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Journal of Clinical Medicine May 2024This perspective work by academic neonatal providers is written specifically for the audience of newborn care providers and neonatologists involved in neonatal...
This perspective work by academic neonatal providers is written specifically for the audience of newborn care providers and neonatologists involved in neonatal hypoglycemia screening. Herein, we propose adding a screen for congenital hyperinsulinism (CHI) by measuring glucose and ketone (i.e., β-hydroxybutyrate (BOHB)) concentrations just prior to newborn hospital discharge and as close to 48 h after birth as possible, at the same time that the mandated state Newborn Dried Blood Spot Screen is obtained. In the proposed protocol, we do not recommend specific metabolite cutoffs, as our primary objective is to simply highlight the concept of screening for CHI in newborns to newborn caregivers. The premise for our proposed screen is based on the known effect of hyperinsulinism in suppressing ketogenesis, thereby limiting ketone production. We will briefly discuss genetic CHI, other forms of neonatal hypoglycemia, and their shared mechanisms; the mechanism of insulin regulation by functional pancreatic islet cell membrane K channels; adverse neurodevelopmental sequelae and brain injury due to missing or delaying the CHI diagnosis; the principles of a good screening test; how current neonatal hypoglycemia screening programs do not fulfill the criteria for being effective screening tests; and our proposed algorithm for screening for CHI in newborns.
PubMed: 38792494
DOI: 10.3390/jcm13102953 -
International Journal of Molecular... May 2024Congenital hyperinsulinism (CHI) is a rare disorder of glucose metabolism and is the most common cause of severe and persistent hypoglycemia (hyperinsulinemic...
Congenital hyperinsulinism (CHI) is a rare disorder of glucose metabolism and is the most common cause of severe and persistent hypoglycemia (hyperinsulinemic hypoglycemia, HH) in the neonatal period and childhood. Most cases are caused by mutations in the and genes that encode the ATP-sensitive potassium channel (K). We present the correlation between genetic heterogeneity and the variable phenotype in patients with early-onset HH caused by gene mutations. In the first patient, who presented persistent severe hypoglycemia since the first day of life, molecular genetic testing revealed the presence of a homozygous mutation in the gene [deletion in the gene c.(2390+1_2391-1)_(3329+1_3330-1)del] that correlated with a diffuse form of hyperinsulinism (the parents being healthy heterozygous carriers). In the second patient, the onset was on the third day of life with severe hypoglycemia, and genetic testing identified a heterozygous mutation in the gene c.1792C>T (p.Arg598*) inherited on the paternal line, which led to the diagnosis of the focal form of hyperinsulinism. To locate the focal lesions, (18)F-DOPA (3,4-dihydroxy-6-[F]fluoro-L-phenylalanine) positron emission tomography/computed tomography (PET/CT) was recommended (an investigation that cannot be carried out in the country), but the parents refused to carry out the investigation abroad. In this case, early surgical treatment could have been curative. In addition, the second child also presented secondary adrenal insufficiency requiring replacement therapy. At the same time, she developed early recurrent seizures that required antiepileptic treatment. We emphasize the importance of molecular genetic testing for diagnosis, management and genetic counseling in patients with HH.
Topics: Humans; Congenital Hyperinsulinism; Sulfonylurea Receptors; Genetic Heterogeneity; Mutation; Female; Infant, Newborn; Male; Hypoglycemia; Phenotype; Infant; Potassium Channels, Inwardly Rectifying
PubMed: 38791571
DOI: 10.3390/ijms25105533 -
Frontiers in Endocrinology 2024
Topics: Humans; Hypoglycemia; Child
PubMed: 38742203
DOI: 10.3389/fendo.2024.1412976 -
BMJ Open Diabetes Research & Care Apr 2024Congenital hyperinsulinism (HI) is the leading cause of persistent hypoglycemia in infants. Current models to study the most common and severe form of HI resulting from...
INTRODUCTION
Congenital hyperinsulinism (HI) is the leading cause of persistent hypoglycemia in infants. Current models to study the most common and severe form of HI resulting from inactivating mutations in the ATP-sensitive potassium channel (K) are limited to primary islets from patients and the mouse model. Zebrafish exhibit potential as a novel KHI model since they express canonical insulin secretion pathway genes and those with identified causative HI mutations. Moreover, zebrafish larvae transparency provides a unique opportunity for in vivo visualization of pancreatic islets.
RESEARCH DESIGN AND METHODS
We evaluated zebrafish as a model for KHI using a genetically encoded Ca sensor (ins:gCaMP6s) expressed under control of the insulin promoter in beta cells of an zebrafish line.
RESULTS
We observed significantly higher islet cytosolic Ca in vivo in compared with zebrafish larvae. Additionally, larval zebrafish had significantly lower whole body glucose and higher whole body insulin levels compared with controls. However, adult zebrafish do not show differences in plasma glucose, plasma insulin, or glucose tolerance when compared with zebrafish.
CONCLUSIONS
Our results identify that zebrafish larvae, but not adult fish, are a demonstrable novel model for advancement of HI research.
Topics: Infant; Adult; Animals; Mice; Humans; KATP Channels; Zebrafish; Potassium Channels, Inwardly Rectifying; Congenital Hyperinsulinism; Insulin; Glucose; Adenosine Triphosphate
PubMed: 38575153
DOI: 10.1136/bmjdrc-2023-003735 -
Diabetologia May 2024The ATP-sensitive potassium (K) channel couples beta cell electrical activity to glucose-stimulated insulin secretion. Loss-of-function mutations in either the...
AIMS/HYPOTHESIS
The ATP-sensitive potassium (K) channel couples beta cell electrical activity to glucose-stimulated insulin secretion. Loss-of-function mutations in either the pore-forming (inwardly rectifying potassium channel 6.2 [Kir6.2], encoded by KCNJ11) or regulatory (sulfonylurea receptor 1, encoded by ABCC8) subunits result in congenital hyperinsulinism, whereas gain-of-function mutations cause neonatal diabetes. Here, we report a novel loss-of-function mutation (Ser118Leu) in the pore helix of Kir6.2 paradoxically associated with sulfonylurea-sensitive diabetes that presents in early adult life.
METHODS
A 31-year-old woman was diagnosed with mild hyperglycaemia during an employee screen. After three pregnancies, during which she was diagnosed with gestational diabetes, the patient continued to show elevated blood glucose and was treated with glibenclamide (known as glyburide in the USA and Canada) and metformin. Genetic testing identified a heterozygous mutation (S118L) in the KCNJ11 gene. Neither parent was known to have diabetes. We investigated the functional properties and membrane trafficking of mutant and wild-type K channels in Xenopus oocytes and in HEK-293T cells, using patch-clamp, two-electrode voltage-clamp and surface expression assays.
RESULTS
Functional analysis showed no changes in the ATP sensitivity or metabolic regulation of the mutant channel. However, the Kir6.2-S118L mutation impaired surface expression of the K channel by 40%, categorising this as a loss-of-function mutation.
CONCLUSIONS/INTERPRETATION
Our data support the increasing evidence that individuals with mild loss-of-function K channel mutations may develop insulin deficiency in early adulthood and even frank diabetes in middle age. In this case, the patient may have had hyperinsulinism that escaped detection in early life. Our results support the importance of functional analysis of K channel mutations in cases of atypical diabetes.
Topics: Infant, Newborn; Adult; Middle Aged; Female; Pregnancy; Humans; Potassium Channels, Inwardly Rectifying; Sulfonylurea Receptors; Congenital Hyperinsulinism; Sulfonylurea Compounds; Mutation; Glyburide; Diabetes, Gestational; Adenosine Triphosphate
PubMed: 38366195
DOI: 10.1007/s00125-024-06103-w -
International Journal of Molecular... Jan 2024The BiP co-chaperone DNAJC3 protects cells during ER stress. In mice, the deficiency of DNAJC3 leads to beta-cell apoptosis and the gradual onset of hyperglycemia. In...
The BiP co-chaperone DNAJC3 protects cells during ER stress. In mice, the deficiency of DNAJC3 leads to beta-cell apoptosis and the gradual onset of hyperglycemia. In humans, biallelic variants cause a multisystem disease, including early-onset diabetes mellitus. Recently, hyperinsulinemic hypoglycemia (HH) has been recognized as part of this syndrome. This report presents a case study of an individual with HH caused by variants and provides an overview of the metabolic phenotype of individuals with HH and variants. The study demonstrates that HH may be a primary symptom of DNAJC3 deficiency and can persist until adolescence. Additionally, glycemia and insulin release were analyzed in young DNACJ3 knockout (K.O.) mice, which are equivalent to human infants. In the youngest experimentally accessible age group of 4-week-old mice, the in vivo glycemic phenotype was already dominated by a reduced total insulin secretion capacity. However, on a cellular level, the degree of insulin release of DNAJC3 K.O. islets was higher during periods of increased synthetic activity (high-glucose stimulation). We propose that calcium leakage from the ER into the cytosol, due to disrupted DNAJC3-controlled gating of the Sec61 channel, is the most likely mechanism for HH. This is the first genetic mechanism explaining HH solely by the disruption of intracellular calcium homeostasis. Clinicians should screen for HH in DNAJC3 deficiency and consider variants in the differential diagnosis of congenital hyperinsulinism.
Topics: Adolescent; Animals; Humans; Mice; Calcium; Congenital Hyperinsulinism; HSP40 Heat-Shock Proteins; Insulin; Insulin Secretion; Molecular Chaperones
PubMed: 38279270
DOI: 10.3390/ijms25021270 -
JHEP Reports : Innovation in Hepatology Jan 2024Congenital portosystemic shunts are often associated with systemic complications, the most challenging of which are liver nodules, pulmonary hypertension, endocrine... (Review)
Review
Congenital portosystemic shunts are often associated with systemic complications, the most challenging of which are liver nodules, pulmonary hypertension, endocrine abnormalities, and neurocognitive dysfunction. In the present paper, we offer expert clinical guidance on the management of liver nodules, pulmonary hypertension, and endocrine abnormalities, and we make recommendations regarding shunt closure and follow-up.
PubMed: 38234409
DOI: 10.1016/j.jhepr.2023.100933 -
Molecular Genetics and Metabolism... Mar 2024Maturity-onset diabetes of the young, type 13 (MODY13) is a specific subclass of monogenic diabetes mellitus that does not exhibit the typical clinical manifestations of...
BACKGROUND
Maturity-onset diabetes of the young, type 13 (MODY13) is a specific subclass of monogenic diabetes mellitus that does not exhibit the typical clinical manifestations of diabetes, necessitating the use of genetic testing for accurate diagnosis. With the progression of monogenic diabetes and MODY, the number of reported MODY13 cases has reached a minimum of 22. Nevertheless, there remains a dearth of information regarding patients diagnosed with MODY13 presenting synonymous variants.
CASE PRESENTATION
This study presents a description of the clinical and genetic features of a 9-year-old male patient diagnosed with MODY13. A noteworthy finding in this case was the occurrence of a "separation phenomenon" between C-peptide and insulin during the standard meal test. Whole exome sequencing (WES) identified a KCNJ11 c.843C > T (p.L281=) mutation in exon 1, which contradicted the previously reported phenotype. Following the onset of ketosis, the patient underwent insulin therapy for a duration of one month, during which the insulin dosage was gradually modified based on blood glucose levels. In order to maintain normoglycemia, he adhered to a diabetic dietary regimen and participated in 1-2 h of moderate exercise daily.
CONCLUSION
The study implies that patient with variant shows a "separation phenomenon" between C-peptide and insulin in standard meal test. Our report also enriched the genotype and phenotype spectrums of MODY13 and highlighted the importance of genetic testing in patients without characteristic clinical symptoms of diabetes.
PubMed: 38226203
DOI: 10.1016/j.ymgmr.2023.101043 -
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 -
Medicine Dec 202317α-Hydroxylase/17, 20-lyase deficiency (17OHD) is a recessively inherited autosomal disease caused by CYP17A1 gene mutations. It is characterized by failure to...
RATIONALE
17α-Hydroxylase/17, 20-lyase deficiency (17OHD) is a recessively inherited autosomal disease caused by CYP17A1 gene mutations. It is characterized by failure to synthesize cortisol, adrenal androgens and gonadal steroids. However, it is rare in clinic combining with type 2 diabetes mellitus (T2DM).
PATIENT CONCERNS
A 21-year-old woman was transferred to an endocrinology clinic because of paroxysmal paralysis. In addition, she presented with hypertension, primary amenorrhea and lack of pubertal development. Blood evaluation revealed hypokalemia, and a low cortisol level with an increased adrenocorticotropic hormone concentration. The renin activity and testosterone and estrogen levels were suppressed, and the gonadotropin levels were high. CT scan showed bilateral adrenal hyperplasia. Besides, this patient had hyperglycemia, hyperinsulinism and negative diabetes type 1 related antibodies. A homozygous mutation c. 985 to 987delinsAA in exon 6 was found in the patient which caused the missense mutation (p.Y329fs).
DIAGNOSES
17α-hydroxylase/17, 20-lyase deficiency combined with T2DM was considered.
INTERVENTIONS
The patient received dexamethasone, estradiol valerate, metformin, amlodipine besylate and D3 calcium carbonate tablets. The doses of dexamethasone was changed according to her blood potassium levels.
OUTCOMES
After treatment, the blood pressure, blood potassium and blood glucose returned to normal range. Besides, she had restored her menstrual cycle.
LESSONS
For patients with hypertension, hypokalemia and lack of pubertal development, the possibility of 17OHD should be considered. The subsequent treatment would be challenging in patients with combined 17OHD and T2DM, considering the potential contribution of glucocorticoids to diabetic balance and osteoporosis.
Topics: Female; Humans; Young Adult; Adrenal Hyperplasia, Congenital; Dexamethasone; Diabetes Mellitus, Type 2; Hydrocortisone; Hypertension; Hypokalemia; Lyases; Mixed Function Oxygenases; Mutation; Potassium; Steroid 17-alpha-Hydroxylase
PubMed: 38206738
DOI: 10.1097/MD.0000000000036727