Albert Aynsley-Green

Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of β-oxidation in insulin secretion

A female infant of nonconsanguineous Indian parents presented at 4 months with a hypoglycemic convulsion. Further episodes of hypoketotic hypoglycemia were associated with inappropriately elevated plasma insulin concentrations. However, unlike other children with hyperinsulinism, this patient had a persistently elevated blood spot hydroxybutyrylcarnitine concentration when fed, as well as when fasted. Measurement of the activity of L-3-hydroxyacyl-CoA dehydrogenase in cultured skin fibroblasts with acetoacetyl-CoA substrate showed reduced activity. In fibroblast mitochondria, the activity was less than 5% that of controls. Sequencing of the short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) genomic DNA from the fibroblasts showed a homozygous mutation (C773T) changing proline to leucine at amino acid 258. Analysis of blood from the parents showed they were heterozygous for this mutation. Western blot studies showed undetectable levels of immunoreactive SCHAD protein in the childs fibroblasts. Expression studies showed that the P258L enzyme had no catalytic activity. We conclude that C773T is a disease-causing SCHAD mutation. This is the first defect in fatty acid beta-oxidation that has been associated with hyperinsulinism and raises interesting questions about the ways in which changes in fatty acid and ketone body metabolism modulate insulin secretion by the beta cell. The patients hyperinsulinism was easily controlled with diazoxide and chlorothiazide.

Practical management of hyperinsulinism in infancy

Hyperinsulinism in infancy is one of the most difficult problems to manage in contemporary paediatric endocrinology. Although the diagnosis can usually be achieved without difficulty, it presents the paediatrician with formidable day to day management problems. Despite recent advances in understanding the pathophysiology of hyperinsulinism, the neurological outcome remains poor, and there is often a choice of unsatisfactory treatments, with life long sequelae for the child and his or her family. This paper presents a state of the art overview on management derived from a consensus workshop held by the European network for research into hyperinsulinism (ENRHI). The consensus is presented as an educational aid for paediatricians and childrens nurses. It offers a practical guide to management based on the most up to date knowledge. It presents a proposed management cascade and focuses on the clinical recognition of the disease, the immediate steps that should be taken to stabilise the infant during diagnostic investigations, and the principles of definitive treatment.

Neonatal hypoglycaemia--the controversy regarding definition.

Major paediatric textbooks and the views of neonatologists in the United Kingdom were surveyed to establish a definition of neonatal hypoglycaemia. The definition ranged from a glucose concentration of less than 1 mmol/l to less than 4 mmol/l. Hypoglycaemia is recognised to cause neurological sequelae and yet there is no accepted definition of the lower limit of normality for circulating blood glucose concentrations.

Engineering a glucose-responsive human insulin-secreting cell line from islets of Langerhans isolated from a patient with persistent hyperinsulinemic hypoglycemia of infancy

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a neonatal disease characterized by dysregulation of insulin secretion accompanied by profound hypoglycemia. We have discovered that islet cells, isolated from the pancreas of a PHHI patient, proliferate in culture while maintaining a beta cell-like phenotype. The PHHI-derived cell line (NES2Y) exhibits insulin secretory characteristics typical of islet cells derived from these patients, i.e. they have no KATP channel activity and as a consequence secrete insulin at constitutively high levels in the absence of glucose. In addition, they exhibit impaired expression of the homeodomain transcription factor PDX1, which is a key component of the signaling pathway linking nutrient metabolism to the regulation of insulin gene expression. To repair these defects NES2Y cells were triple-transfected with cDNAs encoding the two components of the KATP channel (SUR1 and Kir6.2) and PDX1. One selected clonal cell line (NISK9) had normal KATPchannel activity, and as a result of changes in intracellular Ca2+ homeostasis ([Ca2+] i ) secreted insulin within the physiological range of glucose concentrations. This approach to engineering PHHI-derived islet cells may be of use in gene therapy for PHHI and in cell engineering techniques for administering insulin for the treatment of diabetes mellitus.

The endocrinology of feeding in the newborn

During the last 20 years there has been an explosion of interest in and knowledge of hormones and regulatory peptides manufactured by specialized cells in the gut. Evidence has been presented in this chapter to suggest that these substances have essential roles to play in the effective utilization of food in the human adult, and that they also have an essential role to play in the differentiation and functional development of the fetal gut. It is, perhaps, during the days immediately following birth that they have their greatest and most important influence, in determining the successful adaptation to postnatal enteral feeding. There is good evidence to show that the initiation of enteral feeding is an important environmental trigger which provokes massive surges in the concentrations of these peptides in the first postnatal days in both premature and full term infants. The mode of administration and the composition of feeds have further influences, whilst deprivation of enteral feeding prevents the appearance of postnatal hormonal surges. In view of the fact that sub-nutritional volumes of milk are capable of inducing these surges, the concept of minimal enteral feeding in seriously ill premature and full term infants and even the therapeutic use of regulatory peptides warrants further investigation. Finally, it is evident that much more study is required to define the ontogeny, regulation of secretion, interaction and mechanism of effect of these fascinating substances.

Use of central and peripheral temperature measurements in care of the critically ill child

In the presence of constant ambient conditions, a fall in effective circulating blood volume causes peripheral vasoconstriction which is reflected in a fall in peripheral (great toe) temperature and thus in an increase in the central (rectal)/peripheral temperature gradient. We report 5 illustrative clinical situations showing the value of this technique in the medical care of critically ill children. We suggest that such measurements are useful, first in the recognition of dehydration and in assessing the response to treatment, secondly in managing shock, and finally, in differentiating dehydration fever from other causes of fever.

Infantile hyperinsulinism associated with enteropathy, deafness and renal tubulopathy: clinical manifestations of a syndrome caused by a contiguous gene deletion located on chromosome 11p.

We describe the clinical features of a new syndrome causing hyperinsulinism in infancy (HI), severe enteropathy, profound sensorineural deafness, and renal tubulopathy in three children born to two pairs of consanguineous parents. This combination of clinical features is explained by a 122-kb contiguous gene deletion on the short arm of chromosome 11. It deletes 22 of the 39 exons of the gene coding for the SUR1 component of the KATP channel on the pancreatic beta-cell thereby causing severe HI. It also deletes all but two of the 28 exons of the USH1C gene, which causes Usher syndrome and is important for the normal development and function of the ear and the eye, the gastrointestinal tract, and the kidney, thereby accounting for the symptoms of deafness, vestibular dysfunction and retinal dystrophy seen in type 1 Usher syndrome, diarrhoea, malabsorption, and tubulopathy. This contiguous gene deletion provides important insights into the normal development of several body organ systems.

Severe transient neonatal hyperinsulinism associated with hyperlactataemia in non-asphyxiated infants

Transient hyperinsulinism (HI) occurs in infants born to diabetic mothers, in infants experiencing perinatal asphyxia and in infants with intrauterine growth retardation. The precise mechanism of transient HI in these different aetiologies is not fully understood. Lactic acidosis is commonly seen in neonates as a secondary phenomenon due to hypoxia, hypovolaemia, anaemia and infection. The combination of transient HI and lactic acidosis is rare. We present the clinical and biochemical features of five infants presenting with transient HI associated with hyperlactataemia in the absence of markers of perinatal stress. This combination lasted for 3-4 weeks with complete resolution except in one patient in whom the hyperinsulinism lasted until 6 months before resolution. The precise mechanism of this association is not clear but may be related either to immaturity of the pyruvate dehydrogenase complex or to the accumulation of abnormal intramitochondrial intermediary metabolites. Infants presenting with HI should have a free flowing blood sample drawn for the measurement of plasma lactate levels.

Characterization of Ion Channels in Stimulus-Secretion Coupling in Pancreatic Islets

The regulation of insulin secretion from beta-cells of the pancreatic islets of Langerhans is a highly integrated process involving several plasma membrane ion channels. The key to our understanding of the normal process is the hypothesis that glucose-induced closure of K+ channels leads to a depolarization of the cell membrane potential and the opening of voltage-gated Ca2+ channels. Support for this is provided by direct electrophysiological recordings of ion channel activity, and by recent data that have revealed how gene defects in ion channel subunits leads to the loss of regulated insulin secretion. Here, we review the general features of stimulus-response coupling in beta-cells, and how novel initiatives are providing key insights into beta-cell pathogenesis.

Neonatal Hyperinsulinism; New Insights Into KATP Channel Independent Stimulation of Insulin secretion in Human β-cells • 947

Neonatal Hyperinsulinism; New Insights Into KATP Channel Independent Stimulation of Insulin secretion in Human β-cells • 947