J. A. Edge

The risk and outcome of cerebral oedema developing during diabetic ketoacidosis

BACKGROUND Cerebral oedema is a major cause of morbidity and mortality in children with insulin dependent diabetes. AIMS To determine the risk and outcome of cerebral oedema complicating diabetic ketoacidosis (DKA). METHODS All cases of cerebral oedema in England, Scotland, and Wales were reported through the British Paediatric Surveillance Unit between October 1995 and September 1998. All episodes of DKA were reported by 225 paediatricians identified as involved in the care of children with diabetes through a separate reporting system between March 1996 and February 1998. Further information about presentation, management, and outcome was requested about the cases of cerebral oedema. The risk of cerebral oedema was investigated in relation to age, sex, seasonality, and whether diabetes was newly or previously diagnosed. RESULTS A total of 34 cases of cerebral oedema and 2940 episodes of DKA were identified. The calculated risk of developing cerebral oedema was 6.8 per 1000 episodes of DKA. This was higher in new (11.9 per 1000 episodes) as opposed to established (3.8 per 1000) diabetes. There was no sex or age difference. Cerebral oedema was associated with a significant mortality (24%) and morbidity (35% of survivors). CONCLUSIONS This first large population based study of cerebral oedema complicating DKA has produced risk estimates which are more reliable and less susceptible to bias than those from previous studies. Our study indicates that cerebral oedema remains an important complication of DKA during childhood and is associated with significant morbidity and mortality. Little is known of the aetiology of cerebral oedema in this condition and we are currently undertaking a case control study to address this issue.

Evidence for a Role for Insulin and Growth Hormone in Overnight Regulation of 3-Hydroxybutyrate in Normal and Diabetic Adolescents

Objective— To determine the relative effects of growth hormone and insulin on ketogenesis during puberty. Research Design and Methods— We studied overnight changes in plasma ketones—3-hydroxybutyrate and acetoacetate—in 35 normal and 26 IDDM adolescents at different stages of puberty. The diabetic adolescents either were on their normal insulin regimen or were studied during an overnight euglycemic clamp with or without suppression of endogenous growth hormone release. Results— Total ketone body and 3-hydroxybutyrate concentrations in the normal adolescents rose significantly from 2000 (29 ± 5 μM), reaching a peak at 0200 (103 ± 16 μM, P < 0.001 vs. 2000). After a brief fall, a further rise occurred before breakfast. Fasting 3-hydroxybutyrate concentrations showed a negative correlation with fasting insulin levels (r = −0.46, P = 0.005) and decreased with advancing puberty, while insulin concentrations increased. In the diabetic patients on their usual insulin regimen, free insulin levels waned overnight, and an exaggerated rise in ketones was observed before breakfast. During the euglycemic clamp studies, ketone levels were higher than normal throughout the night. Mean overnight growth hormone and free insulin levels also were higher than in the normal control subjects. The addition of the anticholinergic drug pirenzepine reduced growth hormone secretion and obliterated the early-night peak of 3-hydroxybutyrate. Conclusions— We conclude that the early-night peak of ketone concentrations is related to growth hormone release, whereas the fasting levels are largely determined by insulin concentration. Inadequate insulin delivery in the presence of the high growth hormone concentrations characteristic of diabetic adolescents could lead to rapid decompensation and ketoacidosis.

The frequency and amplitude of growth hormone secretory episodes as determined by deconvolution analysis are increased in adolescents with insulin dependent diabetes mellitus and are unaffected by short‐term euglycaemia

OBJECTIVE High overnight plasma growth hormone (GH) levels in insulin‐dependent diabetes mellitus (IDDM) are reflected in both an increase in the GH pulse amplitude and elevated baseline GH concentrations. To determine whether these are a result of an increase in GH secretory episodes, we undertook deconvolution analysis of overnight GH profiles using previously determined half‐life data.

Impact of increased growth hormone secretion on carbohydrate metabolism in adolescents with diabetes

Growth hormone (GH) and fasting insulin concentrations rise during puberty in normal subjects. Any increase in GH secretion in adolescents with insulin‐dependent diabetes mellitus (IDDM) might be expected to lead to further insulin resistance and metabolic disturbance. Despite the high incidence of delayed growth in IDDM, the relationship between Gli, insulin‐like growth factor I (IGF‐I) and IGF binding protein 1 (IGFBP‐1) has not been clearly established. Twenty‐six adolescents with IDDM and 34 healthy siblings underwent measurement of their overnight GH secretory profiles (20.00–08.00 hours, 15‐minute sampling). The diabetic subjects were studied either on their normal insulin regimen (n = 15) or during a euglycaemic clamp (n = 26). A second clamp study was undertaken (n = 7) with addition of pirenzepine to suppress GH secretion. GH profiles in the diabetic subjects were characterized by increases in both pulse amplitude and baseline GH concentrations . Deconvolution analysis also revealed an increase in the frequency of Gil secretory episodes. In the subjects with diabetes, a direct link between the dawn rise in insulin requirements, increased concentrations of 9‐hydroxybutyrate and the elevated concentrations of GH was established. These abnormalities were reversed by the suppression of GH pulse amplitude following pirenzepine. Serum IGF‐I concentrations and IGF‐I bioactivity in the diabetic subjects were low and were positively correlated with mean GH concentrations. In conclusion, well controlled adolescents with IDDM show persisting abnormalities of GH, β‐hydroxybutyrate and IGF‐I despite normoglycaemia. The role of inappropriate insulin delivery in the development of these abnormalities is discussed.

Protocol for systematic review of evidence on the determinants and influence of early glycaemic control in childhood-onset type 1 diabetes

BackgroundLandmark studies in adult-onset type 1 diabetes (T1D) populations indicate that improved glycaemic control through use of intensive insulin therapy is strongly associated with reduced risk for the development of diabetes-related complications and mortality in later years. However, it is unclear whether these associations can be extrapolated to childhood-onset T1D, given the influence of other important biological and psychosocial determinants of glycaemic control, particularly during adolescence. The aims of the review are (1) to investigate the impact of early glycaemic control (within the first 2xa0years after diagnosis) on subsequent glycaemic trends and risk of complications during the life course of childhood-onset T1D and (2) to identify the predictors of early glycaemic control in children and young people (0–25xa0years).MethodsThe methods used in this study are systematic identification, review and mapping of quantitative (intervention and observational) and qualitative literature; assessing the effect and predictors of early glycaemic control in T1D (diagnosed ≤18xa0years) on risk or prevalence of later complications. An iterated search strategy, with no language or period restrictions, was applied to identify studies from six electronic databases. This will be supplemented by hand-searching (reference lists and contacting authors of studies meeting the inclusion criteria). Studies assessing glycaemic control within the first 2xa0years of diagnosis in children (at baseline) will be quality-assessed against predefined criteria and mapped descriptively to future health outcomes. Extracted data will be analysed and synthesised using narrative and forest plots or harvest plots for quantitative evidence and thematic analyses for qualitative studies. To get a deeper understanding of the predictors of early glycaemic control in reducing complications in childhood and adult life, we will integrate qualitative and quantitative evidence using mixed methods or parallel synthesis approach.DiscussionThese linked reviews will be the first to systematically investigate the effects of early glycaemic control and integrate both the quantitative and qualitative evidence on predictors of early glycaemic control in childhood-onset T1D in reducing future diabetes complications. This will help identify and map current research and inform development of effective future interventions.Systematic review registrationPROSPERO CRD42015024546

Predictors of glycemic control in the first year of diagnosis of childhood onset type 1 diabetes: A systematic review of quantitative evidence

Early glycemic control is associated with reduced future vascular complications risk in type 1 diabetes (T1D). The aim of this study was to systematically review evidence on the predictors of glycemic control within 12u2009months of diagnosis of childhood onset T1D. Inclusion criteria for the electronic search were: interventional and observational studies that assessed and quantified an association between the predictor and glycemic control within 12u2009months of diagnosis of childhood onset T1D. A total of 17u2009915 articles were identified from 6 databases and 20 studies were finally included in the analysis. Harvest plots and narrative synthesis were used to summarize data from intervention (nu2009=u20090), prospective/retrospective cohort (nu2009=u200915), and cross‐sectional (nu2009=u20095) studies. Significant predictors of poorer glycemic control 0 to 3u2009months after diagnosis were older age and female gender. Non‐white ethnicity, diabetes autoantibody positivity, measures of deprivation, and non‐private health insurance were potential predictors. Predictors of poorer glycemic control 4 to 12u2009months after diagnosis were: older age, non‐white ethnicity, a single parent family, high hemoglobin A1c (HbA1c) levels at diagnosis, longer T1D duration, and non‐intensive insulin therapy. Potential predictors included: family with health issues, clinical factors, and comorbidities at diagnosis. Most significant predictors of poor glycemic control within 12u2009months of diagnosis of childhood onset T1D are non‐modifiable. These factors need to be recognized and addressed through individualized and multidisciplinary diabetes care. Further research is required to confirm the association of potential predictors with early glycemic control.