| insulin receptor | OKDB#: 384 |
| Symbols: | INSR | Species: | human | ||
| Synonyms: | HHF5, CD220 | Locus: | 19p13.2 in Homo sapiens | HPMR |
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| General Comment |
The insulin receptor is a tetramer of 2 alpha and 2 beta subunits. The alpha and beta subunits are coded by a single gene and
are joined by disulfide bonds, a mechanism parallel to that of the ligand, insulin. Mutation in either the
structural gene or some of the processing steps may lead to insulin resistance. Ullrich et al. (1985) deduced the entire
1,370-amino acid sequence from a cDNA clone. The precursor starts with a 27-amino acid signal sequence, followed by the
receptor alpha subunit, a precursor processing enzyme cleavage site, then the beta subunit containing a single 23-amino acid
transmembrane sequence.
Downing JA studied the effect of a direct arterial infusion of insulin and glucose
on the ovarian secretion rates of androstenedione and oestradiol in ewes with an autotransplanted ovary. They showed that insulin and glucose act together to influence ovarian
function directly and suggest that the effects of short-term nutrition on
ovulation rate may be mediated by a direct ovarian action of insulin and
glucose.
NCBI Summary: This gene encodes a member of the receptor tyrosine kinase family of proteins. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that form a heterotetrameric receptor. Binding of insulin or other ligands to this receptor activates the insulin signaling pathway, which regulates glucose uptake and release, as well as the synthesis and storage of carbohydrates, lipids and protein. Mutations in this gene underlie the inherited severe insulin resistance syndromes including type A insulin resistance syndrome, Donohue syndrome and Rabson-Mendenhall syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015] |
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| General function | Receptor | ||||
| Comment | Moghetti et al reported metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. It was concluded, in women with PCOS metformin treatment reduced hyperinsulinemia and hyperandrogenemia, independently of changes in body weight. In a large number of subjects these changes were associated with striking, sustained improvements in menstrual abnormalities and resumption of ovulation. Higher plasma insulin, lower serum androstenedione, and less severe menstrual abnormalities are baseline predictors of clinical response to metformin. | ||||
| Cellular localization | Plasma membrane, SNP, GWAS+ | ||||
| Comment | family123 | ||||
| Ovarian function | Follicle development, Initiation of primordial follicle growth, Primary follicle growth, Steroid metabolism | ||||
| Comment | Yu et al cultured fetal hamster ovaries for up to 16 days in the presence or absence of various dosages of insulin to evaluate the induction of folliculogenesis in vitro. In the absence of insulin, a few primordial follicle-like structures appeared by the 4th day, and distinct primary follicles (stage 1) appeared by the 12th day of culture. The organelles in the oocytes and adjacent granulosa cells developed along with follicular growth. Moreover, gap junctions between the oocyte and somatic cell plasma membrane also developed as early as 8 days in culture. In the presence of 0.2 microg/ml insulin, primary follicles developed after 8 days, and approximately 4% secondary follicles with 2-3 layers of granulosa cells appeared after 16 days of culture. The results indicate that although primordial and primary follicles can develop after 12 days in vitro in the absence of exogenous insulin, the latter is required for timely progression of follicular development through primary and secondary stages. Franks S et al reviewed insulin action in the normal and polycystic ovary. Insulin has a stimulatory effect on steroidogenesis by granulosa cells of normal and polycystic ovaries and interacts with gonadotropins in an additive or, as in the case of LH, a synergistic manner. These actions seem to be mediated specifically by the insulin receptor rather than by cross-reaction with the type I IGF receptor, even in tissue obtained from women with PCOS with biochemical evidence of insulin resistance. The authors suggest that hyperinsulinemia makes a significant contribution to premature arrest of follicle growth, which is characteristic of anovulation in women with PCOS, and that the interaction of insulin with LH is a key element in this process. Insulin may also have a role in amplifying LH-induced androgen production by theca cells, which may help explain the prominence of symptoms of hyperandrogenism in obese subjects with PCOS. The results of recent clinical studies of insulin-sensitizing agents such as metformin and the thiazoladinedione troglitazone in PCOS have provided encouragement that improvement of insulin sensitivity and consequent lowering of circulating insulin levels by these agents may be of therapeutic value in the management of both anovulation and hirsutism. | ||||
| Expression regulated by | FSH, LH, Steroids, Growth Factors/ cytokines | ||||
| Comment | Adashi EY reviewed the IGF family and folliculogenesis. Poretsky L, et al. reviewed the insulin-related ovarian regulatory system in health and disease. | ||||
| Ovarian localization | Oocyte, Granulosa, Theca, Luteal cells | ||||
| Comment | Insulin Signaling in Mammalian Oocytes. Acevedo N et al. Continual exposure of follicles/oocytes to elevated insulin compromises embryonic developmental competence, yet cellular mechanisms are unknown. Objectives of present studies were to determine if mouse oocytes have insulin receptors, a functional insulin signaling cascade, and whether insulin exposure during oocyte growth or maturation influences meiotic progression and chromatin remodeling. Immunoblot and immunocytochemical analyses of germinal vesicle-intact (GVI) oocytes demonstrated presence of insulin receptor-beta. Insulin receptor expression was increased in oocytes following gonadotropin stimulation, and remained elevated throughout meiotic maturation. Fully-grown GVI oocytes contained 3-phosphoinositide dependent protein kinase-1 (PDPK1), thymoma viral proto-oncogene 1 (AKT1) and glycogen synthase kinase 3 (GSK3). In vitro maturation of GVI oocytes in 5 microg/ml insulin had no influence on meiotic progression or incidence of normal MII chromosome condensation. Treatment of oocytes during maturation had no effect on GSK3A/B protein expression or phosphorylation on S21/9. However, culture of pre-antral follicles for 10 days with 5 microg/ml insulin increased phosphorylation of oocyte GSK3B, indicating GSK3 inactivation. Rate of development to MI was similar between oocytes obtained from insulin treated follicles and controls, yet incidence of abnormal MI chromatin condensation was significantly higher in oocytes obtained from follicles cultured with insulin compared to no insulin. These results demonstrate that oocytes contain a functional insulin signaling pathway and that insulin exposure during oocyte growth results in chromatin remodeling aberrations. These findings begin to elucidate mechanisms by which chronic elevated insulin influences oocyte meiosis, chromatin remodeling, and embryonic developmental competence. | ||||
| Follicle stages | Secondary, Antral, Preovulatory, Corpus luteum | ||||
| Comment | |||||
| Phenotypes |
PCO (polycystic ovarian syndrome) |
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| Mutations |
9 mutations
Species: mouse
Species: human
Species: mouse
Species: human
Species: human
Species: mouse
Species: human
Species: human
Species: mouse
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
| Links |
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| created: | Jan. 15, 2000, midnight | by: |
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| last update: | March 22, 2020, 9:48 a.m. | by: | hsueh email: |
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