Dataset Information

Molecular Genetics, Clinical Characteristics, and Treatment Outcomes of K_ATP-Channel Neonatal Diabetes Mellitus in Vietnam National Children's Hospital.

ABSTRACT:

Background

Neonatal diabetes mellitus (NDM) is defined as insulin-requiring persistent hyperglycemia occurring within the first 6 months of life, which can result from mutations in at least 25 different genes. Activating heterozygous mutations in genes encoding either of the subunits of the ATP-sensitive K⁺ channel (K_ATP channel; KCNJ11 or ABCC8) of the pancreatic beta cell are the most common cause of permanent NDM and the second most common cause of transient NDM. Patients with NDM caused by K_ATP channel mutations are sensitive to sulfonylurea (SU) treatment; therefore, their clinical management can be improved by replacing insulin with oral agents.

Patients and methods

Seventy patients were diagnosed with NDM between May 2008 and May 2021 at Vietnam National Children's Hospital, and molecular genetic testing for all genes known to cause NDM was performed at the Exeter Genomic Laboratory, UK. Patients with ABCC8 or KCNJ11 mutations were transferred from insulin to oral SU. Clinical characteristics, molecular genetics, and annual data relating to glycemic control, SU dose, severe hypoglycemia, and side effects were collected. The main outcomes of interest were SU dose, SU failure (defined as permanent reintroduction of daily insulin), and glycemic control (HbA1c).

Results

Fifty-four of 70 patients (77%) with NDM harbored a genetic mutation and of these; 27 (50%) had activating heterozygous mutations in ABCC8 or KCNJ11. A total of 21 pathogenic mutations were identified in the 27 patients, including 13 mutations in ABCC8 and 8 mutations in KCNJ11. Overall, 51% had low birth weight (below 3rd percentile), 23 (85%) were diagnosed before 3 months of age, and 23 (85%) presented with diabetic ketoacidosis. At diagnosis, clinical and biochemical findings (mean ± SD) were pH 7.16 ± 0.16; HCO3- , 7.9 ± 7.4 mmol/L; BE, -17.9 ± 9.1 mmol/L; HbA1C, 7.98% ± 2.93%; blood glucose, 36.2 ± 12.3 mmol/L; and C-peptide median, 0.09 (range, 0-1.61 nmol/l). Twenty-six patients were successfully transferred from insulin to SU therapy. In the remaining case, remission of diabetes occurred prior to transfer. Glycemic control on SU treatment was better than on insulin treatment: HbA1c and blood glucose level decreased from 7.58% ± 4.63% and 19.04 ± 14.09 mmol/L when treated with insulin to 5.8 ± 0.94% and 6.87 ± 3.46 mmol/L when treated with SU, respectively.

Conclusions

This is the first case series of NDM patients with ABCC8/KCNJ11 mutations reported in Vietnam. SU is safe in the short term for these patients and more effective than insulin therapy, consistent with all studies to date. This is relevant for populations where access to and cost of insulin are problematic, reinforcing the importance of genetic testing for NDM.

SUBMITTER: Ngoc CTB

PROVIDER: S-EPMC8458931 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:INTRODUCTION:The clinical syndrome of neonatal sepsis, comprising signs of infection, septic shock and organ dysfunction in infants ≤4 weeks of age, is a frequent sequel to bloodstream infection and mandates urgent antimicrobial therapy. Bacterial characterisation and antimicrobial susceptibility testing is vital for ensuring appropriate therapy, as high rates of antimicrobial resistance (AMR), especially in low-income and middle-income countries, may adversely affect outcome. Ho Chi Minh City (HCMC) in Vietnam is a rapidly expanding city in Southeast Asia with a current population of almost 8 million. There are limited contemporary data on the causes of neonatal sepsis in Vietnam, and we hypothesise that the emergence of multidrug resistant bacteria is an increasing problem for the appropriate management of sepsis cases. In this study, we aim to investigate the major causes of neonatal sepsis and assess disease outcomes by clinical features, antimicrobial susceptibility profiles and genome composition. METHOD AND ANALYSIS:We will conduct a prospective observational study to characterise the clinical and microbiological features of neonatal sepsis in a major children's hospital in HCMC. All bacteria isolated from blood subjected to whole genome sequencing. We will compare clinical variables and outcomes between different bacterial species, genome composition and AMR gene content. AMR gene content will be assessed and stratified by species, years and contributing hospital departments. Genome sequences will be analysed to investigate phylogenetic relationships. ETHICS AND DISSEMINATION:The study will be conducted in accordance with the principles of the Declaration of Helsinki and the International Council on Harmonization Guidelines for Good Clinical Practice. Ethics approval has been provided by the Oxford Tropical Research Ethics Committee 35-16 and Vietnam Children's Hospital 1 Ethics Committee 73/GCN/BVND1. The findings will be disseminated at international conferences and peer-reviewed journals. TRIAL REGISTRATION NUMBER:ISRCTN69124914; Pre-results.

Project description:AIMS/HYPOTHESIS:Mutations that render ATP-sensitive potassium (K(ATP)) channels insensitive to ATP inhibition cause neonatal diabetes mellitus. In mice, these mutations cause insulin secretion to be lost initially and, as the disease progresses, beta cell mass and insulin content also disappear. We investigated whether defects in calcium signalling alone are sufficient to explain short-term and long-term islet dysfunction. METHODS:We examined the metabolic, electrical and insulin secretion response in islets from mice that become diabetic after induction of ATP-insensitive Kir6.2 expression. To separate direct effects of K(ATP) overactivity on beta cell function from indirect effects of prolonged hyperglycaemia, normal glycaemia was maintained by protective exogenous islet transplantation. RESULTS:In endogenous islets from protected animals, glucose-dependent elevations of intracellular free-calcium activity ([Ca(2+)](i)) were severely blunted. Insulin content of these islets was normal, and sulfonylureas and KCl stimulated increased [Ca(2+)](i). In the absence of transplant protection, [Ca(2+)](i) responses were similar, but glucose metabolism and redox state were dramatically altered; sulfonylurea- and KCl-stimulated insulin secretion was also lost, because of systemic effects induced by long-term hyperglycaemia and/or hypoinsulinaemia. In both cases, [Ca(2+)](i) dynamics were synchronous across the islet. After reduction of gap-junction coupling, glucose-dependent [Ca(2+)](i) and insulin secretion was partially restored, indicating that excitability of weakly expressing cells is suppressed by cells expressing mutants, via gap-junctions. CONCLUSIONS/INTERPRETATION:The primary defect in K(ATP)-induced neonatal diabetes mellitus is failure of glucose metabolism to elevate [Ca(2+)](i), which suppresses insulin secretion and mildly alters islet glucose metabolism. Loss of insulin content and mitochondrial dysfunction are secondary to the long-term hyperglycaemia and/or hypoinsulinaemia that result from the absence of glucose-dependent insulin secretion.

Project description:Background: KATP channels have diverse roles, including regulation of insulin secretion and blood flow, and protection against biological stress responses and are excellent therapeutic targets. Different subclasses of KATP channels exist in various tissue types due to the unique assemblies of specific pore-forming (Kir6.x) and accessory (SURx) subunits. The majority of pharmacological openers and blockers act by binding to SURx and are poorly selective against the various KATP channel subclasses. Methods and Results: We used 3D models of the Kir6.2/SUR homotetramers based on existing cryo-EM structures of channels in both the open and closed states to identify a potential agonist binding pocket in a functionally critical area of the channel. Computational docking screens of this pocket with the Chembridge Core chemical library of 492,000 drug-like compounds yielded 15 top-ranked "hits", which were tested for activity against KATP channels using patch clamping and thallium (Tl+) flux assays with a Kir6.2/SUR2A HEK-293 stable cell line. Several of the compounds increased Tl+ fluxes. One of them (CL-705G) opened Kir6.2/SUR2A channels with a similar potency as pinacidil (EC50 of 9 µM and 11 μM, respectively). Remarkably, compound CL-705G had no or minimal effects on other Kir channels, including Kir6.1/SUR2B, Kir2.1, or Kir3.1/Kir3.4 channels, or Na+ currents of TE671 medulloblastoma cells. CL-705G activated Kir6.2Δ36 in the presence of SUR2A, but not when expressed by itself. CL-705G activated Kir6.2/SUR2A channels even after PIP2 depletion. The compound has cardioprotective effects in a cellular model of pharmacological preconditioning. It also partially rescued activity of the gating-defective Kir6.2-R301C mutant that is associated with congenital hyperinsulinism. Conclusion: CL-705G is a new Kir6.2 opener with little cross-reactivity with other channels tested, including the structurally similar Kir6.1. This, to our knowledge, is the first Kir-specific channel opener.

Dataset Information

Molecular Genetics, Clinical Characteristics, and Treatment Outcomes of K_ATP-Channel Neonatal Diabetes Mellitus in Vietnam National Children's Hospital.

Background

Patients and methods

Results

Conclusions

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Molecular Genetics, Clinical Characteristics, and Treatment Outcomes of KATP-Channel Neonatal Diabetes Mellitus in Vietnam National Children's Hospital.

Background

Patients and methods

Results

Conclusions

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Molecular Genetics, Clinical Characteristics, and Treatment Outcomes of K_ATP-Channel Neonatal Diabetes Mellitus in Vietnam National Children's Hospital.