Mutant Insulin Receptor Research Articles

Structural insights into conformational stability of both wild-type and mutant Insulin Receptor Gene

Type 2 diabetes (T2D) poses a health challenge. It can lead to complications such as heart disease, hypertension, heart failure, and stroke. Factors like obesity and lack of activity can contribute to insulin resistance. The insulin receptor gene (INSR) is responsible for producing insulin receptors. When this gene malfunctions, it can contribute to the development of T2D.In this study, we investigated the stability of the structure of variants of INSR using an extended molecular dynamics simulation and the perturbation effect of compound CheBI_88339 on the protein structure. During the analysis, we observed that all three systems—the wild-type INSR, the R1191Q variant, and the R1191Q variant bound to compound CheBI_88339 (R1191Q-D) reached equilibrium in 30ns without any instability. Throughout the simulation process, it was generally observed that the wild-type INSR exhibited higher stability than the R1191Q variant and R1191Q-D. The Root Mean Square Deviation (RMSD) and root-mean-square fluctuation (RMSF) of INSR, R1191Q and the variant bound to compound CheBI_88339 (R1191Q-D) are 9.28Å, 10.35Å, 8.65Å, 2.59Å, 2.98Å, and 2.89Å respectively.These values indicate that the mutated INSR introduced levels of deviations and flexibility in the protein structure. However, considering the variant bound to compound CheBI_88339 suggests that this drug may contribute to stabilizing the dynamics of the mutant protein. Overall, our findings shed light on the effect of genetic variants and their impact on protein stability. This research provides further insight into the dynamics of INSR and the potential of CheBI_88339 in targeting INSR. However, this study is computational, and further experimental studies are required.

Normal Ovarian Function in Subfertile Mouse with Amhr2-Cre-Driven Ablation of Insr and Igf1r.

Insulin receptor signaling promotes cell differentiation, proliferation, and growth which are essential for oocyte maturation, embryo implantation, endometrial decidualization, and placentation. The dysregulation of insulin signaling in women with metabolic syndromes including diabetes exhibits poor pregnancy outcomes that are poorly understood. We utilized the Cre/LoxP system to target the tissue-specific conditional ablation of insulin receptor (Insr) and insulin-like growth factor-1 receptor (Igf1r) using an anti-Mullerian hormone receptor 2 (Amhr2) Cre-driver which is active in ovarian granulosa and uterine stromal cells. Our long-term goal is to examine insulin-dependent molecular mechanisms that underlie diabetic pregnancy complications, and our conditional knockout models allow for such investigation without confounding effects of ligand identity, source and cross-reactivity, or global metabolic status within dams. Puberty occurred with normal timing in all conditional knockout models. Estrous cycles progressed normally in Insrd/d females but were briefly stalled in diestrus in Igf1rd/d and double receptor (DKO) mice. The expression of vital ovulatory genes (Lhcgr, Pgr, Ptgs2) was not significantly different in 12 h post-hCG superovulated ovaries in knockout mice. Antral follicles exhibited an elevated apoptosis of granulosa cells in Igf1rd/d and DKO mice. However, the distribution of ovarian follicle subtypes and subsequent ovulations was normal in all insulin receptor mutants compared to littermate controls. While ovulation was normal, all knockout lines were subfertile suggesting that the loss of insulin receptor signaling in the uterine stroma elicits implantation and decidualization defects responsible for subfertility in Amhr2-Cre-derived insulin receptor mutants.

Case report: Glycaemic management and pregnancy outcomes in a woman with an insulin receptor mutation, p.Met1180Lys

BackgroundHeterozygous insulin receptor mutations (INSR) are associated with insulin resistance, hyperglycaemia and hyperinsulinaemic hypoglycaemia in addition to hyperandrogenism and oligomenorrhoea in women. Numerous autosomal dominant heterozygous mutations involving the INSR β-subunit tyrosine kinase domain resulting in type A insulin resistance have been previously described. We describe the phenotype, obstetric management and neonatal outcomes in a woman with type A insulin resistance caused by a mutation in the β-subunit of the INSR.Case presentationWe describe a woman with a p.Met1180Lys mutation who presents with hirsutism, oligomenorrhoea and diabetes at age 20. She has autoimmune thyroid disease, Coeliac disease and positive GAD antibodies. She is overweight with no features of acanthosis nigricans and is treated with metformin. She had 11 pregnancies treated with insulin monotherapy (n = 2) or combined metformin and insulin therapy (n = 9). The maximum insulin dose requirement was 134 units/day or 1.68 units/kg/day late in the second pregnancy. Mean birthweight was on the 37th centile in INSR positive offspring (n = 3) and the 94th centile in INSR negative offspring (n = 1).ConclusionThe p.Met1180Lys mutation results in a phenotype of diabetes, hirsutism and oligomenorrhoea. This woman had co-existent autoimmune disease. Her insulin dose requirements during pregnancy were similar to doses observed in women with type 2 diabetes. Metformin may be used to improve insulin sensitivity in women with this mutation. Offspring inheriting the mutation tended to be smaller for gestational age.

Insulin signaling in dopaminergic neurons regulates extended memory formation in Caenorhabditis elegans.

Insulin alters several brain functions, and perturbations in insulin levels could be a precipitating factor for Parkinson's disease, a disease associated with the degeneration of dopaminergic neurons. It is unclear whether insulin alters the dopamine signaling pathway and modulates learning and memory. In Caenorhabditis elegans, daf-2 insulin receptor mutants have extended memory when trained for olfactory adaptation. In this study, we show that the absence of daf-2 receptors in dopamine neurons results in this unusual learning behavior. Our results show that insulin function in memory is dopamine-dependent. In the absence of the daf-2 receptor, the calcium influx in dopamine neurons shows an altered pattern resulting in memory recall for an extended period. These results indicate that learning and memory involve insulin-dopamine crosstalk. Imbalances in this pathway result in changes in memory recall.

Dietary lithium stimulates female fecundity in Drosophila melanogaster.

The trace element lithium exerts a versatile bioactivity in humans, to some extend overlapping with in vivo findings in the model organism Drosophila melanogaster. A potentially essential function of lithium in reproduction has been suggested since the 1980s and multiple studies have since been published postulating a regulatory role of lithium in female gametogenesis. However, the impact of lithium on fruit fly egg production has not been at the center of attention to date. In the present study, we report that dietary lithium (0.1-5.0 mM LiCl) substantially improved life time egg production in D. melanogaster w1118 females, with a maximum increase of plus 45% when supplementing 1.0 mM LiCl. This phenomenon was not observed in the insulin receptor mutant InRE19, indicating a potential involvement of insulin-like signaling in the lithium-mediated fecundity boost. Analysis of the whole-body and ovarian transcriptome revealed that dietary lithium affects the mRNA levels of genes encoding proteins related to processes of follicular maturation. To the best of our knowledge, this is the first report on dietary lithium acting as an in vivo fecundity stimulant in D. melanogaster, further supporting the suggested benefit of the trace element in female reproduction.

Atypical Adolescent Presentation of Novel INSR Mutation with Hyperglycemia

The human Insulin Receptor (INSR) mutation can result in inherited insulin resistance syndrome. Severe Insulin Resistance (IR) results secondary INSR mutations have been reported in adult, adolescent and children manifesting with Hyperinsulinemic Hypoglycaemia (HH). Rabson-Mendenhall Syndrome and Donohue’s Syndrome, Type A insulin resistance syndrome are resultant of the INSR mutation. We report a case of an adolescent boy who presented with very high blood sugars requiring high doses of insulin, with a novel heterozygous INSR mutation.

The insulin receptor regulates the persistence of mechanical nociceptive sensitization in flies and mice.

Early phase diabetes is often accompanied by pain sensitization. In Drosophila, the insulin receptor (InR) regulates the persistence of injury-induced thermal nociceptive sensitization. Whether Drosophila InR also regulates the persistence of mechanical nociceptive sensitization remains unclear. Mice with a sensory neuron deletion of the insulin receptor (Insr) show normal nociceptive baselines; however, it is uncertain whether deletion of Insr in nociceptive sensory neurons leads to persistent nociceptive hypersensitivity. In this study, we used fly and mouse nociceptive sensitization models to address these questions. In flies, InR mutants and larvae with sensory neuron-specific expression of RNAi transgenes targeting InR exhibited persistent mechanical hypersensitivity. Mice with a specific deletion of the Insr gene in Nav1.8+ nociceptive sensory neurons showed nociceptive thermal and mechanical baselines similar to controls. In an inflammatory paradigm, however, these mutant mice showed persistent mechanical (but not thermal) hypersensitivity, particularly in female mice. Mice with the Nav1.8+ sensory neuron-specific deletion of Insr did not show metabolic abnormalities typical of a defect in systemic insulin signaling. Our results show that some aspects of the regulation of nociceptive hypersensitivity by the insulin receptor are shared between flies and mice and that this regulation is likely independent of metabolic effects.

A family with type A insulin resistance syndrome caused by a novel insulin receptor mutation.

A 17-year-old boy was referred to our endocrinology clinic for a clinical investigation of hyperinsulinemia. An oral glucose tolerance test showed plasma glucose concentrations in the normal range. However, insulin concentrations were considerably elevated (0 min: 71 μU/mL; 60 min: 953 μU/mL), suggesting severe insulin resistance. An insulin tolerance test confirmed that he had insulin resistance. There was no apparent hormonal or metabolic cause, including obesity. The patient had no outward features of hyperinsulinemia, including acanthosis nigricans or hirsutism. However, his mother and grandfather also had hyperinsulinemia. Genetic testing showed that the patient (proband), his mother, and his grandfather had a novel p.Val1086del heterozygous mutation in exon 17 of the insulin receptor gene (INSR). Although all three family members have the same mutation, their clinical courses have been different. The onset of the mother's diabetes was estimated at 50 years, whereas the grandfather developed diabetes at 77 years. Type A insulin resistance syndrome is caused by mutations in the insulin receptor (INSR) gene and results in severe insulin resistance. Genetic evaluation should be considered in adolescents or young adults with dysglycemia when an atypical phenotype, such as severe insulin resistance, or a relevant family history is observed. Clinical courses may differ even if the same genetic mutation is found in a family.

Isolation of a novel missense mutation in insulin receptor as a spontaneous revertant in ImpL2 mutants in Drosophila.

Evolutionarily conserved insulin/insulin-like growth factor (IGF) signaling (IIS) correlates nutrient levels to metabolism and growth, thereby playing crucial roles in development and adult fitness. In the fruit fly Drosophila, ImpL2, an ortholog of IGFBP7, binds to and inhibits the function of Drosophila insulin-like peptides. In this study, we isolated a temperature-sensitive mutation in the insulin receptor (InR) gene as a spontaneous revertant in ImpL2 null mutants. The p.Y902C missense mutation is located at the functionally conserved amino acid residue of the first fibronectin type III domain of InR. The hypomorphic InR mutant animals showed a temperature-dependent reduction in IIS and body size. The mutant animals also exhibited metabolic defects, such as increased triglyceride and carbohydrate levels. Metabolomic analysis further revealed that defects in InR caused dysregulation of amino acid and ribonucleotide metabolism. We also observed that InR mutant females produced tiny irregular-shaped embryos with reduced fecundity. In summary, this novel allele of InR is a valuable tool for the Drosophila genetic model of insulin resistance and type 2 diabetes.

Activation of the insulin receptor by an insulin mimetic peptide

Insulin receptor (IR) signaling defects cause a variety of metabolic diseases including diabetes. Moreover, inherited mutations of the IR cause severe insulin resistance, leading to early morbidity and mortality with limited therapeutic options. A previously reported selective IR agonist without sequence homology to insulin, S597, activates IR and mimics insulin’s action on glycemic control. To elucidate the mechanism of IR activation by S597, we determine cryo-EM structures of the mouse IR/S597 complex. Unlike the compact T-shaped active IR resulting from the binding of four insulins to two distinct sites, two S597 molecules induce and stabilize an extended T-shaped IR through the simultaneous binding to both the L1 domain of one protomer and the FnIII-1 domain of another. Importantly, S597 fully activates IR mutants that disrupt insulin binding or destabilize the insulin-induced compact T-shape, thus eliciting insulin-like signaling. S597 also selectively activates IR signaling among different tissues and triggers IR endocytosis in the liver. Overall, our structural and functional studies guide future efforts to develop insulin mimetics targeting insulin resistance caused by defects in insulin binding and stabilization of insulin-activated state of IR, demonstrating the potential of structure-based drug design for insulin-resistant diseases.

Insulin-resistance in paediatric age: Its magnitude and implications.

Insulin resistance (IR) is insulin failure in normal plasma levels to adequately stimulate glucose uptake by the peripheral tissues. IR is becoming more common in children and adolescents than before. There is a strong association between obesity in children and adolescents, IR, and the metabolic syndrome components. IR shows marked variation among different races, crucial to understanding the possible cardiovascular risk, specifically in high-risk races or ethnic groups. Genetic causes of IR include insulin receptor mutations, mutations that stimulate autoantibody production against insulin receptors, or mutations that induce the formation of abnormal glucose transporter 4 molecules or plasma cell membrane glycoprotein-1 molecules; all induce abnormal energy pathways and end with the development of IR. The parallel increase of IR syndrome with the dramatic increase in the rate of obesity among children in the last few decades indicates the importance of environmental factors in increasing the rate of IR. Most patients with IR do not develop diabetes mellitus (DM) type-II. However, IR is a crucial risk factor to develop DM type-II in children. Diagnostic standards for IR in children are not yet established due to various causes. Direct measures of insulin sensitivity include the hyperinsulinemia euglycemic glucose clamp and the insulin-suppression test. Minimal model analysis of frequently sampled intravenous glucose tolerance test and oral glucose tolerance test provide an indirect estimate of metabolic insulin sensitivity/resistance. The main aim of the treatment of IR in children is to prevent the progression of compensated IR to decompensated IR, enhance insulin sensitivity, and treat possible complications. There are three main lines for treatment: Lifestyle and behavior modification, pharmacotherapy, and surgery. This review will discuss the magnitude, implications, diagnosis, and treatment of IR in children.

Regulation of fatty acid desaturase- and immunity gene-expression by mbk-1/DYRK1A in Caenorhabditis elegans

BackgroundIn the nematode Caenorhabditis elegans, longevity in response to germline ablation, but not in response to reduced insulin/IGF1-like signaling, is strongly dependent on the conserved protein kinase minibrain-related kinase 1 (MBK-1). In humans, the MBK-1 ortholog DYRK1A is associated with a variety of disorders, most prominently with neurological defects observed in Down syndrome. To better understand mbk-1’s physiological roles and their dependence on genetic background, we analyzed the influence of mbk-1 loss on the transcriptomes of wildtype and long-lived, germline-deficient or insulin-receptor defective, C. elegans strains by RNA-sequencing.Resultsmbk-1 loss elicited global changes in transcription that were less pronounced in insulin-receptor mutant than in germline-deficient or wildtype C. elegans. Irrespective of genetic background, mbk-1 regulated genes were enriched for functions in biological processes related to organic acid metabolism and pathogen defense. qPCR-studies confirmed mbk-1 dependent induction of all three C. elegans Δ9-fatty acid desaturases, fat-5, fat-6 and fat-7, in wildtype, germline-deficient and insulin-receptor mutant strains. Conversely, mbk-1 dependent expression patterns of selected pathogen resistance genes, including asp-12, dod-24 and drd-50, differed across the genetic backgrounds examined. Finally, cth-1 and cysl-2, two genes which connect pathogen resistance to the metabolism of the gaseous messenger and lifespan regulator hydrogen sulfide (H2S), were commonly suppressed by mbk-1 loss only in wildtype and germline-deficient, but not in insulin-receptor mutant C. elegans.ConclusionOur work reveals previously unknown roles of C. elegans mbk-1 in the regulation of fatty acid desaturase- and H2S metabolic-genes. These roles are only partially dependent on genetic background. Considering the particular importance of fatty acid desaturation and H2S for longevity of germline-deficient C. elegans, we propose that these processes at least in part account for the previous observation that mbk-1 preferentially regulates lifespan in these worms.

Monogenic diabetes due to an INSR mutation in a child with severe insulin resistance.

SummaryWe report a case of an 11-year-old girl presenting with a new diagnosis of diabetes associated with a heterozygous missense mutation in the insulin receptor (INSR) gene. This case highlights that INSR gene variants can be a cause for monogenic diabetes in children and adolescents and the need for genetic evaluation in atypical presentations of diabetes. We also describe the possible role of metformin in treating individuals with type A insulin resistance syndrome due to INSR gene variants.Learning pointsInsulin receptor (INSR) gene variants can be a cause of monogenic diabetes in children and adolescents.Genetic evaluation should be considered in children and adolescents with type 2 diabetes (T2D), particularly where there is an atypical presentation and/or positive family history.Metformin may have a role in the treatment of type A insulin resistance syndrome due to heterozygous mutation of the INSR gene.

Insulin signaling regulates longevity through protein phosphorylation in Caenorhabditis elegans

Insulin/IGF-1 Signaling (IIS) is known to constrain longevity by inhibiting the transcription factor FOXO. How phosphorylation mediated by IIS kinases regulates lifespan beyond FOXO remains unclear. Here, we profile IIS-dependent phosphorylation changes in a large-scale quantitative phosphoproteomic analysis of wild-type and three IIS mutant Caenorhabditis elegans strains. We quantify more than 15,000 phosphosites and find that 476 of these are differentially phosphorylated in the long-lived daf-2/insulin receptor mutant. We develop a machine learning-based method to prioritize 25 potential lifespan-related phosphosites. We perform validations to show that AKT-1 pT492 inhibits DAF-16/FOXO and compensates the loss of daf-2 function, that EIF-2α pS49 potently inhibits protein synthesis and daf-2 longevity, and that reduced phosphorylation of multiple germline proteins apparently transmits reduced DAF-2 signaling to the soma. In addition, an analysis of kinases with enriched substrates detects that casein kinase 2 (CK2) subunits negatively regulate lifespan. Our study reveals detailed functional insights into longevity.

Metreleptin and Metformin Use in an Infant With Congenital Generalized Lipodystrophy Secondary to AGPAT2 Mutation

Background: Congenital generalized lipodystrophy (CGL) is a rare inherited disease characterized by widespread loss of subcutaneous fat and severe metabolic abnormalities. Metreleptin, a synthetic analog of leptin, is a treatment modality that has been shown to decrease fasting triglycerides, fasting glucose, and HbA1c. Metformin use in infants has only been described in a few case reports of CGL and Donohue syndrome (insulin receptor mutation), and there is no established dosing for this age group. We report metreleptin, insulin, and metformin use in an infant with type 1 CGL who presented with marked hypertriglyceridemia, hypoleptinemia, hyperglycemia, and transaminitis.Clinical Case: A 2-month-old African American female born SGA at term presented to her primary care physician for a well child check where she was noted to have poor weight gain, hyperphagia, and abdominal distension. She was subsequently admitted for failure to thrive with weight z-score of -2.17 and length z-score of -0.15. Initial labs were notable for triglycerides of 5,167 mg/dL, HDL 10 mg/dL, blood glucose 324 mg/dL, ALT 212 units/L, AST 215 units/L, and bicarbonate of 17 mmol/L. A random insulin level was elevated at 257 mcIU/mL. Adiponectin was undetectable and leptin was low at 0.3 ng/mL. Hemoglobin A1c was in diabetes mellitus range at 8.9%. She was started on detemir 1.0 units/kg/day on day 1 (titrated to a maximum dose of 4.4 units/kg/day) and metformin 50 mg/kg/day on day 3 of hospitalization. By day 4, triglycerides decreased to 758 mg/dL, AST to 119 units/L and ALT to 124 units/L. Pre-prandial glucoses improved ranging from 113 to 138 mg/dL. As her insurance denied coverage for detemir, she was discharged home on glargine 0.7 units/kg/day and metformin suspension. One month later, she was started on subcutaneous metreleptin, and glargine was discontinued. At 5 months of age, she had triglycerides 229 mg/dl, normal liver enzymes, and normal blood glucoses while on 0.056 mg/kg/day of subcutaneous metreleptin and metformin. Medications were well tolerated without side effects. She had improved growth and met all developmental milestones. Genetic evaluation revealed that she was homozygous for a pathogenic variant, c.589-2A>G; p.Gln196fs*228 (rs116807569), in the AGPAT2 gene.Conclusion: Leptin is important in regulation of lipid and glucose metabolism, and patients with CGL are deficient due to lack of adipose tissue. Metabolic abnormalities, including stabilization of glucoses and improved hypertriglyceridemia, in our patient markedly improved with initiation of metreleptin, metformin, and insulin. We present successful dosing of these treatment modalities without adverse reactions in an infant with CGL.

Homozygous Mutation in the Insulin Receptor Gene Associated with Mild Type A Insulin Resistance Syndrome: A Case Report

Insulin receptor (INSR) mutations lead to heterogeneous disorders that may be as severe as Donohue syndrome or as mild as “type A insulin resistance syndrome”. Patients with severe disorders usually harbor homozygous or compound heterozygous mutations. In contrast, type A insulin resistance syndrome has been associated with heterozygous mutations; homozygous mutations are rarely responsible for this condition. We report a novel, homozygous mutation, p.Leu260Arg in exon 3, of the INSR gene in a female adolescent patient with type A insulin resistance syndrome together with clinical details of her medical follow-up. Different mutations in the INSR gene cause different phenotype and vary depending on the inheritance pattern. This report adds to the literature, increases understanding of the disease mechanism and aids in genetic counseling.

Impact of Probiotic Combination in InR[E19]/TM2 Drosophila melanogaster on Longevity, Related Gene Expression, and Intestinal Microbiota: A Preliminary Study.

The insulin receptor (InR) pertains to the insulin receptor family, which plays a key role in the insulin/insulin-like growth factor (IGF)-like signaling (IIS) pathway. Insulin signaling defects may result in the development of metabolic diseases, such as type 2 diabetes, and the InR mutant has been suggested to bear insulin signaling deficiency. Numerous studies have reported that probiotics are beneficial for the treatment of diabetes; however, the effect of probiotics on patients with InR deficiency has seldom been reported. Therefore, we chose the InR[E19]/TM2 Drosophila melanogaster to investigate. The results indicated that probiotics significantly reduce the mean and median lifespan of InR[E19]/TM2 Drosophila (by 15.56% and 23.82%, respectively), but promote that of wild-type files (by 9.31% and 16.67%, respectively). Significant differences were obtained in the expression of lifespan- and metabolism-related genes, such as Imp-L2, Tor, and GstD2, between the standard diet groups and the probiotics groups. Furthermore, analysis of 16S rDNA via high throughput sequencing revealed that the gut bacterial diversity of Drosophila fed with a probiotic combination also differs from that of Drosophila fed with a standard diet. In summary, these findings indicate that a probiotic combination indeed affects InR[E19]/TM2 Drosophila, but not all of its impacts are positive.

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.

Type A Insulin Resistance Syndrome- Novel insulin receptor gene mutation and familiar phenotypic variability

Type A Insulin Resistance Syndrome is due to heterozygous mutations in the insulin receptor (INSR) gene or its signaling pathway. We present a premenarcheal 14 year-old girl with normal BMI, severe hirsutism, acanthosis nigricans, clitoral hypertrophy, deep voice, enlarged polycystic ovaries, severe hyperinsulinemia and biochemical hyperandrogenism. We identified a novel heterozygous missense variant in the tyrosine kinase domain of INSR (p.Leu1150Pro) and an heterozygous missense variant in SH2B adapter protein 1 involved in the insulin pathway (p.Ala663Val). Interestingly, the patients’ mother and brother had the same INSR mutation although of a milder phenotype, reason why their IR went undiagnosed.

MON-611 Biux2x2

Insulin is critical for lipid synthesis and inhibition of lipolysis. The dyslipidemia of type 2 diabetes (high triglycerides (TG), low HDL) is caused by selective IR with intact insulin signaling in lipogenic pathways. By contrast, knockout of all insulin signaling pathways due to insulin receptor (INSR) mutation leads to low TG and high HDL (in humans and mice), and decreased cholesterogenic gene expression, cholesterol and bile acid synthesis, PCSK9, and hepatic FFA flux (in liver INSR -/- mice). Thyroid hormone (TH) effects on lipids generally oppose those of insulin, and include increased lipolysis, FFA, and bile formation. We used patients with homozygous (-/-) and heterozygous (+/-) INSR mutations as models to understand interactions between TH and insulin action on lipids. Materials and methods: Euthyroid patients age 12-65y with proven INSR -/- (N=5) or +/- (N=2) mutation (22.2+6.5yr; 4 males) were treated with liothyronine (T3) for 2 weeks with peak target level 25-50% above upper limit of normal. Samples were obtained before and after T3 for thyroid hormones (TSH, fT4, TT4, fT3, TT3), lipids (total cholesterol, LDL, HDL, TG, number and size of lipid particles by NMR, ApoA1, ApoB), lipid regulating enzymes (CETP activity, LCAT activity and mass, PCSK9, PTPL, Lp-PLA2), lipolysis (glycerol turnover), and palmitate turnover. Results: After initiation of T3, hyperthyroid state was achieved by day 3 based on fT3 and TT3 with TSH suppression on day 4. On the standard lipid panel, TG decreased from 64.2 at baseline to 52.6mg/dl after T3 (p=.1), total cholesterol from 143±18.2 to 119.7±9.4mg/dl (p=.0009), LDL from 76.3±15.7 to 61.1±15.5mg/dl (p=.02), and HDL from 62.2±11.9 to 55.2±10.3mg/dl (p=.026). NMR analysis of lipoprotein particles showed that triglyceride-rich lipoprotein particles (TRLP) decreased from to 20±9.8 to 13±5.7 nmol/l (p=.06), LDLP from 1115±201 to 937±195 nmol/L (p=.016), large LDLP from 139±73 to 81±48 nmol/l (p=.046), size of the LDLP from 20.5±0.4 to 20.2±0.4 nm (p=.055), ApoB from 55.7±11 to 45.4±11 mg/dl (p=0.015), HDLP from 20±3 to 18.5±2 nm (p=.08), large HDLP from 3.6±1.9 to 2.8±1.8 umol/l (p=.06), size of HDLP particles from 9.5±0.6 to 9.4±0.6 nm (p=.08), and ApoA1 from 144±4 to 129±15 mg/dl (p=.02). No significant increase in FFA was seen after T3. Lipid enzymes were unchanged after T3 except for PLAC activity, which decreased from 128±30 to 111±28 nmol/min/ml (p=0.03). There was no difference in lipolysis or palmitate turnover rate after T3. In conclusion, we found that T3 had the expected effects on lipids in INSR mutation patients. No changes in key lipid enzymes were found after T3, perhaps due to small sample size. Further long-term studies are needed to determine long-term effects of TH on lipid metabolism in the setting of normal vs. impaired insulin signaling.