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Frontiers in Endocrinology 2023Congenital hyperinsulinism (CHI) is a group of clinically and genetically heterogeneous disorders characterized by dysregulated insulin secretion. The aim of the study...
OBJECTIVE
Congenital hyperinsulinism (CHI) is a group of clinically and genetically heterogeneous disorders characterized by dysregulated insulin secretion. The aim of the study was to elucidate genetic etiologies of Taiwanese children with the most severe diazoxide-unresponsive CHI and analyze their genotype-phenotype correlations.
METHODS
We combined Sanger with whole exome sequencing (WES) to analyze CHI-related genes. The allele frequency of the most common variant was estimated by single-nucleotide polymorphism haplotype analysis. The functional effects of the ATP-sensitive potassium (K) channel variants were assessed using patch clamp recording and Western blot.
RESULTS
Nine of 13 (69%) patients with ten different pathogenic variants (7 in , 2 in and 1 in ) were identified by the combined sequencing. The variant p.T1042QfsX75 identified in three probands was located in a specific haplotype. Functional study revealed the human SUR1 (hSUR1)-L366F K channels failed to respond to intracellular MgADP and diazoxide while hSUR1-R797Q and hSUR1-R1393C K channels were defective in trafficking. One patient had a dominant mutation in the gene (p.I211F), and WES revealed mosaicism of this variant from another patient.
CONCLUSION
Pathogenic variants in K channels are the most common underlying cause of diazoxide-unresponsive CHI in the Taiwanese cohort. The p.T1042QfsX75 variant in the gene is highly suggestive of a founder effect. The I211F mutation in the gene and three rare SUR1 variants associated with defective gating (p.L366F) or traffic (p.R797Q and p.R1393C) K channels are also associated with the diazoxide-unresponsive phenotype.
Topics: Humans; Child; Diazoxide; Potassium Channels, Inwardly Rectifying; Sulfonylurea Receptors; Congenital Hyperinsulinism; Genetic Association Studies; Adenosine Triphosphate
PubMed: 38033998
DOI: 10.3389/fendo.2023.1283907 -
Jornal de Pediatria 2024Congenital hyperinsulinism (CHI) is a heterogeneous genetic disease characterized by increased insulin secretion and causes persistent hypoglycemia in neonates and...
OBJECTIVE
Congenital hyperinsulinism (CHI) is a heterogeneous genetic disease characterized by increased insulin secretion and causes persistent hypoglycemia in neonates and infants due to dysregulation of insulin secretion by pancreatic β cells. Babies with severe hypoglycemia and for whom medical treatment has been ineffective usually require surgical treatment with near-total pancreatectomy. To evaluate the clinical and surgical aspects affecting survival outcomes in babies diagnosed with CHI in a single tertiary care center.
METHODS
Retrospective Cohort study involving a single university tertiary center for the treatment of CHI. The authors study the demographics, clinical, laboratory, and surgical outcomes of this casuistic.
RESULTS
61 % were female, 39 % male, Birth weight: 3576 g (±313); Age of onset of symptoms: from the 2nd hour of life to 28 days; Time between diagnosis and surgery ranged between 10 and 60 days; Medical clinical treatment, all patients received glucose solution with a continuous glucose infusion and diazoxide. 81 % of the patients used corticosteroids, 77 %. thiazide, 72 % octreotide, 27 % nifedipine; Neurological sequelae during development and growth: 54 % had some degree of delay in neuropsychomotor development, 27 % obesity. Surgery was performed open in 6 and 12 minimally invasive surgery (MIS).
HISTOPATHOLOGY
2 focal and 16 diffuse, Length of stay (days) was lower in MIS (p < 0.05). Survival was 100 %.
CONCLUSIONS
CHI is a rare and difficult-to-manage tumor that must be performed in a multidisciplinary and tertiary center. Most surgical results are good and the laparoscopic approach to disease has been the best choice for patients.
Topics: Infant; Infant, Newborn; Humans; Male; Female; Retrospective Studies; Brazil; Congenital Hyperinsulinism; Glucose; Treatment Outcome
PubMed: 37866397
DOI: 10.1016/j.jped.2023.09.005 -
Journal of the Endocrine Society May 2024Kabuki syndrome (KS) is associated with congenital hyperinsulinism (HI).
CONTEXT
Kabuki syndrome (KS) is associated with congenital hyperinsulinism (HI).
OBJECTIVE
To characterize the clinical and molecular features of HI in children with KS.
DESIGN
Retrospective cohort study of children with KS and HI evaluated between 1998 and 2023.
SETTING
The Congenital Hyperinsulinism Center of the Children's Hospital of Philadelphia.
PATIENTS
Thirty-three children with KS and HI.
MAIN OUTCOME MEASURES
HI presentation, treatment, course, and genotype.
RESULTS
Hypoglycemia was recognized on the first day of life in 25 children (76%). Median age at HI diagnosis was 1.8 months (interquartile range [IQR], 0.6-6.1 months). Median age at KS diagnosis was 5 months (IQR, 2-14 months). Diagnosis of HI preceded KS diagnosis in 20 children (61%). Twenty-four children (73%) had a pathogenic variant in , 5 children (15%) had a pathogenic variant in , and 4 children (12%) had a clinical diagnosis of KS. Diazoxide trial was conducted in 25 children, 92% of whom were responsive. HI treatment was discontinued in 46% of the cohort at median age 2.8 years (IQR, 1.3-5.7 years).
CONCLUSION
Hypoglycemia was recognized at birth in most children with KS and HI, but HI diagnosis was often delayed. HI was effectively managed with diazoxide in most children. In contrast to prior reports, the frequency of variants in and were similar to their overall prevalence in individuals with KS. Children diagnosed with KS should undergo evaluation for HI, and, because KS features may not be recognized in infancy, and should be included in the genetic evaluation of HI.
PubMed: 38859884
DOI: 10.1210/jendso/bvae101 -
JFMS Open Reports 2024The patient was a castrated male American Shorthair cat, approximately 14 years old, weighing 3.4 kg. The patient had chronic kidney disease (CKD) (International Renal...
CASE SUMMARY
The patient was a castrated male American Shorthair cat, approximately 14 years old, weighing 3.4 kg. The patient had chronic kidney disease (CKD) (International Renal Interest Society stages 3-4) as an underlying disease. The cat was examined at a hospital for intermittent lethargy and seizures. Hypoglycaemia was repeatedly observed, and the insulin level was 1.78 ng/ml (reference interval 0.27-0.69) when the blood glucose was 49 mg/dl. Although the cat was tentatively diagnosed with insulinoma, surgery was not recommended because of the severe CKD. Although frequent feeding and prednisolone treatment were initially attempted, blood glucose decreased to 24-42 mg/dl. Diazoxide was additionally prescribed at a dose of 5.2 mg/kg q12h. The cat's clinical signs improved, and the blood glucose was in the range of 75-103 mg/dl during the first 2 months. It was maintained at >50 mg/dl until the patient died of renal failure 161 days after the start of diazoxide treatment. With regard to adverse events, vomiting once every 2-3 days without weight loss and non-regenerative anaemia were observed, which might have been at least partially caused by diazoxide treatment. An insulinoma was definitively diagnosed via pathological autopsy.
RELEVANCE AND NOVEL INFORMATION
This is the first reported case of long-term treatment with diazoxide in a cat with insulinoma. Since it was effective in situations where conventional therapies were unsuccessful, diazoxide could be useful as a new therapeutic option for cats with insulinoma. Since adverse events, such as progression of vomiting frequency and non-regenerative anaemia, were observed, careful monitoring was required during administration.
PubMed: 38268764
DOI: 10.1177/20551169231220290 -
Frontiers in Neurology 2023One of the most prevalent types of epilepsy is temporal lobe epilepsy (TLE), which has unknown etiological factors and drug resistance. The detailed mechanisms...
One of the most prevalent types of epilepsy is temporal lobe epilepsy (TLE), which has unknown etiological factors and drug resistance. The detailed mechanisms underlying potassium channels in human TLE have not yet been elucidated. Hence, this study aimed to mine potassium channel genes linked to TLE using a bioinformatic approach. The results found that Four key TLE-related potassium channel genes (TERKPCGs) were identified: potassium voltage-gated channel subfamily E member () 1, , potassium inwardly rectifying channel, subfamily J, member 11 (), and . A protein-protein interaction (PPI) network was constructed to analyze the relationship between TERKPCGs and other key module genes. The results of gene set enrichment analysis (GSEA) for a single gene indicated that the four TERKPCGs were highly linked to the cation channel, potassium channel, respiratory chain, and oxidative phosphorylation. The mRNA-TF network was established using four mRNAs and 113 predicted transcription factors. A ceRNA network containing seven miRNAs, two mRNAs, and 244 lncRNAs was constructed based on the TERKPCGs. Three common small-molecule drugs (enflurane, promethazine, and miconazole) target , and . Ten small-molecule drugs (glimepiride, diazoxide, levosimendan, and thiamylal et al.) were retrieved for . Compared to normal mice, the expression of , , , and was downregulated in the brain tissue of the epilepsy mouse model at both the transcriptional and translational levels, which was consistent with the trend of human data from the public database. The results indicated that key potassium channel genes linked to TLE were identified based on bioinformatics analysis to investigate the potential significance of potassium channel genes in the development and treatment of TLE.
PubMed: 37483435
DOI: 10.3389/fneur.2023.1175007 -
Endocrinology, Diabetes & Metabolism Mar 2024Insulin-like growth factor-2 (IGF-2)-mediated hypoglycemia is a rare yet clinically significant entity with considerable morbidity and mortality. Existing literature is... (Review)
Review
INTRODUCTION
Insulin-like growth factor-2 (IGF-2)-mediated hypoglycemia is a rare yet clinically significant entity with considerable morbidity and mortality. Existing literature is limited and fails to offer a comprehensive understanding of its clinical trajectory, management and prognostication.
METHODS
Systematic review of English-language articles reporting primary patient data on IMH was searched using electronic databases (PubMed, Scopus and Embase) from any date up to 21 December 2022. Data were analysed in STATA-16.
RESULTS
The systematic review contains 172 studies, including 1 Randomised controlled trial, 1 prospective observational study, 5 retrospective observational studies, 150 case reports, 11 case series and 4 conference abstracts. A total of 233 patients were analysed, averaging 60.6 ± 17.1 years in age, with comparable proportions of males and females. The commonest tumours associated with Insulin-like Growth Factor-2-mediated hypoglycaemia were fibrous tumours (N = 124, 53.2%), followed by non-fibrous tumours originating from the liver (N = 21, 9%), hemangiopericytomas (N = 20, 8.5%) and mesotheliomas (N = 11, 4.7%). Hypoglycaemia was the presenting feature of NICT in 42% of cases. Predominant clinical features included loss of consciousness (26.7%) and confusion (21%). The mean IGF-2 and IGF-1 levels were 882.3 ± 630.6 ng/dL and 41.8 ± 47.8, respectively, with no significant correlation between these levels and patient outcomes. Surgical removal was the most employed treatment modality (47.2%), followed by medication therapy. The recovery rate was 77%, with chronic liver disease (CLD) significantly associated with a poor outcome (OR: 7.23, P: 0.03). Tumours originating from fibrous tissues were significantly associated with recovery (p < .001). In the logistic regression model, CLD remained a significant predictor of poor outcomes.
CONCLUSION
This systematic review highlights that most non-islet-cell tumour-hypoglycaemia (NICTH) is due to fibrous tumours. NICTs demonstrate a variable prognosis, which is fair if originating from fibrous tissue. Management such as octreotide, corticosteroids, diazoxide, embolization, radiotherapy and surgical resection have disparate success rates.
Topics: Male; Female; Humans; Insulin-Like Growth Factor II; Insulin-Like Peptides; Retrospective Studies; Hypoglycemia; Observational Studies as Topic
PubMed: 38411039
DOI: 10.1002/edm2.471 -
JTCVS Open Sep 2023The adenosine triphosphate-sensitive potassium channel opener diazoxide mimics ischemic preconditioning and is cardioprotective. Clarification of diazoxide's site and...
OBJECTIVE
The adenosine triphosphate-sensitive potassium channel opener diazoxide mimics ischemic preconditioning and is cardioprotective. Clarification of diazoxide's site and mechanism of action could lead to targeted pharmacologic therapies for patients undergoing cardiac surgery. Several mitochondrial candidate proteins have been investigated as potential adenosine triphosphate-sensitive potassium channel components. Renal outer medullary potassium (Kir1.1) and sulfonylurea sensitive regulatory subunit 1 have been suggested as subunits of a mitochondrial adenosine triphosphate-sensitive potassium channel. We hypothesized that pharmacologic blockade or genetic deletion (knockout) of renal outer medullary potassium and sensitive regulatory subunit 1 would result in loss of diazoxide cardioprotection in models of global ischemia with cardioplegia.
METHODS
Myocyte volume and contractility were compared after Tyrode's physiologic solution (20 minutes), stress (hyperkalemic cardioplegia ± diazoxide, ± VU591 (Kir1.1 inhibitor), N = 9 to 23 each, 20 min), and Tyrode's (20 minutes). Isolated mouse (wild-type, sensitive regulatory subunit 1 [-/-], and cardiac knockout renal outer medullary potassium) hearts were given cardioplegia ± diazoxide (N = 9-16 each) before global ischemia (90 minutes) and 30 minutes reperfusion. Left ventricular pressures were compared before and after ischemia.
RESULTS
Stress (cardioplegia) was associated with reduced myocyte contractility that was prevented by diazoxide. Isolated myocytes were not responsive to diazoxide in the presence of VU591. In isolated hearts, diazoxide improved left ventricular function after prolonged ischemia compared with cardioplegia alone in wild-type and knockout (sensitive regulatory subunit 1 [-/-] and cardiac knockout renal outer medullary potassium) mice.
CONCLUSIONS
Isolated myocyte and heart models may measure independent and separate actions of diazoxide. By definitive genetic deletion, these data indicate that sensitive regulatory subunit 1 and renal outer medullary potassium are not implicated in cardioprotection by diazoxide.
PubMed: 37808059
DOI: 10.1016/j.xjon.2023.06.004 -
Neurobiology of Pain (Cambridge, Mass.) 2023Chronic pain is a substantial health burden and options for treating chronic pain remain minimally effective. Ketogenic diets are emerging as well-tolerated, effective...
Chronic pain is a substantial health burden and options for treating chronic pain remain minimally effective. Ketogenic diets are emerging as well-tolerated, effective therapeutic strategies in preclinical models of chronic pain, especially diabetic neuropathy. We tested whether a ketogenic diet is antinociceptive through ketone oxidation and related activation of ATP-gated potassium (K) channels in mice. We demonstrate that consumption of a ketogenic diet for one week reduced evoked nocifensive behaviors (licking, biting, lifting) following intraplantar injection of different noxious stimuli (methylglyoxal, cinnamaldehyde, capsaicin, or Yoda1) in mice. A ketogenic diet also decreased the expression of p-ERK, an indicator of neuronal activation in the spinal cord, following peripheral administration of these stimuli. Using a genetic mouse model with deficient ketone oxidation in peripheral sensory neurons, we demonstrate that protection against methylglyoxal-induced nociception by a ketogenic diet partially depends on ketone oxidation by peripheral neurons. Injection of tolbutamide, a K channel antagonist, prevented ketogenic diet-mediated antinociception following intraplantar capsaicin injection. Tolbutamide also restored the expression of spinal activation markers in ketogenic diet-fed, capsaicin-injected mice. Moreover, activation of K channels with the K channel agonist diazoxide reduced pain-like behaviors in capsaicin-injected, chow-fed mice, similar to the effects observed with a ketogenic diet. Diazoxide also reduced the number of p-ERK cells in capsaicin-injected mice. These data support a mechanism that includes neuronal ketone oxidation and activation of K channels to provide ketogenic diet-related analgesia. This study also identifies K channels as a new target to mimic the antinociceptive effects of a ketogenic diet.
PubMed: 38099277
DOI: 10.1016/j.ynpai.2023.100138 -
BMC Endocrine Disorders Jan 2024ABCC8 variants can cause hyperinsulinemia by activating or deactivating gene expression. This study used targeted exon sequencing to investigate genetic variants of...
BACKGROUND
ABCC8 variants can cause hyperinsulinemia by activating or deactivating gene expression. This study used targeted exon sequencing to investigate genetic variants of ABCC8 and the associated phenotypic features in Chinese patients with hyperinsulinemic hypoglycemia (HH).
METHODS
We enrolled eight Chinese children with HH and analyzed their clinical characteristics, laboratory results, and genetic variations.
RESULTS
The age at presentation among the patients ranged from neonates to 0.6 years old, and the age at diagnosis ranged from 1 month to 5 years, with an average of 1.3 ± 0.7 years. Among these patients, three presented with seizures, and five with hypoglycemia. One patient (Patient 7) also had microcephaly. All eight patients exhibited ABCC8 abnormalities, including six missense mutations (c. 2521 C > G, c. 3784G > A, c. 4478G > A, c. 4532T > C, c. 2669T > C, and c. 331G > A), two deletion-insertion mutations (c. 3126_3129delinsTC and c. 3124_3126delins13), and one splicing mutation (c. 1332 + 2T > C). Two of these mutations (c. 3126_3129delinsTC and c. 4532T > C) are novel. Six variations were paternal, two were maternal, and one was de novo. Three patients responded to diazoxide and one patient responded to octreotide treatment. All there patients had diazoxide withdrawal with age. Two patients (patients 3 and 7) were unresponsive to both diazoxide and octreotide and had mental retardation.
CONCLUSIONS
Gene analysis can aid in the classification, treatment, and prognosis of children with HH. In this study, the identification of seven known and two novel variants in the ABCC8 gene further enriched the variation spectrum of the gene.
Topics: Infant, Newborn; Child; Humans; Congenital Hyperinsulinism; Diazoxide; Octreotide; Mutation; China; Sulfonylurea Receptors
PubMed: 38212772
DOI: 10.1186/s12902-023-01527-8 -
Scientific Reports Feb 2024Alzheimer's disease (AD) is the major form of dementia prevalent in older adults and with a high incidence in females. Identification of early biomarkers is essential...
Alzheimer's disease (AD) is the major form of dementia prevalent in older adults and with a high incidence in females. Identification of early biomarkers is essential for preventive intervention to delay its progression. Furthermore, due to its multifactorial nature, a multi-target approach could be therapeutically beneficial. Our studies included 4- (pre-pathology) and 11-month (mild-pathology) TgF344-AD rats, a transgenic Alzheimer's model that exhibits age-dependent AD progression. We identified two potential early biomarker genes for AD, early growth response 2 (EGR2) and histone 1H2AA (HIST1H2AA), in the hippocampus of 4-month females. Out of 17,168 genes analyzed by RNA sequencing, expression of these two genes was significantly altered in 4-month TgF344-AD rats compared to wild-type littermates. We also evaluated co-treatment with diazoxide (DZ), a potassium channel activator, and dibenzoylmethane (DIB), which inhibits eIF2α-P activity, on TgF344-AD and wild-type rats. DZ/DIB-treatment mitigated spatial memory deficits and buildup of hippocampal Aβ plaques and tau PHF in 11-month TgF344-AD rats but had no effect on wild-type littermates. To our knowledge, this preclinical study is the first to report EGR2 and HIST1H2AA as potential AD biomarkers in females, and the benefits of DZ/DIB-treatment in AD. Evaluations across multiple AD-related models is warranted to corroborate our findings.
Topics: Female; Rats; Animals; Alzheimer Disease; Rats, Transgenic; Diazoxide; Rats, Inbred F344; Spatial Memory; Biomarkers; Disease Models, Animal; Amyloid beta-Peptides; Chalcones
PubMed: 38355687
DOI: 10.1038/s41598-024-54156-z