Güemes Hidalgo, Maria; (2018) Characterisation of pancreatic hormones in children with hyperinsulinaemic hypoglycaemia. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Introduction: Insulin and glucagon are key hormones involved in glucose physiology and the secretion of both is dysregulated in children with hyperinsulinaemic hypoglycaemia (HH). Glucagon-like peptide 1 (GLP-1) and Glucose-dependent insulinotropic peptide (GIP) are incretins released in the gut in response to glucose ingestion. Amylin is secreted in response to nutrients and pancreatic polypeptide (PP) is released in the circulation in response to nutrient ingestion (especially protein and fat) and a glucose load. The roles of these hormones have not been fully explored in children with different types of HH and severe insulin resistance syndrome. / Aims: 1. To understand the role of insulin, glucagon, amylin and PP at a genetic, histological and circulating plasma concentrations level in different types of HH. 2. To identify the role of circulating GLP-1 and GIP during fast and feeds in children with HH. 3. To elucidate the role of insulin hepatic clearance (IHE) in children with HH. 4. To characterise the role of pancreatic and gut hormones in children with insulin resistance syndrome [(Donohue syndrome (DS)]. / Methods: Gene expression of insulin, glucagon, amylin and PP was determined by real-time quantitative Polymerase Chain Reaction (RTqPCR) from pancreatic samples of children with HH (n=6). These hormones were also localised by same-slide double-staining immunohistochemistry (IHC) in pancreata of children with HH (n=7). By the use of a multiplex immunoassay, circulating concentrations of the above hormones and GLP-1 and GIP were determined during fast (n=24) and after feeds [mixed meal (MM) and oral glucose tolerance test (OGTT)] (n=14) in HH children and in controls. IHE was determined by the C-peptide:insulin molar ratio (n=38). Pancreatic and gut peptides were also measured during MM test in children with DS (n=2). / Results: In pancreata of patients with HH, the expression of insulin is inappropriately high and not paralleled by that of amylin. The expression of glucagon is decreased in HH patients and there is no difference in PP expression between controls and HH cases. Histologically, amylin and PP do not co-localise with insulin, glucagon or each other in control or HH pancreata; and no difference was found in the localisation of these hormones when comparing control, diffuse and focal HH tissue. The plasma concentrations of amylin tend to decrease during a fast in HH cases as opposed to controls. In HH cases, MM test triggers a more potent response than OGTT for glucose, insulin, amylin, PP, GLP-1 and GIP and it does not suppress glucagon. The pattern of PP during fast, OGTT and MM is similar in HH patients to controls. GLP-1 and GIP are normally released in HH cases during OGTT and only in excess after MM, as it also happens for idiopathic postprandial hypoglycaemia (PPHH) where GIP concentrations are increased. Plasma circulating concentrations of pancreatic and gut hormones in controls and HH cases are included in this study. There is no difference in the IHE of children with HH versus controls. In DS patient’s high amylin levels accompany the supra-physiological concentrations of insulin, with low GIP and PP, whilst glucagon is undetectable. / Conclusions: There is an independent regulation of insulin and amylin in the β-cell of children with HH. This potentially indicates a β-cell preserved mechanism through amylin, to minimise the hypoglycaemia triggered by insulin in HH. There seems to be a limited, if any, role for PP in glucose regulation. The secretion of GLP-1 and GIP is not constitutively abnormal in all forms of HH, however raised GIP levels could explain idiopathic PPHH in children. This agrees with the potential use of incretin receptor blockers for some forms of HH. The robust response of glucose, pancreatic hormones and incretins to MM in children with HH indicates the relevance of feed modification strategies in the management of this condition. This study confirms that IHE is preserved in HH. Abnormal pancreatic and incretin levels may be contributing to the biochemical features of DS. RTqPCR methodology for investigating pancreatic hormones in children with HH has been optimised herein, however further studies with bigger number of samples are needed to confirm our findings.

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