Insulin Receptor Gene Research Articles

Taenia solium insulin receptors: promising candidates for cysticercosis treatment and prevention

Insulin signaling pathway is an ancient and highly conserved pathway known to play critical roles in cell growth, control and metabolic regulation. In this study, we identified and characterized two insulin receptor genes (TsIR-1316 and TsIR-4810) from Taenia solium. TsIR-1316 was grouped with E. multilocularis insulin receptor (EmIR-1) and TsIR-4810 was closer to Taenia pisiformis insulin-like growth factor receptor (TpIR) on the same branch with a very high bootstrap value. TsIR-1316 was located on the integument of larvae and adult worms, as well as the ovary of adults and eggs. Alternatively, TsIR-4810 was located in the parenchyma and reproductive organs of the adult worms. By using in vitro cultivation systems with Cysticercus pisiformis as a model, we demonstrated that anti-TsIRs-LBD antibodies could effectively block the insulin signaling pathway, resulting in reduced phosphorylation of the insulin receptor as well as lower levels of glucose uptake and glycogen synthesis. The rabbits immunized with TsIR-1316-LBD, TsIR-4810-LBD and TsIR-1316-LBD + TsIR-4810-LBD produced protection against infection of T. pisiformis as demonstrated by a 94.6%, 96% and 80% reduction of establishment of larvae, respectively. These data suggested that TsIR-1316-LBD and TsIR-4810-LBD are promising vaccine candidates or novel drug targets against swine cysticercosis.

Effect of Gymnema sylvestre on Insulin Receptor (IR) and Proglucagon Gene Expression in Streptozotocin Induced Diabetic Rats

Effect of Gymnema sylvestre on Insulin Receptor (IR) and Proglucagon Gene Expression in Streptozotocin Induced Diabetic Rats

Mating status affects Drosophila lifespan, metabolism and antioxidant system

In Drosophila melanogaster, lifespan and fitness traits were investigated as a function of mating status. Four mating protocols were used: virgin males and females, males and females allowed to copulate only once; males and females that had multiple copulations with one partner over the 5-day mating period; and polygamous males and females that had multiple copulations with different partners over the 5-day mating period. Virgin females had the longest lifespan, and polygamous females had the shortest lifespan, potentially due to injuries, infections or exposure to toxic accessory gland products obtained from different males. Reduced lifespan was also observed in males mated to multiple females. Unexpectedly, mating decreased the amount of food eaten by flies. Mating to different partners decreased the amount of fat in both sexes. The number of eggs laid and their quality was increased in females mated to multiple males. Mating status influenced superoxide dismutase (SOD) and peroxidase (PX) activities, as well as the content of advanced glycation end products (AGEs). The mRNA levels of the insulin receptor (InR) gene were significantly increased in the polygamously mated female group compared to the virgin group. Levels of dTOR mRNA were lower in polygamous females. These results indicate that insulin/IGF-1 signaling (IIS) and Drosophila target of rapamycin (dTOR) pathways can mediate the link between mating status and longevity in Drosophila.

Elucidating the roles of naturally occurring silent mutations in Polycystic Ovary Syndrome (PCOS)

Polycystic ovary syndrome (PCOS) is a complex genetic disorder, which often causes infertility in women. Most of the PCOS-related genes are also linked with metabolic diseases, inflammatory responses, or certain types of cancer. GWAS studies connect single nucleotide polymorphisms (SNPs) with these diseases, emphasizing their critical role in understanding the impacts of SNPs that exchange nucleotides. However, their response to changes in protein conformation and corresponding functional characteristics remains ambiguous. The present study provides evidence that elucidates for the role of specific SNPs known as silent mutations by studying impacts on INSR (insulin receptor), FST (follistatin), and AR (androgen receptor) genes, all strongly associated with PCOS pathogenesis. Although silent mutations do not change the amino acid type, their effects on protein expression may cause disease progression. To assess the potential impacts of silent mutations, we first calculated the anti-codon availabilities through RFMapp. To avoid the controversial issues regarding anti-codon stability for certain SNPs, MFE (minimum free energy) was calculated as a measure of the thermodynamic stability of newly formed mRNA structures to provide more information. For rs2059806 and rs1799817 located in the INSR gene, we reported depletion in anti-codon availabilities of newly existed codons. For rs6152 and rs2059806 cases, we calculated both increase and decrease in mRNA stabilities, which were noted as instabilities of the tRNA-mRNA complex. With the results obtained, we referred to the case of codon optimality for providing a plausible explanation between the existence of these SNPs and PCOS. Herein, the effects of silent mutations on complex PCOS diseases have been demonstrated.

Two Novel Variants and One Previously Reported Variant in the Insulin Receptor Gene in Two Cases with Severe Insulin Resistance Syndrome

Donohue syndrome (DS) and Rabson-Mendenhall syndrome (RMS) are rare diseases caused by biallelic variants within the insulin receptor gene (INSR). Here, we report 2 cases: one with DS and the other with RMS. The case with DS presented with intrauterine growth retardation, nipple hypertrophy, clitoromegaly, distended abdomen, hypertrichosis, and dysmorphic features. The second case showed severe acanthosis nigricans, hyperkeratosis, and hypertrichosis. In both cases, abnormal glucose homeostasis due to severe insulin resistance was observed. The diagnosis of DS and RMS was established based on clinical characteristics, abnormal glucose homeostasis, high serum insulin levels, and determination of pathogenic variants in the INSR gene. The first case with DS has 2 novel homozygous variants, NM_000208.3, c.3122delA (p.N1041Mfs*16) and c.3419C>G (p.A1140G), and the second case with RMS has a previously reported homozygous variant NM_000208.3, c.3529+5G>A (IVS19+5G>A) in the INSR gene.

Maternal obesity modulates sexually dimorphic epigenetic regulation and expression of leptin receptor in offspring hippocampus

Maternal obesity during pregnancy is associated with a greater risk for obesity and neurodevelopmental deficits in offspring. This developmental programming of disease is proposed to involve neuroendocrine, inflammatory, and epigenetic factors during gestation that disrupt normal fetal brain development. The hormones leptin and insulin are each intrinsically linked to metabolism, inflammation, and neurodevelopment, which led us to hypothesise that maternal obesity may disrupt leptin or insulin receptor signalling in the developing brain of offspring. Using a C57BL/6 mouse model of high fat diet-induced maternal obesity (mHFD), we performed qPCR to examine leptin receptor (Lepr) and insulin receptor (Insr) gene expression in gestational day (GD) 17.5 fetal brain. We found a significant effect of maternal diet and offspring sex on Lepr regulation in the developing hippocampus, with increased Lepr expression in female mHFD offspring (p < 0.05) compared to controls. Maternal diet did not alter hippocampal Insr in the fetal brain, or Lepr or Insr in prefrontal cortex, amygdala, or hypothalamus of female or male offspring. Chromatin immunoprecipitation revealed decreased binding of histones possessing the repressive histone mark H3K9me3 at the Lepr promoter (p < 0.05) in hippocampus of female mHFD offspring compared to controls, but not in males. Sex-specific deregulation of Lepr could be reproduced in vitro by exposing female hippocampal neurons to the obesity related proinflammatory cytokine IL-6, but not IL-17a or IFNG. Our findings indicate that the obesity-related proinflammatory cytokine IL-6 during pregnancy leads to sexually dimorphic changes in the modifications of histones binding at the Lepr gene promoter, and concomitant changes to Lepr transcription in the developing hippocampus. This suggests that exposure of the fetus to metabolic inflammatory molecules can impact epigenetic regulation of gene expression in the developing hippocampus.

Indomethacin decreases insulin secretion by reducing KCa3.1 as a biomarker of pancreatic tumor and causes apoptotic cell death.

Insulinomas originate from pancreatic β cells and it is the most widely known tumor. Indomethacin is a nonsteroidal anti-inflammatory drug, which is used for blocking the production of some natural substances that cause inflammationand decreasepain. In this study, Iaimed to investigate the effects of indomethacin on rat insulinoma INS-1 cells. The relationship between cell death and insulin metabolism was determined with the administration of indomethacin.The cell viability by WST-1; the apoptosis and necrosis levels by ELISA kits; malondialdehyde levels by spectrophotometer;andbeclin, intracellular insulin, insulin secretion, KCa3.1, insulin receptor (IR), glucose transporter type 2 (GLUT2), activating transcription factor 2 (ATF2), Elk1, c-Jun, Akt and phosphorylated ATF2, Elk1, c-Jun, Akt, intracellular betacellulin and betacellulin secretion levels by Western blot analysis investigated.The Ins1, Ins2, IR, GLUT2, ATF2, Elk1, c-Jun, Akt, and Betacellulin gene expression levels were determined by the real-time quantitative reverse transcription-polymerase chain reaction method. Apoptotic cell death was observed with the administration of indomethacin. The insulin secretion and Ins1, Ins2 gene expression levels decreased. The insulin receptor and GLUT2 levels increased, while KCa3.1 (KCNN4) levels decreased with the administration of indomethacin to insulinoma INS-1 cells. A decrease was observed in the total c-Jun, phosphorylated ATF2, Elk1, c-Jun, and Akt levels. Betacellulin secretion levels increased. In insulinoma INS-1 cells, apoptotic cell death occurred in the following manner: (i) indomethacin might decrease insulin secretion by reducing KCa3.1, (ii) might inactivate the JNK/ERK pathway with the inactivity of transcription factors.

Role of Vitamin D as an Adjuvant to Oral Hypoglycemic Drugs in Treatment of Type-2 Diabetic Patients

Background: Type 2 diabetes mellitus (T2DM) is considered as one of the nonskeletal diseases related with deficiency of vitamin D. Both T2DM and vitamin D deficiency have similar risk factors, such as obesity, aging, and sedentary lifestyle. Cardiovascular diseases (CVDs) and metabolic syndrome disorders are also associated with vitamin D deficiency. Vitamin D plays an important functional role in glucose homeostasis through its effects on insulin secretion and sensitivity. It may reduce insulin resistance (IR) indirectly through its effect on calcium and phosphate metabolism and through upregulation of the insulin receptor gene. Thus, this study was designed to evaluate role of vitamin D as an adjuvant to oral hypoglycemic drugs in treatment of Type 2 diabetic patients.&#x0D; Aims and Objectives : Vitamin D deficiency appears to be related to the development of diabetes mellitus type 2 and the metabolic syndrome. Vitamin D may affect glucose homeostasis, vitamin D levels having been found to be inversely related to glycosylated hemoglobin levels in diabetes mellitus. The aim of the study was to evaluate role of vitamin D as an adjuvant to oral hypoglycemic drugs in treatment of Type 2 diabetic patients.&#x0D; Materials and Methods: The study was done on 60 patients diagnosed with T2DM. A total of 60 patients, control group were type 2 Diabetic patients on oral hypoglycemic drugs without vitamin D supplementation (n=30) and study group was type 2 Diabetic patients on oral hypoglycemic drugs with vitamin D supplementation (n=30).&#x0D; Results: The mean aged of patients was 43.27±8.80 in control group and 47.93±8.39 in study group. The family history of diabetes mellitus was 39 patients. HbA1C, FBG, Postprandial were decreased in study group as compared to control group from baseline (0 day) to 90 days, respectively. Other parameters like hemoglobin, Serum Creatinine serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase were slight changes in study group as compared to control group from baseline (0 day) to 90 days, respectively.&#x0D; Conclusion: The present study demonstrated that vitamin D as an adjuvant to oral hypoglycemic drugs in treatment in diabetic patients, vitamin D levels being related to glycemic control in diabetes mellitus type 2. These findings may have therapeutic implications as cautious vitamin D supplementation may improve glycemic control in diabetes mellitus type 2.

Detrimental Effects of Sodium Fluoride on the Expression of Insulin Receptor in the Olfactory Bulb and Hippocampus of Male Mice.

Fluoride exposure is associated with lowered cognitive function ability, intelligence quotient, and mental decline, especially in children. The brain insulin receptor (IR) signaling system is related to neuronal plasticity and consequent cognitive ability. In our previous study, NaF exposure decreased IR expressions in olfactory bulb (OB) and hippocampus after Y-maze test in male mice. In order to further explore whether the Y-maze test affected IR gene and protein expression levels in the OB and hippocampus under the NaF exposure, healthy male mice were randomly allotted into four groups and challenged with 0, 50, 100, and 150mg/L NaF for three continuous months. The results showed that femur fluorine content of the NaF-exposed groups increased significantly in a dose-dependent manner. NaF significantly decreased brain protein content and organ coefficient of the treated male mice. The protein and mRNA expression levels of the IR were significantly decreased in the OB and hippocampus of the NaF-treated mice. Interestingly, indicators (brain protein content and organ coefficient) measured in the present study were significantly lower than our previous study indicators (mice tested Y-maze test), especially the expression levels of IR protein and mRNA in the same concentration groups. Taken together, these results indicated that Y-maze test could promote the expression levels of IR protein and mRNA in the OB and hippocampus, while NaF had a stronger inhibitory effect, which resulted in adverse effects on the expression levels of IR in the OB and hippocampus of male mice.

Incidence of ROS1-Rearranged Non-Small-Cell Lung Carcinoma in India and Efficacy of Crizotinib in LungAdenocarcinoma Patients.

BackgroundThe ROS1 gene is a member of the “sevenless” subfamily of tyrosine-kinase insulin-receptor genes. ROS1-fusion rearrangement causes constitutive downstream signal transduction, with an oncogenic role in non-small-cell lung carcinoma (NSCLC). Fortunately, crizotinib, an ALK1 tyrosine-kinase inhibitor, provides long-term disease control. The objective of this molecular epidemiological study was to estimate the frequency of ROS1 rearrangements and evaluate treatment outcomes with crizotinib therapy.MethodsPatients with stage IV NSCLC adenocarcinoma histology were considered for this study. The study was conducted according to the ethical principles stated in the latest version of the Declaration of Helsinki and the applicable guidelines for good clinical practice. Clinical characteristics and treatment details were collected from patients' medical records.ResultsA total of 709 stage IV NSCLC adenocarcinoma patients were included in the study. There were 457 (64.46%) men and 252 (35.54%) women, with a median age of 60 years. ROS1-gene rearrangement was positive in 20 (2.82%) cases, 13 using Fluorescent In-Situ Hybridization (FISH), and two and five cases, respectively, using immunohistochemistry (IHC) and next-generation sequencing (NGS), followed by confirmation with FISH. Fourteen of the 20 patients with ROS1-gene rearrangement received crizotinib therapy, with an objective response rate of 64.28%. At a median follow-up of 6 months, the study had not achieved the end points of median progression free survival and overall survival.ConclusionROS1-gene rearrangement was present at a relatively higher frequency of 2.8% in north Indian patients with lung adenocarcinoma and was successfully targeted by crizotinib therapy. Although the only US Food and Drug Administration and Conformité Européenne approved method for testing ROS1 rearrangement is NGS, FISH alone or IHC with D4D6 antibody as initial screen with subsequent confirmation of IHC-positive cases by FISH are cost-effective methods in institutions lacking NGS facilities.

Enhancement of glucose homeostasis through the PI3K/Akt signaling pathway by dietary with Agaricus blazei Murrill in STZ-induced diabetic rats.

Agaricus blazei Murrill (ABM) is an edible fungus. This study investigated the protective role of ABM fruiting body against streptozotocin (STZ)‐induced diabetic rats. After 4 weeks of ABM supplement, glucose homeostasis was improved in diabetic rats. Quantitative real‐time and Western blot analyses suggested that ABM could promote the gene and protein expression level of insulin receptor, pyruvate dehydrogenase kinase, phospho‐kinase B, kinase B, phosphatidylinositol 3‐kinase, insulin receptor substrate 1, glucose transporter‐4, and glutamine synthetase, while inhibiting the expression of glycogen synthase kinase 3β and c‐jun N‐terminal kinase 1 and 2. According to multivariate and univariate statistical analysis, liver metabolite profiles of the normal and diabetic rats fed basal and experimental diet were clearly separated. The differential liver metabolites from diabetic rats fed basal and ABM diet‐related pathways including the glycolysis pathway, pentose phosphate pathway, tricarboxylic acid cycle, and oxidative phosphorylation were analyzed. A total of 18 potential biomarker metabolites were identified as differential biomarkers associated with ABM supplement diet.

Ficus deltoidea extract down-regulates protein tyrosine phosphatase 1B expression in a rat model of type 2 diabetes mellitus: a new insight into its antidiabetic mechanism.

Ficus deltoidea var. deltoidea Jack (FD) is a well-known plant used in Malay folklore medicine to lower blood glucose in diabetic patients. For further research of the antihyperglycemic mechanisms, the protein tyrosine phosphatase 1B (PTP1B)-inhibitory effect of FD was analysed both in vitro and in vivo. To optimise a method for FD extraction, water, 50, 70, 80, 90 and 95% ethanol extracts were prepared and determined for their total phenolic and triterpene contents, and PTP1B-inhibition capacity. Among the tested extracts, 70% ethanol FD extract showed a significant PTP1B inhibition (92·0% inhibition at 200 µg/ml) and high phenolic and triterpene contents. A bioassay-guided fractionation of the 70% ethanol extract led to the isolation of a new triterpene (3β,11β-dihydroxyolean-12-en-23-oic acid; F3) along with six known compounds. In vivo, 4 weeks' administration of 70% ethanol FD extract (125, 250 and 500 mg/kg/d) to streptozotocin-nicotinamide-induced type 2 diabetic rats reversed the abnormal changes of blood glucose, insulin, total Hb, GLUT2, lipid profile, and oxidative stress in liver and pancreas. Moreover, FD reduced the mRNA expression of the key gluconeogenic enzymes (phosphoenolpyruvate carboxykinase and glucose 6-phosphatase) and restored insulin receptor and GLUT2 encoding gene (Slc2a2) expression. In addition, FD significantly down-regulated the hepatic PTP1B gene expression. These results revealed that FD could potentially improve insulin sensitivity, suppress hepatic glucose output and enhance glucose uptake in type 2 diabetes mellitus through down-regulation of PTP1B. Together, our findings give scientific evidence for the traditional use of FD as an antidiabetic agent.

Variation in the rates of evolution of the insulin and glucagon hormone and receptor genes in rodents

Insulin and glucagon are important hormones for regulating blood glucose levels. Rodents are useful models for understanding human physiology, however, differences exist between rodents and humans. Here I examined the evolution of the genes encoding insulin (Ins) and glucagon (Gcg, which also encodes GLP-1 and GLP-2) and the receptors for these hormones (Insr, Gcgr, Glp1r, and Glp2r). Our results show that the insulin 1 gene (Ins1) that originated by retroposition in some rodents such as mice, experienced selective constraints that are as strong as those acting upon the Ins2 gene found in the locus-of-origin. Previous studies had shown that the insulin hormones and genes in hystricomorph rodents, such as the guinea pig, have altered function and selective constraints, respectively. Here I show that the insulin receptor genes in hystricomorph rodents also experienced changes in evolutionary rates, but that these changes did not alter sites involved in hormone binding. While glucagon, but not GLP-1 and GLP-2, in hystricomorph rodents also show increased rates of sequence evolution, no changes in the evolution of the glucagon receptor gene (Gcgr) was seen. Intriguingly, the GLP2 receptor gene (Glp2r) in mice-like rodents evolved more rapidly than those in hystricomorph rodents. When the rates of evolution of the genes encoding the receptors for proglucagon-derived peptides, which are all G-protein coupled receptors, were compared, the GLP-1 receptor gene (Glp1r) was found to display increased levels of sequence constraint compared to the Gcgr and Glp2r genes.

Association of GWAS identified INSR variants (rs2059807 & rs1799817) with polycystic ovarian syndrome in Indian women

Polycystic ovary syndrome (PCOS), a gynaecological endocrine disorder affects 9% of Indian women and is linked to type II diabetes. The association of INSR (INSulin Receptor gene) variants (rs2059807 and rs1799817) with PCOS was established through genome-wide association studies, yet requires validation for the Indian population. This case-control study included 253 PCOS women and 308 age-matched control. The minor allele frequency of rs2059807 had an odds ratio of 13.5 and that of rs1799817 was 11.8. The cohort with rs2059807 MAF presented elevated levels of luteinising hormone [PCOS vs Control: 6.32 ± 2.26 mIU/mL vs 4.97 ± 3.27 mIU/mL], estradiol [116.01 ± 60.63 pg/mL vs 65.04 ± 44.98 pg/mL], and decreased HDL – C [50.4 ± 11.59 mg/dL vs 64 ± 15.49 mg/dL] showing disturbances in the hormonal patterns. The rs1799817 polymorphism cohort had elevated levels of serum insulin [17.99 ± 11.6 mIU/mL vs 11.67 ± 6.63 mIU/mL], blood glucose [199.15 ± 63.72 mg/dL vs 96.6 ± 24.3 mg/dL], and testosterone [0.91 ± 0.2 nmol/L vs 0.53 ± 0.16 nmol/L] thereby triggering metabolic dysfunction and predisposed to lifestyle disorder. Also, the SNPs were found to be in linkage equilibrium and contributed to the development of PCOS differentially.

Structure and function of the insulin receptor-a personal perspective.

Immunoprecipitation with autoantibodies to the insulin receptor derived from patients with extreme insulin resistance and acanthosis nigricans revealed that the receptor is comprised of two subunits of 135 kDa (α subunit) and 95 kDa (β subunit) and that insulin induces the rapid phosphorylation of the β subunit in intact cells. Incubation of a highly purified insulin receptor preparation with [γ-32P]ATP also resulted in tyrosine phosphorylation of the β subunit in an insulin-dependent manner, suggesting that the receptor itself is a tyrosine-specific protein kinase. Furthermore, a Japanese boy with insulin resistance and acanthosis nigricans was found to be heterozygous for a mutation of the insulin receptor gene that resulted in the replacement of glycine-996 with valine in the ATP binding site of the receptor. Expression of the mutant receptor in cultured cells revealed it to be deficient in tyrosine kinase activity and mediation of insulin action, suggesting that the tyrosine kinase activity of the insulin receptor is essential for insulin action in vivo.

Clinical characteristics of insulin resistance syndromes: A nationwide survey in Japan.

Aims/IntroductionInsulin 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 MethodsWe 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.ResultsWe 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.ConclusionsInformation yielded by this first nationwide survey should provide epidemiological insight into these rare conditions and inform better healthcare for affected patients.

Transcriptional Regulation of INSR, the Insulin Receptor Gene.

The insulin receptor gene encodes an evolutionarily conserved signaling protein with a wide spectrum of functions in metazoan development. The insulin signaling pathway plays key roles in processes such as metabolic regulation, growth control, and neuronal function. Misregulation of the pathway features in diabetes, cancer, and neurodegenerative diseases, making it an important target for clinical interventions. While much attention has been focused on differential pathway activation through ligand availability, sensitization of overall signaling may also be mediated by differential expression of the insulin receptor itself. Although first characterized as a “housekeeping” gene with stable expression, comparative studies have shown that expression levels of the human INSR mRNA differ by tissue and in response to environmental signals. Our recent analysis of the transcriptional controls affecting expression of the Drosophila insulin receptor gene indicates that a remarkable amount of DNA is dedicated to encoding sophisticated feedback and feed forward signals. The human INSR gene is likely to contain a similar level of transcriptional complexity; here, we summarize over three decades of molecular biology and genetic research that points to a still incompletely understood regulatory control system. Further elucidation of transcriptional controls of INSR will provide the basis for understanding human genetic variation that underlies population-level physiological differences and disease.

Type A insulin resistance syndrome misdiagnosed as polycystic ovary syndrome: a case report

BackgroundType A insulin resistance syndrome, one type of the hereditary insulin resistance syndromes, is a rare disorder. Patients with type A insulin resistance syndrome are nonobese and demonstrate severe hyperinsulinemia, hyperandrogenism, and acanthosis nigricans. The clinical features are more severe in affected females than in males, and they mostly become apparent at the age of puberty. In many cases, when severe insulin resistance is covered up by other signs or symptoms of type A insulin resistance syndrome, patients are often easily misdiagnosed with other diseases, such as polycystic ovary syndrome.Case presentationOur patient was a 27-year-old Han Chinese woman who sought treatment because of a menstrual disorder and hirsutism. Tests showed that her levels of insulin and testosterone were elevated, and gynecological color Doppler ultrasound suggested multiple cystic changes in the bilateral ovaries. After a diagnosis of polycystic ovary syndrome was made, pulsatile gonadotropin-releasing hormone therapy and metformin were administered, but the patient’s symptoms did not improve in 1 year of follow-up. Considering that the previous diagnosis might have been incorrect, venous blood samples were collected from the patient and her relatives for genetic analysis. Subsequently, using Illumina sequencing, it was found that the proband, her father, and two brothers all had the c.3601C>T heterozygous missense mutation in exon 20 of the insulin receptor gene. The diagnosis was corrected to type A insulin resistance syndrome, and the patient’s treatment was modified.ConclusionWe report a case of a young woman with type A insulin resistance syndrome that was misdiagnosed as polycystic ovary syndrome. We discuss the causes, clinical features, diagnosis, and treatment of type A insulin resistance syndrome to improve the recognition of the disease and reduce its misdiagnosis. Female patients with high androgen levels and severe hyperinsulinemia should be considered for the possibility of hereditary insulin resistance syndromes (such as type A insulin resistance syndrome). Gene sequencing helps in making an early diagnosis and developing a targeted treatment strategy.

Exercise Intensity Alter Insulin Receptor Gene Expression in Diabetic Type - 2 Rat Model.

AIM:To analyse the differential expression of the insulin receptor (IR) gene between moderate continuous and severe continuous training in the T2DM rat model.METHODS:This was an experimental study. Healthy male Wistar was used in this study, which divided into sedentary, moderate continuous training, and severe continuous training. Treated groups were assigned to run on the treadmill three times a week for eight weeks consequently.RESULTS:The result shown that expression of mRNA IR gene in treated groups decline compared to control. There was a difference mRNA IR gene expression after eight weeks of exercise between MCT and control, SCT and control so are MCT and SCT. IR expression on skeletal muscle in treated groups was different compared with control. The distribution of IR on skeletal muscles in treatment groups was significantly increased compared control, but there was no significant difference distribution between MCT and SCT. HOMA-IR post-test in SCT was lower than MCT but FBG post-test lower in MCT than SCT.CONCLUSION:The intensity of exercise makes a difference in IR gene expression between moderate continuous training and severe continuous training after eight weeks of assigned exercise in T2DM rat models.

Thyroid Hormone Effects on Glucose Disposal in Patients With Insulin Receptor Mutations

Patients with mutations of the insulin receptor gene (INSR) have extreme insulin resistance and are at risk for early morbidity and mortality from diabetes complications. A case report suggested that thyroid hormone could improve glycemia in INSR mutation in part by increasing brown adipose tissue (BAT) activity and volume. To determine if thyroid hormone increases tissue glucose uptake and improves hyperglycemia in INSR mutation. Single-arm, open-label study of liothyronine. National Institutes of Health. Patients with homozygous (n = 5) or heterozygous (n = 2) INSR mutation. Liothyronine every 8 hours for 2 weeks (n = 7); additional 6 months' treatment in those with hemoglobin A1c (HbA1c) > 7% (n = 4). Whole-body glucose uptake by isotopic tracers; tissue glucose uptake in muscle, white adipose tissue (WAT) and BAT by dynamic [18F] fluorodeoxyglucose positron emission tomography/computed tomography; HbA1c. There was no change in whole-body, muscle, or WAT glucose uptake from baseline to 2 weeks of liothyronine. After 6 months, there was no change in HbA1c (8.3 ± 1.2 vs 9.1 ± 3.0%, P = 0.27), but there was increased whole-body glucose disposal (22.8 ± 4.9 vs 30.1 ± 10.0 µmol/kg lean body mass/min, P = 0.02), and muscle (0.7 ± 0.1 vs 2.0 ± 0.2 µmol/min/100 mL, P < 0.0001) and WAT glucose uptake (1.2 ± 0.2 vs 2.2 ± 0.3 µmol/min/100 mL, P < 0.0001). BAT glucose uptake could not be quantified because of small volume. There were no signs or symptoms of hyperthyroidism. Liothyronine administered at well-tolerated doses did not improve HbA1c. However, the observed increases in muscle and WAT glucose uptake support the proposed mechanism that liothyronine increases tissue glucose uptake. More selective agents may be effective at increasing tissue glucose uptake without thyroid hormone-related systemic toxicity.Clinical Trial Registration Number: NCT02457897; https://clinicaltrials.gov/ct2/show/NCT02457897.