The Functional Characterization Study Of Two Cases With Hyperinsulineamia

BackgroundHyperinsulinemia is a big challenge in clinic. The manifestation varies due to different kinds of disorders and diseases. Though the damage of β-cells can be effectively corrected if detected in an incipient stage, patients with unexplained severe insulin resistance still remain a big challenge for clinicians.Type A insulin-resistant syndrome is an common disorder characterized by severe insulin resistance resulting from mutation or polymorphism of insulin receptor gene. It normally develops in female adolescents with the phenotype of insulin resistance, acanthosis nigricans, and hyperandrogenism in the absence of obesity or lipoatrophy. The insulin receptor gene （INSR, Gene ID:3643, MIM:610549; GeneBank: NC₀00019.10） is located on human chromosome 19q13 and has 22 independent exons. The encoded protein consists of a polypeptide of 1328 amino acids, which is a member of the receptor tyrosine kinase family of proteins. Binding of insulin or other ligands to this receptor activates the insulin signaling pathway, therefore, glucose uptake and release, as well as the synthesis and storage of carbohydrates, lipids and protein is regulated. For the lack of correlation analysis between phenotype and genotype of INSR gene, detecting novel mutation an analysis provide a new insight into the function of insulin receptor and help clinicians better understand this disorder in order to search effective treatment.Insulin autoimmune syndrome （IAS）, or Hirata’s disease is characterized by spontaneous hypoglycemia without evidence of exogenous insulin administration, a high serum concentration of total immunoreactive insulin, and the presence of insulin autoantibodies in high titer. It is a typical representative of diabetes caused by rare immune factors whose pathogenesis is involved in genetic susceptibility, drug effects, release and discharge of insulin. Detecting this disorder correctly can contribute to provide comprehensive understanding of severe insulin resistance, apart from avoid miss diagnosis and misdiagnosis in practice.ObjectiveHere, we aimed at investigating clinical and genetic characteristics of a suspect Chinese type A insulin resistance patient（patient A）, in addition, we review the literature in genetics, diagnosis and treatment of this disorder; a Chinese insulinautoimmune syndrome patient（patient B） was also analyzed on clinical characteristics, diagnosis as well as advances about this disorder.Subjects and MethodsPatient A was performed fully physical examination and thorough medical history, as well as reinforcement CT of adrenal, OGTT, insulin/C-peptide release test and other related accessory examination. Meanwhile, all 22 exons of INSR gene of the patient were sequenced directly and analysis of correlations between phenotype and genotype was made. On the other hand, continuous glucose monitoring was performed in patient B based on a fully medical history, physical examination, and blood tests results. Follow-ups of these two patients were performed.Results1. Routine ECG, gynaecological ultrasonic examination, biochemistry measurement, determination of gonadal hormones（FSH, LH, PRL, T, P, E2）, antibodies of insulin, islet cells and glutamic acid decarboxylase revealed that insulin autoantibody of these two patients was positive, and patient A revealed no other abnormality, while patient B was hyperthyroidism and hyperlipidemia. Severe insulin resistance was discovered by OGTT and insulin/C-peptide release tests.2. Identification of the mutation and follow-up. Genetic analysis of patient A revealed one synonymous mutation （c.3255C>T） which was at codon 1085（p.1085H）In light of obvious insulin resistance of the patient, polymorphism of the INSR gene was considered as a pathogenic factor. In the 1.5-year follow-up of patient A, insulin resistance and other symptoms improved efficiently when the patient took drugs regularly, however, patient A’s condition deteriorated later with failing to take drugs. Patient B was cured after prednisolone treatment and both blood glucose and serum insulin maintained normal in the next six-month follow up.ConclusionsTAIRS should be under consideration on condition that an adolescent female is found with hyperinsulinism, acanthosis nigricans and hyperandrogenism; sequencing of INSR gene is necessary to confirm a diagnosis, variations of the gene can be associated with insulin receptor dysfunction. IAS could be an important nosogenesis for spontaneous hypoglycemia among middle-aged and aged population, diagnosis of these disease depend on drug history and positive IAA.All these provide further insights into severe insulin resistance and help clinicians better understand this disorder.