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Objective This study aimed to assess insulin resistance according to maternal age at childbirth. Patients and methods The data used in this study were obtained from the 2010 Korean National Health and Nutrition Examination Survey. This study included a total of 2233 nondiabetic female subjects ≥30 years of age that were subdivided into groups according to their obesity and abdominal obesity ( AOB) statuses. The homoeostasis model assessment of insulin resistance ( HOMA- IR) was used to quantify the insulin resistance according to age at first childbirth and last childbirth. Results Age at first childbirth showed a negative relationship with HOMA- IR in both the nonobese and non- AOB groups, while age at last childbirth showed a positive relationship with HOMA- IR in both the nonobese and non- AOB groups. A multivariate logistic regression analysis revealed that ages at first and last childbirth were significantly associated with the highest HOMA- IR quartile. The odds ratio was 0·9 (95% confidence interval: 0·82-0·98) for age at first childbirth, and 1·07 (95% confidence interval: 1·01-1·14) for age at last childbirth in the nonobese and non- AOB groups. Conclusion In conclusion, this study suggests that insulin resistance is increased in females who experienced their first childbirth at a younger age or their last childbirth at a later age, particularly in nonobese individuals. Because these data suggest that childbearing age could be an independent risk factor for diabetes, a high-quality prospective study assessing the relationship between childbearing age and insulin resistance should be performed. [ABSTRACT FROM AUTHOR]

Background Because insulin signaling is essential for endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) production, the loss of bioavailable NO might be a common molecular mechanism underlying the development of insulin resistance and endothelial dysfunction. Although dietary nitrite acts as a substrate for systemic NO generation, thereby serving as a physiological alternative source of NO for signaling, it is not precisely known how dietary nitrite affects type 2 diabetes mellitus. Here we report the therapeutic effects of dietary nitrite on the metabolic and histological features of KKA y diabetic mice. Methods KKA y mice were divided into three groups (without nitrite, and with 50 mg/L and 150 mg/L nitrite in drinking water), and two groups of C57BL/6J mice served as controls (without nitrite and with 150 mg/L nitrite in drinking water). After 10 weeks, blood samples, visceral adipose tissues, and gastrocnemius muscles were collected after a 16-hour fast to assess the homeostasis model assessment of insulin resistance (HOMA-IR) levels, the histology of the adipose tissue, insulin-stimulated sequential signaling to glucose transporter 4 (GLUT4), and nitrite and nitrate contents in the muscle using an HPLC system. Results KKA y mice developed obesity with enhanced fasting plasma levels of glucose and insulin and exhibited increased HOMA-IR scores compared with the C57BL/6J control mice. Dietary nitrite dose-dependently reduced the size of the hypertrophic adipocytes and TNF-α transcription in the adipose tissue of KKA y diabetic mice, which also restored the insulin-mediated signal transduction, including p85 and Akt phosphorylation, and subsequently restored the GLUT4 expression in the skeletal muscles. Conclusions These results suggest that dietary nitrite provides an alternative source of NO, and subsequently improves the insulin-mediated signaling and the metabolic and histological features in KKA y diabetic mice. [ABSTRACT FROM AUTHOR]

Background/Aims: Donohue and Rabson-Mendenhall syndrome are rare autosomal recessive disorders caused by mutations in the insulin receptor gene, INSR. Phenotypic features include extreme insulin resistance, linear growth retardation, paucity of fat and muscle, and soft tissue overgrowth. The insulin receptor is also expressed in the kidney, where animal data suggest it plays a role in glomerular function and blood pressure (BP) regulation, yet such a role in the human kidney is untested. Patients with biallelic INSR mutations provide a rare opportunity to ascertain its role in man. Methods: Retrospective review of patients with INSR mutations. Data for BP, renal imaging, plasma creatinine and electrolyte levels, as well as urine protein, albumin and calcium excretion were sought from the treating clinicians. Results: From 33 patients with INSR mutations, data were available for 17 patients. Plasma creatinine was low (mean ± SD: 25 ± 9 μmol/l) and mean plasma electrolyte concentrations were within the normal range (n = 13). Systolic BP ranged between the 18th and 91st percentile for age, sex, height and weight (n = 9; mean ± SD: 49 ± 24). Twenty-four-hour urinary calcium data were available from 10 patients and revealed hypercalciuria in all (mean ± SD: 0.32 ± 0.17 mmol/kg/day; normal <0.1). Nephrocalcinosis was present in all patients (n = 17). Urinary albumin excretion (n = 7) ranged from 4.3-122.5 μg/min (mean ± SD: 32.4 ± 41.0 μg/min; normal <20). Conclusions: INSR dysfunction is associated with hypercalciuria and nephrocalcinosis. No other consistent abnormality of renal function was noted. Normotension and stable glomerular function with only moderate proteinuria is in contrast to genetically modified mice who have elevated BP and progressive diabetic nephropathy. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction. Leprechaunism is a rare autosomal recessive condition characterized by dysmorhic features, growth failure and disordered glucose homeostasis. Case report. A term infant was born to a first cousin, who previously lost a baby with Leprechaunism. Pregnancy and delivery were uneventful. Birth weight, length and head circumference were all below the third centile. Clinical examination at birth reveals large low set ears, depressed nasal bridge, gingival hyperplasia, prominent nipples, umbilical hernia, lipodystrophy, hypertrichosis, and wrinkled loose skin. Examination of the genitalia showed a prominent phallus, posterior fusion of the labioscrotal folds and no palpable gonads. A clinical diagnosis of Leprechaunism was made based on the family history and the clinical phenotype. In addition to the presence of ambiguous genitalia, management of this infant was complicated by poor glycemic control with frequent hyper and hypoglycemic episodes. Insulin was inappropriately high (1626.1 mU/mL, normal 3-17 Mu/mL) when glucose was relatively low (3.2 mmol/L) indicating insulin resistance. ACTH stimulation test confirmed an intact adrenal function with normal 17 hydroxyprogesterone and cortisol. Testosterone and adrenal androgens were normal. Chromosomal study showed 46 XX and MRI abdomen revealed normal pancreas and internal female organs. Accordingly, this infant was assigned as a female. Severe hyper and hypoglycemic episodes responded to introduction of frequent nasogastric formula milk feeding together with insulin glargine. Glycemic control improved with glycated hemoglobin of 8%. Conclusion. This case report illustrates a management challenge of a newborn infant with Leprechaunism, ambiguous genitalia and poor glycemic control and discuss treatment options. [ABSTRACT FROM AUTHOR]

Diabetic ketosis had been identified as a characteristic of type 1 diabetes mellitus (T1DM), but now emerging evidence has identified that they were diagnosed as T2DM after long time follow up. This case control study was aimed at comparing the clinical characteristic, β-cell function, and insulin resistance of ketosis and nonketotic onset T2DM and providing evidence for treatment selection. 140 cases of newly diagnosed T2DM patients were divided into ketosis (62 cases) and nonketotic onset group (78 cases). After correction of hyperglycemia and ketosis with insulin therapy, plasma C-peptide concentrations were measured at 0, 0.5, 1, 2, and 3 hours after 75 g glucose oral administration. Area under the curve (AUC) of C-peptide was calculated. Homoeostasis model assessment was used to estimate basal β-cell function (HOMA-β) and insulin resistance (HOMA-IR). Our results showed that ketosis onset group had higher prevalence of nonalcoholic fatty liver disease (NAFLD) than nonketotic group (P = 0.04). Ketosis onset group had increased plasma C-peptide levels at 0 h, 0.5 h, and 3 h and higher AUC0-0.5, AUC0-1, AUC0-3 (P < 0.05). Moreover, this group also had higher HOMA-β and HOMA-IR than nonketotic group (P < 0.05). From these data, we concluded that ketosis onset T2DM had better islet β-cell function and more serious insulin resistance than nonketotic onset T2DM. [ABSTRACT FROM AUTHOR]

Research in recent years has led to the recognition of the importance of nonalcoholic fatty liver disease (NAFLD) and its relationship to the metabolic syndrome (MS). This has led to a growing interest in the potential prognostic value of NAFLD for adverse cardiovascular disease (CVD) outcome. On the other hand, searching for new risk factors for chronic kidney disease (CKD) development and progression is very important. Growing evidence suggests that the MS is an important factor in the pathogenesis of CKD. The best confirmation of this pathogenic link is hypertensive and diabetic nephropathy as the main causes of CKD. Furthermore, the possible link between NAFLD and CKD has also attracted research interest and recent data suggest an association between these two conditions. These findings have fuelled concerns that NAFLD may be a new and added risk factor for the development and progression of CKD. NAFLD and CKD share some important cardiometabolic risk factors and possible common pathophysiological mechanisms, and both are linked to an increased risk of incident CVD events. Therefore, common factors underlying the pathogenesis of NAFLD and CKD may be insulin resistance, oxidative stress, activation of rennin-angiotensin system, and inappropriate secretion of inflammatory cytokines by steatotic and inflamed liver. [ABSTRACT FROM AUTHOR]

Donohue syndrome (leprechaunism; OMIM *246200) is a rare, recessively inherited disorder of extreme insulin resistance due to mutations in the insulin receptor gene ( INSR) causing either defects in insulin binding or receptor autophosphorylation and tyrosine kinase activity. We report a patient with pronounced clinical picture of leprechaunism who developed severe progressive hypertrophic obstructive cardiomyopathy (HOCM) and renal tubular dysfunction which improved on continuous subcutaneous infusion of recombinant human insulin-like growth factor-1 (rhIGF-I). INSR gene molecular analysis and insulin receptor (IR) autophosphorylation on cultured fibroblasts were performed. A novel homozygous missense mutation p.Leu795Pro was found, located in the extracellular portion of the β subunit of the insulin receptor. The post-binding defect of the insulin receptor signaling in cultured fibroblasts demonstrated decreased insulin receptor autophosphorylation. Conclusion: Treatment with rhIGF-I partially reversed severe progressive HOCM and renal tubular dysfunction in a patient with Donohue syndrome associated with a novel p.Leu795Pro INSR gene mutation causing a severe decrease in IR autophosphorylation. [ABSTRACT FROM AUTHOR]

Leprechaunism is a rare autosomal recessive disease that is characterized by severe insulin resistance. This disease is caused by a defective insulin receptor and features abnormal glucose metabolism and retarded intrauterine and postnatal growth. However, there are few reports on the long-term course of leprechaunism. We reported the long-term clinical course and rh-IGF-1 treatment in a patient with leprechaunism. During follow-up her diabetes gradually deteriorated despite of treatment of rh-IGF-1. Furthermore, she developed endometrioid adenocarcinoma at the age of 24 yr. The development of endometrial disease must be carefully followed up in this disease. [ABSTRACT FROM AUTHOR]

Objectives: We aim to report a case of Donohue syndrome (DS) which is a rare genetically encoded, autosomal inherited recessive disorder linked with severe insulin-resistant diabetes., Case Presentation: We hereby report a case of a 4 month -old girl infant with DS. The patient exhibited dysmorphic facial features, severe growth retardation, fasting hypoglycemia, postprandial hyperglycemia, and hyperinsulinemia which are the hallmarks of DS. The diagnosis of DS was confirmed by genetic analysis. The patient was treated with high-dose insulin and frequent nasogastric formula milk feeding to achieve reasonable glycemic control., Conclusions: We reported a typical case of DS in a 4-month-old female infant characterized by peculiar dysmorphic features and failure to thrive. She also fulfilled the biochemical criteria of fasting hypoglycemia, postprandial hyperglycemia, and severe hyperinsulinemia. The diagnosis was confirmed by a molecular genetic study. Our patient achieved reasonable glycemic control after treatment with high-dose insulin., Competing Interests: Competing interests: The authors state no conflict of interest., (© 2022 the author(s), published by De Gruyter, Berlin/Boston.)

Donohue syndrome (Leprechaunism) is an extremely rare, autosomal recessively inherited genetic disease. It is caused by mutations at the insulin receptor gene, which lias a profound effect during fetal development and thereafter. It is characterized by elfin face, hypertrichosis, acanthosis nigricans, reduced subcutaneous fat, and intrauterine and postnatal growth retardation. Diagnosis is established according to the physical examination and laboratory investigations. Definitive diagnosis is possible with demonstration of the mutations at the insulin receptor gene. The prognosis is usually grave, most of them die early in infancy. hi this paper, a 57 day- old male diagnosed with Donohue syndrome, who had other endocrine pathologies besides abnormal glucose metabolism, is presented due to its very rare occurrence. [ABSTRACT FROM AUTHOR]

Donohue syndrome (DS) is a rare autosomal recessive condition caused by mutations in the gene encoding the insulin receptor. It is characterised by severe metabolic and endocrine derangement, prenatal and postnatal linear growth impairment, soft tissue overgrowth, and poor development of adipose tissue and muscle. Causes of death, which is often within the first year of life, include intercurrent infection and, in some cases, heart failure. Management is currently based on case reports and very small case series only, and no formal guidelines or recommendations exist. We describe a preterm infant who had typical features of DS but who later developed hypertrophic cardiomyopathy with heart failure leading to death at 10 weeks old. Molecular genetic analysis revealed compound heterozygosity for the previously reported p.Arg890X nonsense mutation and the novel p.Tyr818Cys missense mutation in the INSR gene. Tyrosine 818 falls in an exquisitely conserved residue of the αβ fibronectin domain of the insulin receptor, whose structure and function are much less well understood than other parts of the receptor. We discuss management options for DS, including the therapeutic dilemma around whether recombinant human insulin-like growth factor 1, one of the few available treatments for the syndrome, may exacerbate hypertrophic cardiomyopathy and cardiac failure. [ABSTRACT FROM AUTHOR]

The article discusses the Donohue syndrome in a five day-old neonate with characteristic severe pre- and postnatal linear growth impairment, abnormal glucose metabolism and overgrowth of soft tissue. The neonate, which died within two months secondary to hypoglycemia, was reportedly homozygous for deletion of exon three of the insulin receptor gene. It is stated that both parents were healthy but were heterozygous for the deletion and that a founder effect may be shown in the Middle East.