Clinical Manifestations of Hyperandrogenism and Ovulatory Dysfunction Are Not Associated with His1058 C/T SNP (rs1799817) Polymorphism of Insulin Receptor Gene Tyrosine Kinase Domain in Kashmiri Women with PCOS

Background. Polycystic ovary syndrome (PCOS) is the most common endocrine metabolic disorder affecting premenopausal women. Besides primary features like anovulation, hyperandrogenism, and polycystic ovaries, women with PCOS present with multiple metabolic, cardiovascular, and psychological disorders. The etiology is multifactorial and the different genetic variants are suggested to play an important role in pathogenesis. Insulin resistance is a ubiquitous finding in PCOS and SNPs in genes involved in the insulin signaling pathway are possible candidates that can explain the development of clinical manifestations of PCOS. Aim. We aimed to investigate the association of INSR His1058 C/T (rs1799817) single nucleotide polymorphism with PCOS in Kashmiri women. The genotypic-phenotypic correlation of the tested SNP with hyperandrogenism, ovulatory dysfunction, and metabolic markers was evaluated. Results. The allele frequency (OR = 1.00, 95% CI = 0.67–1.48, χ2 = 0.01, P = 0.99 ) and genotype distribution (χ2 = 3.73, P = 0.15 ) in INSR C/T polymorphism were comparable with controls. No significant association was found with PCOS in dominant ( P = 0.194 ), recessive ( P = 0.442 ), and homo vs. het. ( P = 0.5 ) genotype models. Genotype-phenotype correlation analysis revealed that variant TT genotype had significantly higher HOMA ( P = 0.029 ) and reduced insulin sensitivity QUICKI ( P = 0.037 ) values. There was no significant variation in the prevalence of hirsutism, acne, alopecia, menstrual disturbances, acanthosis nigricans, and obesity (all P > 0.05 ) in different INSR C/T genotypes. Conclusion. The INSR C/T SNP (rs1799817) does not increase the risk of PCOS in Kashmiri women. This SNP is unlikely to play a significant role in the development and manifestation of clinical symptoms of polycystic ovary syndrome.

Congenital insulin resistance in the practice of the pediatrician and pediatric endocrinologist -path to diagnosis

Introduction. Hyperinsulinemic hypoglycemia in children is most commonly due to congenital hyperinsulinism. When hyperinsu-linemia is accompanied by fasting hypoglycemia and postprandial hyperglycemia, rare syndromes of severe insulin resistance, which include Rabson - Mendenhall syndrome, should be suspected. This article provides an analytical review of current data on this rare genetic pathology and presents a clinical case of a previously undescribed combination of Rabson-Mendenhall syndrome with mutations in the insulin receptor gene INSR in the compound heterozygous state with multiple congenital anomalies of other organs.Clinical case. Patient N, 5.5 months old boy, with suspected congenital hyperinsulinism due to episodes of frequent severe hypoglycemia from the first day of life. At the age of 5 months, an episode of hypoglycemia up to 2.2 mmol/L was registered at an appointment with a pediatric endocrinologist. An examination was ordered, which found that against a background decrease in blood glucose to 1.9 mmol/L, C-Peptide level >5000 ng/mL, insulin level >300 lU/mL, cortisol - 971 nmol/L, TSH -3.88 mlU/L, free T4 - 10.53 pmol/L (10-23.2).The importance of early diagnosis of severe insulin resistance to prevent developmental disorders in children is emphasized. The issue of organizing multiple effective monitoring of a patient’s glycemia required special attention in this clinical case. Due to the features of metabolism in young children, we abandoned flash glucose monitoring systems and used a modern glucose meter with an integration program with a mobile application and the ability to generate reports for subsequent analysis as a reliable means of glycemic control.Summary. Based on the results of the genetic study in association with the clinical phenotype, age of debut, the patient was clinically diagnosed with Rabson-Mendenhall syndrome.Discussion. The paradoxical nature of glycemic fluctuations (severe fasting hypoglycemia and postprandial diabetic hyperglycemia) is quite typical for syndromes of severe insulin resistance and should draw the attention of an informed primary care physician.Conclusion. Careful attention to the symptoms of hypoglycemia, especially with a debut in the neonatal period, recurrent episodes, and the severity of the decrease in blood glycemia. If normal or elevated levels of insulin and C-peptide are detected against the background of hypoglycemia, the first thing to think about is congenital hyperinsulinism.

Long-term effects of metreleptin in Rabson-Mendenhall Syndrome on glycemia, growth, and kidney function

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 one year treatment with recombinant leptin (metreleptin) improves glycemia in RMS. Objective Determine effects of long-term metreleptin in RMS on glycemia, anthropometrics, the growth hormone axis, and kidney function. Design/Participants/Intervention/Setting Comparison of patients with RMS during non-randomized open-label treatment with metreleptin (≥0.15 mg/kg/day) versus 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 Measure(s) A1c; glucose; insulin; 24-hour urine glucose; standard deviation scores (SDS) for height, weight, BMI, and IGF-1; growth hormone (GH), 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. GH increased after metreleptin treatment vs. control, with no difference in SDS between groups for IGF-1 or height. Reduced BMI predicted higher GH, while reduced A1c predicted higher IGF-1. Conclusions 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.

Cap analysis of gene expression (CAGE) sequencing reveals alternative promoter usage in complex disease

The role of alternative promoter usage in tissue specific gene expression has been well established, however, its role in complex diseases is poorly understood. We performed cap analysis of gene expression (CAGE) tag sequencing from the left ventricle (LV) of a rat model of hypertension, the spontaneously hypertensive rat (SHR), and a normotensive strain, the Brown Norway (BN) to understand role of alternative promoter usage in complex disease. We identified 26,560 CAGE-defined transcription start sites (TSS) in the rat LV, including 1,970 novel cardiac TSS resulting in new transcripts. We identified 27 genes with alternative promoter usage between SHR and BN which could lead to protein isoforms differing at the amino terminus between two strains. Additionally, we identified 475 promoter switching events where a shift in TSS usage was within 100bp between SHR and BN, altering length of the 5 prime UTR. Genomic variants located in the shifting promoter regions showed significant allelic imbalance in F1 crosses, confirming promoter shift. We found that the insulin receptor gene (Insr) showed a switch in promoter usage between SHR and BN in heart and liver. The Insr promoter shift was significantly associated with insulin levels and blood pressure within a panel of BXH/HXB recombinant inbred (RI) rat strains. This suggests that the hyperinsulinemia due to insulin resistance might lead to hypertension in SHR. Our study provides a preliminary evidence of alternative promoter usage in complex diseases.

Neofunctionalization of a second insulin receptor gene in the wing-dimorphic planthopper, Nilaparvata lugens

A single insulin receptor (InR) gene has been identified and extensively studied in model species ranging from nematodes to mice. However, most insects possess additional copies of InR, yet the functional significance, if any, of alternate InRs is unknown. Here, we used the wing-dimorphic brown planthopper (BPH) as a model system to query the role of a second InR copy in insects. NlInR2 resembled the BPH InR homologue (NlInR1) in terms of nymph development and reproduction, but revealed distinct regulatory roles in fuel metabolism, lifespan, and starvation tolerance. Unlike a lethal phenotype derived from NlInR1 null, homozygous NlInR2 null mutants were viable and accelerated DNA replication and cell proliferation in wing cells, thus redirecting short-winged–destined BPHs to develop into long-winged morphs. Additionally, the proper expression of NlInR2 was needed to maintain symmetric vein patterning in wings. Our findings provide the first direct evidence for the regulatory complexity of the two InR paralogues in insects, implying the functionally independent evolution of multiple InRs in invertebrates.

A New Mutation of the INSR Gene in a 13-Year-Old Girl with Severe Insulin Resistance Syndrome in China

Background. Mutations in insulin receptor genes can cause severe insulin resistance syndrome. Compared with Rabson-Mendenhall Syndrome and Donohue’s Syndrome, type A insulin resistance syndrome is generally not serious. The main manifestations in woman with type A insulin resistance syndrome are hyperinsulinemia, insulin resistance, acanthosis nigricans, hyperandrogenism, and polycystic ovary. Case Presentation. A 13-year-old girl (Han nationality) visited the hospital due to hairiness and acanthosis nigricans. Further examination revealed severe hyperinsulinemia, insulin resistance, elevated blood glucose, hyperandrogenism, and polycystic ovary. Analysis of the insulin receptor gene by sequencing showed the presence of a nucleotide change in intron 7 (c. 1610+1G > A). The mutation was a splicing mutation, which can obviously affect the mRNA splicing of the insulin receptor and cause its function loss. The patient was finally diagnosed with type A insulin resistance syndrome. After 2 months of metformin treatment, the patient had spontaneous menstrual cramps and significantly improved acanthosis nigricans and sex hormones. Conclusion. We report for the first time a new splicing mutation on the insulin receptor gene at the 7th intron (c.1610+1G > A), which leads to type A insulin resistance syndrome. In clinically suspected patients with polycystic ovary syndrome, if there are extremely high blood levels of insulin in the blood, genetic testing should be performed to detect insulin receptor gene mutation of type A insulin resistance syndrome.

Use of a sodium--glucose cotransporter 2 inhibitor, empagliflozin, in a patient with Rabson-Mendehall Syndrome

Rabson-Mendenhall Syndrome (RMS) is a rare condition caused by mutations in the insulin receptor gene. The affected patients have severe insulin resistance and the treatment is challenging due to difficulties in reaching satisfactory glycemic control. We report a case where iSGT2 was used as an adjunct therapy to insulin.

Single Nucleotide Polymorphism of Insulin Receptor Gene rs2059806 in Polycystic Ovary Syndrome- A Case-control Study

Introduction: One of the most common endocrinopathies faced in clinical practice is Polycystic Ovary Syndrome (PCOS). Furthermore, it is one of the major causative factors of anovulatory infertility affecting a large number of female population worldwide. They are also at a greater risk for developing impaired glucose tolerance, type 2 diabetes mellitus and cardiovascular disease. Decreased sensitivity to insulin is a common feature observed in women with this syndrome. Aim: To assess whether polymorphism of insulin receptor gene has a significant role to develop the PCOS. Materials and Methods: This was a case-control, observational, hospital-based study, conducted at Department of Biochemistry, Calcutta National Medical College, Kolkata from January 2018 to September 2018. Total 123 patients with PCOS cases and 111 normo-ovulatory normal control female subjects were selected. Blood samples were collected for estimation of serum testosterone and Deoxyribonucleic Acid (DNA) extraction. Polymerase Chain Reaction (PCR) followed by Restriction Fragment Length Polymorphism (RFLP) pattern of PCR fragments of DNA samples were determined. The study analysed and compared the genotyping and allele frequencies of rs2059806 polymorphism in control and case group. For comparison, chi-square test was performed (Odds ratio, p<0.05). Results: Amongst the 123 PCOS cases and 111 normal female subjects of the study, mean age of PCOS patients were 22.59±4.7 years and that of control subjects was 21.9±5.1 years. The present study observed an increase in mutant G allele in PCOS subjects (Odds ratio-2.18, p=0.0035). Conclusion: The polymorphism of insulin receptor gene rs2059806 may have a probable role in the development of PCOS.