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Title: Physiology and pharmacology of glucagon and somatostatin in children with congenital hyperinsulinism
Author: Shah, P. H.
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2017
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Introduction: The endocrine portion of pancreas secretes various hormones like insulin (by β-cells), glucagon (by α-cells) and somatostatin (by δ-cells), which regulates glucose metabolism. Hyperinsulinaemic hypoglycaemia (HH) is a relatively rare cause of hypoglycaemia in children and can lead to permanent neurological damage if not treated promptly. Histologically, there are mainly two types of hyperinsulinism – diffuse and focal. Long-acting somatostatin analogue (Lanreotide autogel, LA) has been used in adults with neuroendocrine conditions through its effect on somatostatin receptors 2 (SSTR2) and 5 (SSTR5). Recently, there have been case reports of use of LA therapy in diffuse form of congenital hyperinsulinism. Glucagon infusion is used in the management of children with HH. There are no studies on the pharmacology of LA and glucagon in children with HH. Aims: 1. To understand pharmacokinetics/pharmacodynamics of long acting somatostatin analogue (Somatuline autogel or Lanreotide autogel) and principles of radioimmunoassay for measuring Lanreotide concentration in children with HH. 2. To determine somatostatin and glucagon receptor expression on the diffuse, focal and normal pancreatic islets using immunohistochemistry. 3. To understand the role of glucagon and somatostatin and principles of radioimmunoassay for measuring them in children with HH. 4. To understand Pharmacokinetics of intravenous glucagon infusion in children with HH and understanding the principles of radioimmunoassay for measuring glucagon concentration. Methods: 1. Children were started on 30mg LA administered every 4-weekly. Plasma LA concentrations were collected in both groups (those on diazoxide and octreotide) and measured by radioimmunoassay (>3years of age) after obtaining written consent from child and parents. The samples were collected at times 0,+1,+2,+4,+24 and +96 hours post 1st dose, before each dose for 6 months and then at 12 months of treatment. Children >3 years of age had paediatric quality of life (PedsQL) assessment and continuous glucose monitoring (CGMS) pre and 1-year post-LA. 2. Formalin fixed pancreatic tissue sections were studied on those children who had pancreatectomy prior to starting LA therapy for immunohistochemistry. 3. Children admitted for management of HH were included in the study after obtaining written consent from child and parents. Plasma insulin, glucagon and somatostatin were collected at the start and end of the fast or at the time of hypoglycaemia. Glucagon and somatostatin were measured by radioimmunoassay. Descriptive statistics mean, standard deviation (SD) and three quartiles (Q1, Q2 & Q3) were obtained to check normality assumptions for patients with HH and control group respectively. 4. Children admitted for management of HH in a tertiary hospital were included in the study after obtaining written consent from child and parents. Plasma glucagon concentrations measured by radioimmunoassay (in pmol/l) were collected at times 0min, +30min, +60min and +90min after initiation of glucagon infusion (at 1mcg/kg/hour; 2.5mcg/kg/hour and 5mcg/kg/hour respectively). Also, blood glucose was measured at the same times. Glucagon concentrations were checked for normality assumptions. Data was analysed using log transformation. Results: 1. 21 children were commenced on LA. Pharmacokinetic data on 21 children showed that LA concentrations significantly peak after 2-4 hours of administration. After the first dose of LA, there was a strong correlation (r=0.836, p-value<0.001) between the LA concentration and blood glucose. There was no significant difference in LA concentrations between two groups (diazoxide and octreotide) at each time period. Blood glucose concentrations <3.5mmol/l were significantly reduced 1-year post-LA compared with pre-LA (p-value = 0.004). The quality of life improved in health, emotion, social, school and psychosocial functioning 1 year post commencing LA. 2. SSTR2 and SSTR5 expression was greater in diffuse and normal compared to focal pancreatic tissue. 3. 26 children with HH and 7 children as controls (resolved HH) were included in the study. Both mean and median were different and hence 50th centile (Q2 or median) is considered for calculation. Among HH patients, median insulin concentration was significantly increased at the start of fast compared to end of fast (p-value = 0.001). There was no significant change in glucagon and somatostatin concentration at the start and at the end of the fast (at the time of hypoglycaemia) (p-value >0.05). Among control group, median insulin concentration was significantly decreased and glucagon concentration was significantly increased (p-value < 0.05) at the end of the fast respectively. However, there was no significant change in somatostatin concentration at the start and end of the fast (p-value >0.05). 4. 12 children were included in the study. Mean log glucagon (LnGlucagon) concentration at glucagon dose of 1 mcg/kg/hour (4 patients), 2.5 mcg/kg/hour (4 patients) and 5 mcg/kg/hour (4 patients) were 3.296±0.448, 4.446±1.426 and 3.928±1.018 respectively, with an overall mean of 3.88 ± 1.12. There was a significant difference in concentrations between the dose of 1 mcg/kg/hour with 2.5 and 5 mcg/kg/hour whereas no significant difference was observed between 2.5 and 5 mcg/kg/hour doses. LnGlucagon concentrations significantly increased with all three doses (p-value <0.001). There was a strong positive correlation (r=0.619, p-value=0.011) between glucagon dose 5mcg/kg/hour and blood glucose concentrations. Conclusion: 1. Significant benefits were observed in terms of frequency of hypoglycaemia and quality of life one year after starting LA therapy. 2. Immunohistochemistry suggests that diffuse disease is more likely to respond to LA than focal disease. 3. This study suggests that in HH glucagon secretion is severely impaired from the alpha-cell whereas somatostatin secretion from the delta-cell is unaffected. The mechanisms that lead to impaired glucagon secretion in HH are unknown. Somatostatin does not seem to have any significant role as a glucoregulatory hormone in patients with HH. 4. This is the first study to measure plasma glucagon concentrations in response to an intravenous infusion of glucagon. This study shows that 2.5-5mcg/kg/hour of IV glucagon can increase blood glucose levels significantly.
Supervisor: Hussain, K. ; Amin, R. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available