| dc.description.abstract | ATP-dependent potassium (KATP) channels are present in the human pancreas, brain, nerve and muscle and play a crucial role in key biological pathways. In the pancreas, KATP channels regulate insulin secretion from beta cells in response to glucose. They comprise 4 Kir6.2 subunits, encoded by the KCNJ11 gene, which form the channel pore, and 4 SUR1 subunits, encoded by the ABCC8 gene, which regulate channel activity and form the binding site for sulphonylurea drugs. Mutations in KATP channel genes account for ~half of cases of neonatal diabetes, which is diabetes diagnosed in the first 6 months of life; this may be permanent (PNDM) requiring lifelong treatment, or transient (TNDM) where the diabetes remits and relapses in later childhood or adulthood. Activating mutations in the KCNJ11 gene are the commonest cause of PNDM. A genetic diagnosis is crucial for patients with these mutations because ~90% can be treated with oral sulphonylureas instead of insulin injections. Sulphonylureas can bind and close mutant KATP channels allowing endogenous insulin secretion and resulting in improved metabolic control and quality of life at least in the short-term. Severe sulphonylurea-related hypoglycaemia does not occur but mild-moderate episodes, typically related to food, have been reported by affected individuals. The long-term response to sulphonylurea therapy and the regulation of insulin secretion in response to food in people with KCNJ11 mutations remain key research questions with important clinical implications. Individuals with KCNJ11 PNDM can also have central nervous system (CNS) involvement; at its most severe this leads to Developmental delay, Epilepsy and Neonatal Diabetes (DEND) syndrome. Sulphonylurea therapy can also benefit the neurological features, which are thought to result from the action of sulphonylureas on brain KATP channels, although the response is only partial in contrast to the excellent glycaemic response. In order to provide appropriate multidisciplinary assessment and support, it is important to establish the specific neurological, psychiatric, and neuropsychological deficits that are present in children and adults with sulphonylurea-treated KCNJ11 neonatal diabetes, and their impact on affected families. The overall aim of this thesis is to assess the response to sulphonylurea therapy in patients with PNDM due to mutations in the KCNJ11 gene, by undertaking clinical studies that investigate the glycaemic response as well as the CNS features in affected individuals. In chapter 1 we assess the long-term efficacy and safety of sulphonylurea therapy in KCNJ11 PNDM, by following clinical outcomes relating to both glycaemia and neurological features over 10 years in 81 patients who transferred from insulin to sulphonylureas before December 2006. We show that sulphonylurea therapy is effective and safe long-term, with 93% of individuals remaining on sulphonylureas without adjunctive therapies at most recent follow-up with no reports of severe hypoglycaemia or severe side-effects in over 800 patient years, and normal growth and BMI in children. In addition, we show that neurological features are present in 38/81 individuals and despite initial improvement in 18 individuals on transfer to sulphonylureas, there is persistence of these features to some degree long-term. In chapter 2 we assess the physiological response to different foods in adults >18 years with sulphonylurea-treated KCNJ11 PNDM, by measuring glucose, insulin and glucagon levels after a high-protein meal and a high-carbohydrate meal in 5 affected individuals and comparing these with 5 non-diabetic controls. We show that individuals with sulphonylurea treated KCNJ11 PNDM have similar insulin levels in response to both a carbohydrate and protein meal despite having higher glucose values in response to a carbohydrate meal than to a protein meal. This contrasts with controls who have higher insulin secretion after carbohydrate than protein and therefore more tightly regulated glucose levels in response to both meals. The findings suggest that individuals with sulphonylurea-treated KCNJ11 PNDM cannot modulate insulin secretion in response to glucose, consistent with a dependence on non-KATP pathways for insulin secretion. In chapter 3 we assess the psychiatric and neuropsychological profile of children <18 years with sulphonylurea-treated KCNJ11 neonatal diabetes. In study A we use standardised questionnaires to measure psychiatric morbidity and impact in 10 children with KCNJ11 mutations and compared outcomes with school-age population norms. We show that psychiatric disorders are present in 6/10 children, mainly consisting of autism, attention deficit hyperactivity disorder (ADHD) and anxiety disorders. These disorders are related to the specific mutation (V59M or R201C), have high impact on families and frequently go unrecognised clinically. In study B we use a battery of neuropsychological tests to assess neuropsychological functioning in affected children and compare outcomes to non-diabetic sibling controls. We show that learning difficulties and specific neuropsychological impairments are frequently present even in those children with mutations not consistently associated with a severe CNS phenotype, and that such features are absent from unaffected sibling controls. In chapter 4 we investigate the neurological, neuropsychological and behavioural features in adults with KCNJ11 neonatal diabetes, by assessing 8 individuals (7 sulphonylurea-treated) with KCNJ11 mutations using standardised neuropsychological tests, questionnaires, and clinical history and examination. Outcomes are compared to 4 adults with neonatal diabetes due to mutations in the INS gene, thereby controlling for the presence of hyperglycaemia from birth. We show that adults with KCNJ11 mutations have learning difficulties, features of autism spectrum disorder (ASD), subtle motor dysfunction, moderately reduced IQ, and impaired attention, perceptual reasoning and working memory which persist despite long term sulfonylurea therapy and represent the major burden of disease once glycemia is well controlled on sulphonylureas. The severity of the CNS features varies with the specific mutation and they do not occur in individuals with neonatal diabetes due to INS mutations, suggesting they occur as a consequence of dysfunctional brain KATP channels as opposed to indirect effects of lifelong diabetes. The conclusions section summarises the data chapters and describes how the work fits together as a coherent whole, as well as identifying directions for future research specific to each of the studies undertaken. The research in this thesis offers original and novel insights into both the CNS features of KCNJ11 neonatal diabetes and the glycaemic response to sulphonylurea therapy. Patients with KCNJ11 neonatal diabetes represent a unique human experimental model for the study of KATP channel biological pathways in both the pancreas and brain. Treatment of the condition with sulphonylureas remains one of the best examples of precision medicine and illustrates the benefits of targeted treatments in monogenic disease. | en_GB |
