, sweat and tachycardia. HI is a heterogeneous disorder with two main clinically indistinguishable histopathological lesions: diffuse and focal. Atypical lesions are under characterization. Recessive ABCC8 mutations (encoding SUR1, subunit of a potassium channel) and, more rarely, recessive KCNJ11 (encoding Kir6.2, subunit of the same potassium channel) mutations, are responsible for most severe diazoxide-unresponsive HI. Focal HI, also diazoxide-unresponsive, is due to the combination of a paternally-inherited ABCC8 or KCNJ11 mutation and a paternal isodisomy of the 11p15 region, which is specific to the islets cells within the focal lesion. Genetics and 18F-fluoro-L-DOPA positron emission tomography (PET) help to diagnose diffuse or focal forms of HI. Hypoglycemias must be rapidly and intensively treated to prevent severe and irreversible brain damage. This includes a glucose load and/or a glucagon injection, at the time of hypoglycemia, to correct it. Then a treatment to prevent the recurrence of hypoglycemia must be set, which may include frequent and glucose-enriched feeding, diazoxide and octreotide. When medical and dietary therapies are ineffective, or when a focal HI is suspected, surgical treatment is required. Focal HI may be definitively cured when the partial pancreatectomy removes the whole lesion. By contrast, the long-term outcome of diffuse HI after subtotal pancreatectomy is characterized by a high risk of diabetes, but the time of its onset is hardly predictable.
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              Fish oil and omega-3 fatty acids in cardiovascular disease: do they really work?

              Johanna M. Geleijnse, Satoshi Yasuda, Daan Kromhout … (2012)
              Omega-3 fatty acids, which are found abundantly in fish oil, exert pleiotropic cardiometabolic effects with a diverse range of actions. The results of previous studies raised a lot of interest in the role of fish oil and omega-3 fatty acids in primary and secondary prevention of cardiovascular diseases. The present review will focus on the current clinical uses of omega-3 fatty acids and provide an update on their effects. Since recently published trials in patients with coronary artery diseases or post-myocardial infarction did not show an effect of omega-3 fatty acids on major cardiovascular endpoints, this review will examine the limitations of those data and suggest recommendations for the use of omega-3 fatty acids.
              Article 0 comments Cited 71 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Journal
                Journal ID (nlm-ta): Front Endocrinol (Lausanne)
                Journal ID (iso-abbrev): Front Endocrinol (Lausanne)
                Journal ID (publisher-id): Front. Endocrinol.
                Title: Frontiers in Endocrinology
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 1664-2392
                Publication date (Electronic preprint): 10 January 2014
                Publication date (Electronic): 12 March 2014
                Publication date Collection: 2014
                Volume: 5
                Electronic Location Identifier: 31
                Affiliations
                [1] 1Department of Paediatric Endocrinology, Manchester Academic Health Science Centre, Royal Manchester Children’s Hospital, Central Manchester University Hospitals NHS Foundation Trust , Manchester, UK
                [2] 2Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester , Manchester, UK
                [3] 3Institute of Population Health, Faculty of Medical and Human Sciences, University of Manchester , Manchester, UK
                [4] 4School of Mathematics, University of Manchester , Manchester, UK
                [5] 5Faculty of Life Sciences, University of Manchester , Manchester, UK
                Author notes

                Edited by: Fabrizio Barbetti, University of Tor Vergata, Italy

                Reviewed by: Arianna Maiorana, Bambino Gesù Children’s Hospital, Italy; Carlo Dionisi-Vici, Bambino Gesù Children’s Research Institute, Italy

                *Correspondence: Indraneel Banerjee, Department of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Oxford Road, Manchester M13 9WL, UK e-mail: indi.banerjee@ 123456manchester.ac.uk ; indi.banerjee@ 123456cmft.nhs.uk

                This article was submitted to Pediatric Endocrinology, a section of the journal Frontiers in Endocrinology.

                Article
                DOI: 10.3389/fendo.2014.00031
                PMC ID: 3952031
                PubMed ID: 24659984
                SO-VID: 1068860d-75f9-4905-a6db-86f84e3e59fc
                Copyright © Copyright © 2014 Skae, Avatapalle, Banerjee, Rigby, Vail, Foster, Charalambous, Bowden, Padidela, Patel, Ehtisham, Cosgrove, Dunne and Clayton.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                Date received : 16 December 2013
                Date accepted : 21 February 2014
                Page count
                Figures: 7, Tables: 3, Equations: 0, References: 45, Pages: 9, Words: 7172
                Categories
                Subject: Endocrinology
                Subject: Clinical Trial

                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: congenital hyperinsulinism,hypoglycemia,clinical trial,omega-3-polyunsaturated fatty acids,diazoxide
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: congenital hyperinsulinism, hypoglycemia, clinical trial, omega-3-polyunsaturated fatty acids, diazoxide

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