-
Journal of Diabetes Investigation May 2020Insulin resistance syndrome (IRS) of type A or B is triggered by gene abnormalities of or autoantibodies to the insulin receptor, respectively....
AIMS/INTRODUCTION
Insulin resistance syndrome (IRS) of type A or B is triggered by gene abnormalities of or autoantibodies to the insulin receptor, respectively. Rabson-Mendenhall/Donohue syndrome is also caused by defects of the insulin receptor gene (INSR), but is more serious than type A IRS. Here, we carried out a nationwide survey of these syndromes in Japan.
MATERIALS AND METHODS
We sent questionnaires to a total of 1,957 academic councilors or responsible individuals at certified facilities of the Japan Diabetes Society, as well as at the department pediatrics or neonatology in medical centers with >300 beds.
RESULTS
We received 904 responses with information on 23, 30 and 10 cases of type A or B IRS and Rabson-Mendenhall/Donohue syndrome, respectively. Eight cases with type A IRS-like clinical features, but without an abnormality of INSR, were tentatively designated type X IRS, with five of these cases testing positive for PIK3R1 mutations. Fasting serum insulin levels at diagnosis (mean ± standard deviation) were 132.0 ± 112.4, 1122.1 ± 3292.5, 2895.5 ± 3181.5 and 145.0 ± 141.4 μU/mL for type A IRS, type B IRS, Rabson-Mendenhall/Donohue syndrome and type X IRS, respectively. Type A and type X IRS, as well as Rabson-Mendenhall/Donohue syndrome were associated with low birthweight. Type B IRS was diagnosed most frequently in older individuals, and was often associated with concurrent autoimmune conditions and hypoglycemia.
CONCLUSIONS
Information yielded by this first nationwide survey should provide epidemiological insight into these rare conditions and inform better healthcare for affected patients.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antigens, CD; Asian People; Child; Child, Preschool; Donohue Syndrome; Female; Health Surveys; Humans; Infant; Infant, Newborn; Japan; Male; Metabolic Syndrome; Middle Aged; Receptor, Insulin; Young Adult
PubMed: 31677333
DOI: 10.1111/jdi.13171 -
Journal of the American Heart... Apr 2019Background Obesity is a precursor to heart failure with preserved ejection fraction. Biomarkers that identify preclinical metabolic heart disease ( MHD ) in young obese...
Background Obesity is a precursor to heart failure with preserved ejection fraction. Biomarkers that identify preclinical metabolic heart disease ( MHD ) in young obese patients would help identify high-risk individuals for heart failure prevention strategies. We assessed the predictive value of GAL3 (galectin-3), FSTL3 (follistatin-like 3 peptide), and NT-proBNP (N-terminal pro-B-type natriuretic peptide) to identify stage B MHD in young obese participants free of clinically evident cardiovascular disease. Methods and Results Asymptomatic obese patients (n=250) and non-obese controls (n=21) underwent echocardiographic cardiac phenotyping. Obese patients were classified as MHD positive ( MHD - POS ; n=94) if they had abnormal diastolic function or left ventricular hypertrophy and had estimated pulmonary artery systolic pressure ≥35 mm Hg. Obese patients without such abnormalities were classified as MHD negative (MHD-NEG; n=52). Serum biomarkers timed with echocardiography. MHD - POS and MHD-NEG individuals were similarly obese, but MHD - POS patients were older, with more diabetes mellitus and metabolic syndrome. Right ventricular coupling was worse in MHD - POS patients ( P<0.001). GAL 3 levels were higher in MHD - POS versus MHD -NEG patients (7.7±2.3 versus 6.3±1.9 ng/mL, respectively; P<0.001). Both GAL 3 and FSTL 3 levels correlated with diastolic dysfunction and increased pulmonary artery systolic pressure but not with left ventricular mass. In multivariate models including all 3 biomarkers, only GAL 3 remained associated with MHD (odds ratio: 1.30; 95% CI , 1.01-1.68; P=0.04). Conclusions In young obese individuals without known cardiovascular disease, GAL 3 is associated with the presence of preclinical MHD . GAL 3 may be useful in screening for preclinical MHD and identifying individuals with increased risk of progression to obesity-related heart failure with preserved ejection fraction.
Topics: Adult; Biomarkers; Blood Proteins; Case-Control Studies; Echocardiography; Female; Follistatin-Related Proteins; Galectin 3; Galectins; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Hypertrophy, Left Ventricular; Male; Metabolic Diseases; Middle Aged; Natriuretic Peptide, Brain; Obesity; Peptide Fragments
PubMed: 30929550
DOI: 10.1161/JAHA.118.011100 -
Pediatric Critical Care Medicine : a... May 2019Many hospitals aim to extubate children early after cardiac surgery, yet it remains unclear how this practice associates with extubation failure. We evaluated adjusted...
OBJECTIVES
Many hospitals aim to extubate children early after cardiac surgery, yet it remains unclear how this practice associates with extubation failure. We evaluated adjusted extubation failure rates and duration of postoperative mechanical ventilation across hospitals and assessed cardiac ICU organizational factors associated with extubation failure.
DESIGN
Secondary analysis of the Pediatric Cardiac Critical Care Consortium clinical registry.
SETTING
Pediatric Cardiac Critical Care Consortium cardiac ICUs.
PATIENTS
Patients with qualifying index surgical procedures from August 2014 to June 2017.
INTERVENTIONS
None.
MEASUREMENTS AND MAIN RESULTS
We modeled hospital-level adjusted extubation failure rates using multivariable logistic regression. A previously validated Pediatric Cardiac Critical Care Consortium model was used to calculate adjusted postoperative mechanical ventilation. Observed-to-expected ratios for both metrics were derived for each hospital to assess performance. Hierarchical logistic regression was used to assess the association between cardiac ICU factors and extubation failure. Overall, 16,052 surgical hospitalizations were analyzed. Predictors of extubation failure (p < 0.05 in final case-mix adjustment model) included younger age, underweight, greater surgical complexity, airway anomaly, chromosomal anomaly/syndrome, longer cardiopulmonary bypass time, and other preoperative comorbidities. Three hospitals were better-than-expected outliers for extubation failure (95% CI around observed-to-expected < 1), and three hospitals were worse-than-expected (95% CI around observed-to-expected > 1). Two hospitals were better-than-expected outliers for both extubation failure and postoperative mechanical ventilation, and three were worse-than-expected for both. No hospital was an outlier in opposite directions. Greater nursing hours per patient day and percent nursing staff with critical care certification were associated with lower odds of extubation failure. Cardiac ICU factors such as fewer inexperienced nurses, greater percent critical care trained attendings, cardiac ICU-dedicated respiratory therapists, and fewer patients per cardiac ICU attending were not associated with lower odds of extubation failure.
CONCLUSIONS
We saw no evidence that hospitals trade higher extubation failure rates for shorter duration of postoperative mechanical ventilation after pediatric cardiac surgery. Increasing specialized cardiac ICU nursing hours per patient day may achieve better extubation outcomes and mitigate the impact of inexperienced nurses.
Topics: Airway Extubation; Cardiac Surgical Procedures; Child; Female; Hospitals; Humans; Infant; Infant, Newborn; Male; Nursing Staff, Hospital; Outcome Assessment, Health Care; Postoperative Period; Registries; Respiration, Artificial; Time Factors
PubMed: 30807544
DOI: 10.1097/PCC.0000000000001877 -
Pediatric Critical Care Medicine : a... Feb 2019To develop a postoperative mortality case-mix adjustment model to facilitate assessment of cardiac ICU quality of care, and to describe variation in adjusted cardiac ICU... (Observational Study)
Observational Study
OBJECTIVE
To develop a postoperative mortality case-mix adjustment model to facilitate assessment of cardiac ICU quality of care, and to describe variation in adjusted cardiac ICU mortality across hospitals within the Pediatric Cardiac Critical Care Consortium.
DESIGN
Observational analysis.
SETTING
Multicenter Pediatric Cardiac Critical Care Consortium clinical registry.
PARTICIPANTS
All surgical cardiac ICU admissions between August 2014 and May 2016. The analysis included 8,543 admissions from 23 dedicated cardiac ICUs.
INTERVENTIONS
None.
MEASUREMENTS AND MAIN RESULTS
We developed a novel case-mix adjustment model to measure postoperative cardiac ICU mortality after congenital heart surgery. Multivariable logistic regression was performed to assess preoperative, intraoperative, and immediate postoperative severity of illness variables as candidate predictors. We used generalized estimating equations to account for clustering of patients within hospital and obtain robust SEs. Bootstrap resampling (1,000 samples) was used to derive bias-corrected 95% CIs around each predictor and validate the model. The final model was used to calculate expected mortality at each hospital. We calculated a standardized mortality ratio (observed-to-expected mortality) for each hospital and derived 95% CIs around the standardized mortality ratio estimate. Hospital standardized mortality ratio was considered a statistically significant outlier if the 95% CI did not include 1. Significant preoperative predictors of mortality in the final model included age, chromosomal abnormality/syndrome, previous cardiac surgeries, preoperative mechanical ventilation, and surgical complexity. Significant early postoperative risk factors included open sternum, mechanical ventilation, maximum vasoactive inotropic score, and extracorporeal membrane oxygenation. The model demonstrated excellent discrimination (C statistic, 0.92) and adequate calibration. Comparison across Pediatric Cardiac Critical Care Consortium hospitals revealed five-fold difference in standardized mortality ratio (0.4-1.9). Two hospitals had significantly better-than-expected and two had significantly worse-than-expected mortality.
CONCLUSIONS
For the first time, we have demonstrated that variation in mortality as a quality metric exists across dedicated cardiac ICUs. These findings can guide efforts to reduce mortality after cardiac surgery.
Topics: Age Factors; Cardiac Surgical Procedures; Child, Preschool; Critical Care; Extracorporeal Membrane Oxygenation; Female; Heart Defects, Congenital; Hospital Mortality; Humans; Infant; Infant, Newborn; Intensive Care Units, Pediatric; Logistic Models; Male; Respiration, Artificial; Retrospective Studies; Risk Adjustment; Risk Factors; Severity of Illness Index
PubMed: 30489488
DOI: 10.1097/PCC.0000000000001776 -
Neural Development Sep 2018Proper patterning of dendritic and axonal arbors is a critical step in the formation of functional neuronal circuits. Developing circuits rely on an array of molecular...
BACKGROUND
Proper patterning of dendritic and axonal arbors is a critical step in the formation of functional neuronal circuits. Developing circuits rely on an array of molecular cues to shape arbor morphology, but the underlying mechanisms guiding the structural formation and interconnectivity of pre- and postsynaptic arbors in real time remain unclear. Here we explore how Down syndrome cell adhesion molecule (DSCAM) differentially shapes the dendritic morphology of central neurons and their presynaptic retinal ganglion cell (RGC) axons in the developing vertebrate visual system.
METHODS
The cell-autonomous role of DSCAM, in tectal neurons and in RGCs, was examined using targeted single-cell knockdown and overexpression approaches in developing Xenopus laevis tadpoles. Axonal arbors of RGCs and dendritic arbors of tectal neurons were visualized using real-time in vivo confocal microscopy imaging over the course of 3 days.
RESULTS
In the Xenopus visual system, DSCAM immunoreactivity is present in RGCs, cells in the optic tectum and the tectal neuropil at the time retinotectal synaptic connections are made. Downregulating DSCAM in tectal neurons significantly increased dendritic growth and branching rates while inducing dendrites to take on tortuous paths. Overexpression of DSCAM, in contrast, reduced dendritic branching and growth rate. Functional deficits mediated by tectal DSCAM knockdown were examined using visually guided behavioral assays in swimming tadpoles, revealing irregular behavioral responses to visual stimulus. Functional deficits in visual behavior also corresponded with changes in VGLUT/VGAT expression, markers of excitatory and inhibitory transmission, in the tectum. Conversely, single-cell DSCAM knockdown in the retina revealed that RGC axon arborization at the target is influenced by DSCAM, where axons grew at a slower rate and remained relatively simple. In the retina, dendritic arbors of RGCs were not affected by the reduction of DSCAM expression.
CONCLUSIONS
Together, our observations implicate DSCAM in the control of both pre- and postsynaptic structural and functional connectivity in the developing retinotectal circuit, where it primarily acts as a neuronal brake to limit and guide postsynaptic dendrite growth of tectal neurons while it also facilitates arborization of presynaptic RGC axons cell autonomously.
Topics: Animals; Avoidance Learning; Axons; Cell Adhesion Molecules; Dendrites; Down-Regulation; Gene Expression Regulation, Developmental; Image Processing, Computer-Assisted; Microscopy, Confocal; Morpholinos; Neurons; Photic Stimulation; Retina; Superior Colliculi; Synapses; Transfection; Vesicular Glutamate Transport Proteins; Vesicular Inhibitory Amino Acid Transport Proteins; Visual Pathways; Xenopus Proteins; Xenopus laevis
PubMed: 30219101
DOI: 10.1186/s13064-018-0118-5 -
Diabetologia Jul 2018Bi-allelic loss-of-function mutations in the INSR gene (encoding the insulin receptor [INSR]) commonly cause extreme insulin resistance and early mortality. Therapeutic... (Comparative Study)
Comparative Study
AIMS/HYPOTHESIS
Bi-allelic loss-of-function mutations in the INSR gene (encoding the insulin receptor [INSR]) commonly cause extreme insulin resistance and early mortality. Therapeutic options are limited, but anti-INSR antibodies have been shown to activate two mutant receptors, S323L and F382V. This study evaluates four well-characterised murine anti-INSR monoclonal antibodies recognising distinct epitopes (83-7, 83-14, 18-44, 18-146) as surrogate agonists for potential targeted treatment of severe insulin resistance arising from insulin receptoropathies.
METHODS
Ten naturally occurring mutant human INSRs with defects affecting different aspects of receptor function were modelled and assessed for response to insulin and anti-INSR antibodies. A novel 3T3-L1 adipocyte model of insulin receptoropathy was generated, permitting conditional knockdown of endogenous mouse Insr by lentiviral expression of species-specific short hairpin (sh)RNAs with simultaneous expression of human mutant INSR transgenes.
RESULTS
All expressed mutant INSR bound to all antibodies tested. Eight mutants showed antibody-induced autophosphorylation, while co-treatment with antibody and insulin increased maximal phosphorylation compared with insulin alone. After knockdown of mouse Insr and expression of mutant INSR in 3T3-L1 adipocytes, two antibodies (83-7 and 83-14) activated signalling via protein kinase B (Akt) preferentially over signalling via extracellular signal-regulated kinase 1/2 (ERK1/2) for seven mutants. These antibodies stimulated glucose uptake via P193L, S323L, F382V and D707A mutant INSRs, with antibody response greater than insulin response for D707A.
CONCLUSIONS/INTERPRETATION
Anti-INSR monoclonal antibodies can activate selected naturally occurring mutant human insulin receptors, bringing closer the prospect of novel therapy for severe insulin resistance caused by recessive mutations.
Topics: 3T3-L1 Cells; Adipocytes; Animals; Antibodies; Antigens, CD; CHO Cells; Cricetulus; Glucose; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Mice; Mutation; Phosphorylation; Receptor, Insulin; Signal Transduction
PubMed: 29700562
DOI: 10.1007/s00125-018-4606-2 -
International Journal of Molecular... Apr 2018Mutations in the insulin receptor (INSR) gene underlie rare severe INSR-related insulin resistance syndromes (SIR), including insulin resistance type A,... (Review)
Review
Mutations in the insulin receptor (INSR) gene underlie rare severe INSR-related insulin resistance syndromes (SIR), including insulin resistance type A, Rabson⁻Mendenhall syndrome and Donohue syndrome (DS), with DS representing the most severe form of insulin resistance. Treatment of these cases is challenging, with the majority of DS patients dying within the first two years of life. rhIGF-I (mecasermin) has been reported to improve metabolic control and increase lifespan in DS patients. A case report and literature review were completed. We present a case involving a male patient with DS, harbouring a homozygous mutation in the INSR gene (c.591delC). Initial rhIGF-I application via BID (twice daily) injection was unsatisfactory, but continuous subcutaneous rhIGF-I infusion via an insulin pump improved weight development and diabetes control (HbA1c decreased from 10 to 7.6%). However, our patient died at 22 months of age during the course of a respiratory infection in in Libya. Currently available data in the literature comprising more than 30 treated patients worldwide seem to support a trial of rhIGF-I in SIR. rhIGF-I represents a treatment option for challenging SIR cases, but careful consideration of the therapeutic benefits and the burden of the disease is warranted. Continuous application via pump might be advantageous compared to single injections.
Topics: Blood Glucose; Donohue Syndrome; Humans; Infant; Infant, Newborn; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Male; Models, Biological; Mutation; Receptor, Insulin; Recombinant Proteins; Treatment Outcome
PubMed: 29695048
DOI: 10.3390/ijms19051268 -
Turk Pediatri Arsivi Dec 2017Donohue syndrome (Leprechaunism) is characterized by severe insulin resistance, hyperinsulinemia, postprandial hyperglycemia, preprandial hypoglycemia, intrauterine and...
Donohue syndrome (Leprechaunism) is characterized by severe insulin resistance, hyperinsulinemia, postprandial hyperglycemia, preprandial hypoglycemia, intrauterine and postnatal growth retardation, dysmorphic findings, and clinical and laboratory findings of hyperandrogenemia due to homozygous or compound heterozygous inactivating mutations in the insulin receptor gene. A female newborn presented with lack of subcutaneous fat tissue, bilateral simian creases, hypertrichosis, especially on her face, gingival hypertrophy, cliteromegaly, and prominent nipples. Her laboratory tests revealed hyperandrogenism, postprandial hyperglycemia and preprandial hypoglycemia, and very high concurrent insulin levels. She was diagnosed as having Donohue syndrome. Metformin and continuous nasogastric feeding were administrated. During follow-up, relatively good glycemic control was obtained. However, severe hypertrophic obstructive cardiomyopathy and severe malnutrition developed. She died aged 75 days of severe heart failure and pneumonia. Her insulin receptors gene analysis revealed a compound heterozygous mutation. One of these mutations was a p.R813 (c.2437C>T) mutation, which was defined previously and shown also in her father, the other mutation was a novel p.777-790delVAAFPNTSSTSVPT mutation, also shown in her mother. The parents were heterozygous for these mutations.
PubMed: 29483803
DOI: 10.5152/TurkPediatriArs.2017.3193 -
Journal of the Endocrine Society Nov 2017Hyperinsulinemia is often observed in obese people, owing to their insulin resistance accompanied by visceral fat accumulation, but the frequency of hyperinsulinemia in...
CONTEXT
Hyperinsulinemia is often observed in obese people, owing to their insulin resistance accompanied by visceral fat accumulation, but the frequency of hyperinsulinemia in nonobese people is not well known. Mutations in the insulin receptor gene are known to cause insulin resistance and hyperinsulinemia in type A insulin resistance syndrome, Rabson-Mendenhall syndrome, and Donohue syndrome. However, insulin receptor gene abnormalities have not been investigated in asymptomatic hyperinsulinemic subjects.
PURPOSE
The aim of the current study was to investigate the prevalence of hyperinsulinemia in nonobese Japanese subjects and to examine the involvement of insulin receptor gene mutations.
METHODS
We enrolled 11,046 subjects who received health checkups. From these, we extracted nonobese subjects (body mass index <25 kg/m) who exhibited hyperinsulinemia (serum fasting immunoreactive insulin ≥15 µU/mL). Genetic analysis was performed for the insulin receptor gene in 11 nonobese subjects with hyperinsulinemia.
RESULTS
The prevalence of hyperinsulinemia without apparent diabetes in nonobese subjects was 0.4% (33/8630). In the 11 analyzed subjects, two novel heterozygous nonsense mutations were detected [c.2106 T>G (p.Y702X) and c.2779-2780 GC>A]. The prevalence of insulin receptor gene mutations was 18.2% (2/11).
CONCLUSIONS
To our knowledge, this is the first report of the prevalence of hyperinsulinemia in nonobese healthy subjects. We identified two novel mutations in the insulin receptor gene. These findings indicate that mutations in the insulin receptor gene may be related to fasting hyperinsulinemia, and insulin receptor gene screening may be useful for determining the cause of unexplained hyperinsulinemia.
PubMed: 29264459
DOI: 10.1210/js.2017-00332 -
Journal of Clinical Research in... Jun 2018Mutations in the insulin receptor () gene are responsible for Donohue syndrome (DS) and Rabson-Mendenhall syndrome (RMS). Insulin resistance is a feature of both...
Mutations in the insulin receptor () gene are responsible for Donohue syndrome (DS) and Rabson-Mendenhall syndrome (RMS). Insulin resistance is a feature of both diseases. Our patient was a Chinese neonate suffering from abnormal glucose homeostasis, hyperinsulinemia, dry skin, heavy hair, growth retardation and an elevated testosterone level. To search for candidate point mutations, small insertions or deletions and copy number variants, 2742 inherited disease-gene panel sequencing was performed. One pathogenic mutation (c.3355C>T, p.Arg1119Trp) and a novel 2.43Kb deletion (chr19:7150507-7152938) in were found. The patient was diagnosed as RMS. Sanger sequencing and real-time quantitative polymerase chain reaction (PCR) confirmed the missense variant and microdeletion, respectively. We therefore supposed that these variants were candidate mutations in this case. We report a novel 2.43Kb deletion in gene and provide further proof of the power of next generation sequencing in rare disease diagnosis.
Topics: Antigens, CD; China; Donohue Syndrome; Humans; Infant, Newborn; Infant, Newborn, Diseases; Male; Mutation; Receptor, Insulin
PubMed: 29082893
DOI: 10.4274/jcrpe.5080