Ethnic variation in the correlation between waist to height ratio and total daily insulin requirement in children with type 1 diabetes: a cross-sectional study.

INTRODUCTION: Total daily insulin required to achieve glycaemic control in type 1 diabetes (T1D) depends on numerous factors. Correlation of insulin requirement to body mass index and waist circumference has been variably reported in the literature and that of waist-to-height ratio has not been studied. AIMS: To study the correlation between daily insulin requirement [total daily dose (TDD)] and waist-to-height ratio (WHtR) in a multiethnic population. METHODS: A cross-sectional study of children (5-18 years) with T1D attending a diabetes clinic in a multiethnic population in Bradford, UK was conducted. Physical measurements were undertaken in the clinic setting and data collected from case notes and patients/carers. RESULTS: Sixty nine patients with mean age 12.7(±3.1) yr, duration of diabetes 5.4(±3.5) yr and hemoglobin A1c (HbA1c) 80(±18)mmol/mol(9.5 ± 1.6%) were recruited. Nearly 54% (n = 37) were white and 46% were non-white (29 Asian Pakistani; 1 Indian; 2 mixed White Afro-Caribbean). The two groups had similar demographics and disease profiles. Non-whites compared with whites had a higher prevalence of obesity (15 vs 5%, p < 0.01), family history of type 2 diabetes (T2D) (49% vs. 33%), microalbuminuria (22% vs. 11%, p < 0.05) and deprivation (mean index of multiple deprivation score 42 vs. 30, p < 0.001). WHtR and TDD were poorly correlated in the whole group. There was however a significant positive correlation in Caucasians (r = 0.583, N = 37, p < 0.01) and a negative correlation in Asian Pakistanis (r = -0.472, N = 32, p < 0.01); with a significant negative correlation seen in subjects with relatives with T2D (r = -0.86, N = 6, p = 0.02). CONCLUSIONS: The variation in correlations highlights that the two ethnic groups behave differently and should therefore be studied separately with regards to factors influencing insulin requirements with careful consideration to the presence of parental IR. Further prospective studies are required to explore the reasons for these differences.

Presentation and characteristics of children with screen-detected type 1 diabetes: learnings from the ELSA general population pediatric screening study.

INTRODUCTION: We describe the identification and management of general population screen-detected type 1 diabetes (T1D) and share learnings for best practice. RESEARCH DESIGN AND METHODS: Children diagnosed with T1D through a general population screening initiative, the EarLy Surveillance for Autoimmune diabetes (ELSA) study, were reviewed and described.Parents provided written, informed consent for inclusion in the case series. RESULTS: 14 children with insulin requiring (stage 3) T1D are described. These cases offer unique insights into the features of screen-detected T1D. T1D is identified sooner through screening programs, characterized by absent/short symptom duration, median presenting glycated hemoglobin 6.6% (49 mmol/mol) and insulin requirements<0.5 units/kg/day. ELSA identified four children at stage 3 and another 4 progressed within 4 months of ELSA completion, including two single seropositive children. Six children developed stage 3 T1D prior to ELSA completion, including two children (14%, n=2/14) with diabetic ketoacidosis prior to confirmed antibody status. CONCLUSIONS: There are three main learnings from this case series. First, T1D identified through screening is at an earlier stage of its natural history and requires personalized insulin regimens with lower total daily insulin doses. Second, single autoantibody seropositivity can rapidly progress to stage 3. Finally, insulin requirement can manifest at any stage of the T1D screening pathway, and therefore early education around symptom recognition is essential for families participating in screening programs.

An SCN9A channelopathy causes congenital inability to experience pain.

The complete inability to sense pain in an otherwise healthy individual is a very rare phenotype. In three consanguineous families from northern Pakistan, we mapped the condition as an autosomal-recessive trait to chromosome 2q24.3. This region contains the gene SCN9A, encoding the alpha-subunit of the voltage-gated sodium channel, Na(v)1.7, which is strongly expressed in nociceptive neurons. Sequence analysis of SCN9A in affected individuals revealed three distinct homozygous nonsense mutations (S459X, I767X and W897X). We show that these mutations cause loss of function of Na(v)1.7 by co-expression of wild-type or mutant human Na(v)1.7 with sodium channel beta(1) and beta(2) subunits in HEK293 cells. In cells expressing mutant Na(v)1.7, the currents were no greater than background. Our data suggest that SCN9A is an essential and non-redundant requirement for nociception in humans. These findings should stimulate the search for novel analgesics that selectively target this sodium channel subunit.

Impact of COVID-19 on Children and Young Adults With Type 2 Diabetes: A Narrative Review With Emphasis on the Potential of Intermittent Fasting as a Preventive Strategy.

Background: The world is still struggling to control the COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The level of uncertainty regarding the virus is still significantly high. The virus behaves differently in children and young adults. Most children and adolescents are either asymptomatic or have mild symptoms. They generally have a very good prognosis. However, it is not well-known whether children and young adults with type 2 diabetes are at risk of getting a severe infection of COVID-19. Many Muslim children with type 2 diabetes have been performing dawn to dusk fasting during the month of Ramadan, before and during the COVID-19 pandemic, and the impact of this on their health has not been well investigated. Previous studies in adults have suggested that intermittent fasting may be beneficial in different ways including reversal of type 2 diabetes and prevention of COVID-19 infection. Objective: The primary aim of this narrative review is to summarise the impacts of the COVID-19 pandemic on children and young adults with type 2 diabetes, and to identify the knowledge gaps in the literature. It also explores the potential of intermittent fasting in reversing the pathogenesis of diabetes and highlighting how this approach could prevent these patients from developing chronic complications. Methods: This narrative review has been produced by examining several databases, including Google Scholar, Research Gate, PubMed, Cochrane Library, MEDLINE (EBSCO), and Web of Science. The most common search terms used were "COVID-19 AND Children", "SARS-CoV-2 AND/OR Children", "COVID-19 AND Diabetes" "COVID-19 Epidemiology", "COVID-19 AND Ramadan fasting", "COVID-19 and Intermittent fasting." All the resources used are either peer-reviewed articles/reports and/or official websites of various media, governmental and educational organisations. Results: Having reviewed the currently limited evidence, it has been found that the incidence of COVID-19 among children with type 2 diabetes seems to be not much different from children without diabetes. However, these patients are still vulnerable to any infection. Several studies have reported that prevention programmes such as intermittent fasting are effective to protect these groups of patients from developing any complications. Moreover, observing Ramadan fasting as a type of intermittent fasting could be beneficial for some children with established diabetes, prediabetes and people at risk. Conclusion: Children and young adults with type 2 diabetes are not at risk of severe COVID-19 infection as the case in adults with diabetes. More research is needed to identify the impact of COVID-19 and to investigate the efficacy and safety of intermittent fasting, including Ramadan fasting, among these age groups. Implementing these cost-effective programmes may have a great impact in minimising the incidence of diabetes. Moreover, this could be effective particularly at prediabetes stage by preventing these people from going onto develop type 2 diabetes and taking medications for the rest of their life and protecting people from complications linked to disease and infection.

A further example of a distinctive autosomal recessive syndrome comprising neonatal diabetes mellitus, intestinal atresias and gall bladder agenesis.

We report a patient born to consanguineous parents as a further example of a recently described phenotype comprising neonatal diabetes, intestinal atresias and gall bladder agenesis. Other reports have described cases with overlapping patterns including malrotation, biliary atresia and pancreatic hypoplasia (e.g. as described by Martínez-Frías). We propose that these cases may represent variations of the same syndrome. It is likely that this disorder is inherited as an autosomal recessive trait. Our case is the first to have neonatal diabetes without a demonstrable structural pancreatic abnormality, showing that a deficit in pancreatic function is involved. We sequenced genes with a recognized role in monogenic forms of diabetes, including KCNJ11, ABCC8, GCK, IPF1, HNF1beta, NeuroD1 and TCF7L2, as well as a novel candidate gene, HNF6, known to be involved in hepatobiliary and pancreatic development, but did not identify mutations.

Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.

BACKGROUND: Patients with permanent neonatal diabetes usually present within the first three months of life and require insulin treatment. In most, the cause is unknown. Because ATP-sensitive potassium (K(ATP)) channels mediate glucose-stimulated insulin secretion from the pancreatic beta cells, we hypothesized that activating mutations in the gene encoding the Kir6.2 subunit of this channel (KCNJ11) cause neonatal diabetes. METHODS: We sequenced the KCNJ11 gene in 29 patients with permanent neonatal diabetes. The insulin secretory response to intravenous glucagon, glucose, and the sulfonylurea tolbutamide was assessed in patients who had mutations in the gene. RESULTS: Six novel, heterozygous missense mutations were identified in 10 of the 29 patients. In two patients the diabetes was familial, and in eight it arose from a spontaneous mutation. Their neonatal diabetes was characterized by ketoacidosis or marked hyperglycemia and was treated with insulin. Patients did not secrete insulin in response to glucose or glucagon but did secrete insulin in response to tolbutamide. Four of the patients also had severe developmental delay and muscle weakness; three of them also had epilepsy and mild dysmorphic features. When the most common mutation in Kir6.2 was coexpressed with sulfonylurea receptor 1 in Xenopus laevis oocytes, the ability of ATP to block mutant K(ATP) channels was greatly reduced. CONCLUSIONS: Heterozygous activating mutations in the gene encoding Kir6.2 cause permanent neonatal diabetes and may also be associated with developmental delay, muscle weakness, and epilepsy. Identification of the genetic cause of permanent neonatal diabetes may facilitate the treatment of this disease with sulfonylureas.

Atypical diabetes in children: ketosis-prone type 2 diabetes.

Ketosis-prone type 2 diabetes mellitus also known as atypical or flatbush diabetes is being increasingly recognised worldwide. These patients are typically obese, middle-aged men with a strong family history of type 2 diabetes. The aetiology and pathophysiological mechanism is still unclear but some initial research suggests that patients with ketosis-prone type 2 diabetes have a unique predisposition to glucose desensitisation. These patients have negative autoantibodies typically associated with type 1 diabetes but have shown to have human leucocyte antigen (HLA) positivity. At initial presentation, there is an impairment of both insulin secretion and action. ß Cell function and insulin sensitivity can be markedly improved by initiating aggressive diabetes management to allow for discontinuation of insulin therapy within a few months of treatment. These patients can be maintained on oral hypoglycaemic agents and insulin therapy can be safely discontinued after few months depending on their ß cell function.

Paediatric Boerhaave's syndrome: a case report and review of the literature.

We report a case of paediatric Boerhaave's syndrome in 15-year-old girl associated with massive dilatation of the stomach into the pelvis and transient hepatitis of uncertain aetiology. This cluster of clinical finding has not previously been reported. The young girl initially presented with abdominal pain, vomiting and lower urinary tract symptoms. She was initially treated for urinary tract infection after urine dipstick showed leucocytes and nitrates. Later she was found to have the spectrum of findings as described. Patient was treated by restricting to strict no oral intake and gastric decompression. Enteral nutrition maintained via a feeding jejunostomy.Boerhaave's syndrome frequently presents in the context of other emetogenic illnesses which may mimic its features as a result the diagnosis can be difficult. A high index of clinical suspicion is therefore required. We review the literature of paediatric Boerhaave's syndrome to aid the clinician with this diagnostic conundrum.