-
Pediatric Endocrinology, Diabetes, and... 2010Insulin plays a very important role in maintaining homeostasis of the whole organism. It regulates glucose metabolism, glycogen synthesis, lipid and protein metabolism.... (Review)
Review
Insulin plays a very important role in maintaining homeostasis of the whole organism. It regulates glucose metabolism, glycogen synthesis, lipid and protein metabolism. Insulin receptors are present in virtually all cells, which is reflected by the diversity of regulatory processes in which this hormone is involved. Any dysfunction of insulin signalling pathway as a result of insulin receptor gene mutations is linked with various forms of insulin resistance, including insulin resistance type A, Donohue or Rabson-Mendenhall syndrome, which differ in the level of severity. Molecular analysis of insulin receptor gene may lead to a better understanding of molecular mechanisms underlying various types of insulin resistance and help to develop a more efficient treatment. They may also be used as a powerful tool in prenatal diagnostics as well as in pregnancy planning.
Topics: Adult; Donohue Syndrome; Female; Humans; Infant, Newborn; Insulin Resistance; Pregnancy; Receptor, Insulin
PubMed: 21092701
DOI: No ID Found -
American Journal of Medical Genetics.... Jan 2021Genetic diseases are a major cause of neonatal morbidity and mortality. The clinical differential diagnosis in severely ill neonates, especially in premature infants, is...
Genetic diseases are a major cause of neonatal morbidity and mortality. The clinical differential diagnosis in severely ill neonates, especially in premature infants, is challenging. Next generation sequencing (NGS) diagnostics is a valuable tool, but the turnaround time is often too long to provide a diagnosis in the time needed for clinical guidance in newborn intensive care units (NICU). To minimize turnaround time, we developed an ultra-rapid whole genome sequencing pipeline and tested it in clinical practice. Our pilot case, was a preterm infant presenting with several crises of dehydration, hypoglycaemia and hyponatremia together with nephrocalcinosis and hypertrophic cardiomyopathy. Whole genome sequencing was performed using a paired-end 2x75bp protocol. Sequencing data were exported after 50 sequencing cycles for a first analysis. After run completion, the rapid-sequencing protocol, a second analysis of the 2 x 75 paired-end run was performed. Both analyses comprised read-mapping and SNP-/indel calling on an on-site Edico Genome DRAGEN server, followed by functional annotation and pathogenicity prediction using in-house scripts. After the first analysis within 17 h, the emergency ultra-rapid protocol identified two novel compound heterozygous variants in the insulin receptor gene (INSR), pathogenic variants in which cause Donohue Syndrome. The genetic diagnosis could be confirmed by detection of hyperinsulinism and patient care adjusted. Nonetheless, we decided to pursue RNA studies, proving the functional effect of the novel splice variant and reduced expression levels of INSR in patients skin fibroblasts.
Topics: Antigens, CD; Dehydration; Female; Genetic Diseases, Inborn; High-Throughput Nucleotide Sequencing; Humans; Hypoglycemia; Infant; Infant Mortality; Infant, Newborn; Infant, Premature; Intensive Care Units, Neonatal; Male; Molecular Sequence Annotation; Polymorphism, Single Nucleotide; Protein Isoforms; Receptor, Insulin; Whole Genome Sequencing
PubMed: 33048476
DOI: 10.1002/ajmg.a.61917 -
Diabetes Research and Clinical Practice Aug 2010
Topics: Donohue Syndrome; Humans; Male; Middle Aged; Time Factors
PubMed: 20627358
DOI: 10.1016/j.diabres.2010.04.023 -
JAMA Jun 1979The fat embolism syndrome is a symptom complex of acute respiratory failure after long-bone fractures. It is thought to be caused by deposition of embolic fat within the...
The fat embolism syndrome is a symptom complex of acute respiratory failure after long-bone fractures. It is thought to be caused by deposition of embolic fat within the pulmonary capillaries, resulting in a capillary leak within the lung. The source of the embolic fat appears to be marrow fat. Alterations in circulating free fatty acids, increases in fibrin split products, and increases in platelet adhesiveness have been observed to occur in this syndrome and probably play an important part in the production of the pulmonary lesion. The signs and symptoms of the syndrome are hypoxemia, tachypnea, petechiae, fever, altered sensorium, and chest roentgenograms similar to signs of the adult respiratory distress syndrome (ARDS). Early recognition is facilitated by monitoring of arterial blood gas levels for hypoxemia. Treatment is directed at ARDS using graduated oxygen therapy and steroids.
Topics: Blood Coagulation Disorders; Embolism, Fat; Humans; Lung; Prognosis; Syndrome
PubMed: 448826
DOI: No ID Found -
European Neurology 1972
Topics: Abnormalities, Multiple; Child; Chromosomes, Human, 6-12 and X; Dwarfism; Female; Humans; Intellectual Disability; Lipodystrophy; Male; Progeria; Trisomy
PubMed: 5019154
DOI: 10.1159/000114410 -
Journal of Pediatric Endocrinology &... Nov 2014Donohue syndrome (DS) is a severe form of congenital insulin resistance due to mutation(s) in the insulin receptor (INSR) gene. Given the similarities between insulin...
Donohue syndrome (DS) is a severe form of congenital insulin resistance due to mutation(s) in the insulin receptor (INSR) gene. Given the similarities between insulin and insulin-like growth factor 1 (IGF-1) receptors, recombinant human IGF-1 (rhIGF-1) has been used to treat severe insulin resistance due to INSR mutation(s). Traditional subcutaneous therapy may be limited by the shortened IGF-1 half-life in these patients. We report the case of a female with molecularly confirmed DS treated with continuous rhIGF-1 therapy via an insulin pump. With treatment, the patient's hemoglobin A1c decreased from 9.8% to 8.8%, and her weight increased by 0.8 kg. Development of an ovarian tumor complicated her course, but it was unclear whether this was related to rhIGF-1 therapy. Limited treatment options exist for patients with DS. The use of continuous rhIGF-1 via an insulin pump may be a viable option, although further experience is needed to establish safety and efficacy.
Topics: Antigens, CD; Donohue Syndrome; Female; Humans; Infant, Newborn; Infusion Pumps; Injections, Subcutaneous; Insulin-Like Growth Factor I; Mutation; Prognosis; Receptor, Insulin; Recombinant Proteins
PubMed: 25153212
DOI: 10.1515/jpem-2013-0402 -
Cardiovascular Revascularization... 2007Transient left ventricular apical ballooning syndrome, also called "Tako-Tsubo cardiomyopathy," is increasingly being recognized as a cause of cardiomyopathy occurring... (Review)
Review
Transient left ventricular apical ballooning syndrome, also called "Tako-Tsubo cardiomyopathy," is increasingly being recognized as a cause of cardiomyopathy occurring during stress, with characteristic apical ballooning appearance of the left ventricle and the finding of normal coronary arteries on angiogram. In this manuscript, we review the available literature about the pathogenesis and characteristics of this syndrome.
Topics: Coronary Angiography; Female; Humans; Male; Risk Factors; Sex Factors; Syndrome; Takotsubo Cardiomyopathy
PubMed: 18053952
DOI: 10.1016/j.carrev.2007.02.001 -
The American Journal of Dermatopathology Apr 2012Areolar hyperplasia is only reported when exaggerated, and even so, exaggerated areolar sebaceous hyperplasia is rare. We have recently seen a case of areolar sebaceous...
Areolar hyperplasia is only reported when exaggerated, and even so, exaggerated areolar sebaceous hyperplasia is rare. We have recently seen a case of areolar sebaceous hyperplasia in a 32-year-old woman with Donohue syndrome (leprechaunism), who also had an invasive ductal carcinoma in the same breast. The patient showed typical "elfin-like" face with wide nostrils and thick lips, large and low-set ears, and dysplastic nails. The areola showed a yellowish thickened plaque of 5-cm diameter that corresponded to a hyperplasia of the sebaceous glands. Immunohistochemistry for the mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) was performed on the sebaceous hyperplasia and on the breast carcinoma, and no lack of expression of the markers was evidenced. We have found no other reported case of areolar sebaceous hyperplasia either in cases of breast carcinoma or in cases of leprechaunism.
Topics: Adult; Breast Neoplasms; Carcinoma, Ductal, Breast; Donohue Syndrome; Female; Humans; Hyperplasia; Immunohistochemistry; Nipples; Sebaceous Glands
PubMed: 22172957
DOI: 10.1097/DAD.0b013e318231311a -
The New England Journal of Medicine Dec 2021In the phase 1-2 portion of an adaptive trial, REGEN-COV, a combination of the monoclonal antibodies casirivimab and imdevimab, reduced the viral load and number of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In the phase 1-2 portion of an adaptive trial, REGEN-COV, a combination of the monoclonal antibodies casirivimab and imdevimab, reduced the viral load and number of medical visits in patients with coronavirus disease 2019 (Covid-19). REGEN-COV has activity in vitro against current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern.
METHODS
In the phase 3 portion of an adaptive trial, we randomly assigned outpatients with Covid-19 and risk factors for severe disease to receive various doses of intravenous REGEN-COV or placebo. Patients were followed through day 29. A prespecified hierarchical analysis was used to assess the end points of hospitalization or death and the time to resolution of symptoms. Safety was also evaluated.
RESULTS
Covid-19-related hospitalization or death from any cause occurred in 18 of 1355 patients in the REGEN-COV 2400-mg group (1.3%) and in 62 of 1341 patients in the placebo group who underwent randomization concurrently (4.6%) (relative risk reduction [1 minus the relative risk], 71.3%; P<0.001); these outcomes occurred in 7 of 736 patients in the REGEN-COV 1200-mg group (1.0%) and in 24 of 748 patients in the placebo group who underwent randomization concurrently (3.2%) (relative risk reduction, 70.4%; P = 0.002). The median time to resolution of symptoms was 4 days shorter with each REGEN-COV dose than with placebo (10 days vs. 14 days; P<0.001 for both comparisons). REGEN-COV was efficacious across various subgroups, including patients who were SARS-CoV-2 serum antibody-positive at baseline. Both REGEN-COV doses reduced viral load faster than placebo; the least-squares mean difference in viral load from baseline through day 7 was -0.71 log copies per milliliter (95% confidence interval [CI], -0.90 to -0.53) in the 1200-mg group and -0.86 log copies per milliliter (95% CI, -1.00 to -0.72) in the 2400-mg group. Serious adverse events occurred more frequently in the placebo group (4.0%) than in the 1200-mg group (1.1%) and the 2400-mg group (1.3%); infusion-related reactions of grade 2 or higher occurred in less than 0.3% of the patients in all groups.
CONCLUSIONS
REGEN-COV reduced the risk of Covid-19-related hospitalization or death from any cause, and it resolved symptoms and reduced the SARS-CoV-2 viral load more rapidly than placebo. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT04425629.).
Topics: Adolescent; Adult; Antibodies, Monoclonal, Humanized; Antibodies, Neutralizing; Antiviral Agents; COVID-19; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Female; Hospitalization; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Pregnancy; Pregnancy Complications, Infectious; Proportional Hazards Models; Viral Load; Young Adult; COVID-19 Drug Treatment
PubMed: 34587383
DOI: 10.1056/NEJMoa2108163 -
The Journal of Clinical Endocrinology... Feb 2022Rabson-Mendenhall syndrome (RMS) is caused by biallelic pathogenic variants in the insulin receptor gene (INSR) leading to insulin-resistant diabetes, microvascular...
CONTEXT
Rabson-Mendenhall syndrome (RMS) is caused by biallelic pathogenic variants in the insulin receptor gene (INSR) leading to insulin-resistant diabetes, microvascular complications, and growth hormone resistance with short stature. Small, uncontrolled studies suggest that 1-year treatment with recombinant leptin (metreleptin) improves glycemia in RMS.
OBJECTIVE
This study aimed to determine effects of long-term metreleptin in RMS on glycemia, anthropometrics, the growth hormone axis, and kidney function.
METHODS
We compared RMS patients during nonrandomized open-label treatment with metreleptin (≥ 0.15 mg/kg/day) vs no metreleptin over 90 months (5 subjects in both groups at different times, 4 only in metreleptin group, 2 only in control group). Main outcome measures were A1c; glucose; insulin; 24-hour urine glucose; standard deviation scores (SDS) for height, weight, body mass index (BMI), and insulin-like growth factor 1 (IGF-1); growth hormone; and estimated glomerular filtration rate.
RESULTS
Over time, metreleptin-treated subjects maintained 1.8 percentage point lower A1c vs controls (P = 0.007), which remained significant after accounting for changes in insulin doses. Metreleptin-treated subjects had a reduction in BMI SDS, which predicted decreased A1c. Growth hormone increased after metreleptin treatment vs control, with no difference in SDS between groups for IGF-1 or height. Reduced BMI predicted higher growth hormone, while reduced A1c predicted higher IGF-1.
CONCLUSION
Metreleptin alters the natural history of rising A1c in RMS, leading to lower A1c throughout long-term follow-up. Improved glycemia with metreleptin is likely attributable to appetite suppression and lower BMI SDS. Lower BMI after metreleptin may also worsen growth hormone resistance in RMS, resulting in a null effect on IGF-1 and growth despite improved glycemia.
Topics: Antigens, CD; Blood Glucose; Body Height; Body Mass Index; Body Weight; Donohue Syndrome; Glomerular Filtration Rate; Glycated Hemoglobin; Human Growth Hormone; Humans; Insulin; Insulin-Like Growth Factor I; Kidney; Leptin; Receptor, Insulin; Treatment Outcome
PubMed: 34718628
DOI: 10.1210/clinem/dgab782