The two isotypes of the human insulin receptor (HIR-A and HIR-B) follow different internalization kinetics

Vogt, Beate; Carrascosa, Jóse M.; Ermel, B; Ullrich, Axel; Häring, Hans‐Ulrich

doi:10.1016/0006-291x(91)90639-o

Cited by 103 publications

(54 citation statements)

References 6 publications

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“…Some functional differences between the two isoforms with regard to insulin activation have emerged. For instance, the IR-A shows a faster internalization and recycling time (Vogt et al 1991, Yamaguchi et al 1993) and may have a less efficient kinase activity (Kosaki et al 1995). In murine 32D cells, IR-A induces mitogenic and antiapoptotic signals and nuclear translocation of IRS1 , whereas IR-B induces cell differentiation but not IRS1 nuclear translocation .…”

Section: Functional Characteristics Of Ir-a Versus Ir-bmentioning

confidence: 99%

Insulin receptor and cancer

Belfiore

Malaguarnera²

2011

Endocrine-Related Cancer

243

223

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The widespread epidemic of obesity and type 2 diabetes has raised concern for the impact of these disorders as risk factors for cancer and has renewed the interest for studies regarding the involvement of hyperinsulinemia and insulin receptor (IR) in cancer progression. Overexpression of IR in cancer cells may explain their increased sensitivity to hyperinsulinemia. Moreover, IR isoform A (IR-A) together with autocrine production of its ligand IGF2 is emerging as an important mechanism of normal and cancer stem cell expansion and is a feature of several malignancies. De novo activation of the IR-A/IGF2 autocrine loop also represents a mechanism of resistance to anticancer therapies. Increasing knowledge of the IR role in cancer has important implications for cancer prevention, which should include control of insulin resistance and hyperinsulinemia in the population and meticulous evaluation of new antidiabetic drugs for their metabolic:mitogenic ratio. We are now aware that several anticancer treatments may induce or worsen insulin resistance that may limit therapy efficacy. Future anticancer therapies need to target the IR-A pathway in order to inhibit the tumor promoting effect of IR without impairing the metabolic effect of insulin.

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Section: Functional Characteristics Of Ir-a Versus Ir-bmentioning

confidence: 99%

Insulin receptor and cancer

Belfiore

Malaguarnera²

2011

Endocrine-Related Cancer

243

223

View full text Add to dashboard Cite

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“…IR-A shows a higher affinity for insulin and a higher internalization rate than IR-B (Vogt et al 1991, Yamaguchi et al 1991, whereas IR-B is considered to transmit the insulin signal more efficiently than IR-A as long as it has a greater kinase activity (Kellerer et al 1992, Kosaki et al 1995. Besides, recent studies have shown that IR-A and IR-B activate different downstream pathways.…”

Section: Introductionmentioning

confidence: 99%

Differential gene expression of insulin receptor isoforms A and B and insulin receptor substrates 1, 2 and 3 in rat tissues: modulation by aging and differentiation in rat adipose tissue

Serrano

Villar²,

Martı́nez

et al. 2005

Journal of Molecular Endocrinology

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The insulin receptor (IR) occurs as two alternatively spliced isoforms, IR-A (exon 11−) and IR-B (exon 11+), which exhibit functional differences and are expressed in a tissue-specific manner. The IR substrate (IRS) proteins 1, 2 and 3 also differ in function and tissue distribution. Here we show the differential gene expression of IRs and IRSs in several rat target tissues of insulin action. IR-B is significantly higher than IR-A in epididymal white adipose tissue and adipogenesis induces a shift in the alternatively spliced species of IR from the A to the B isoform. Moreover, since aging in the rat is associated with the development of insulin resistance we looked for alterations of expression of these proteins in adipocytes from old rats. Our results reveal that there is a specific decrease in the expression of the IR-B isoform, as well as both mRNA and protein levels of IR, IRS-1 and IRS-3 being significantly decreased, in epididymal adipose tissue from old compared with adult rats. It is concluded that the down-regulation of early components of the insulin transduction pathway in a primary insulin target tissue could be related to the insulin resistance of aging.

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“…The human insulin receptor gene is a single-copy gene located on the short arm of chromosome 19, consisting of 22 exons spanning more than 120 kb. It encodes a transmembrane protein consisting of two extracellular a-subunits and two transmembrane /-subunits (a232)-Insulin binds extracellularly, leading to autophosphorylation and activation of the receptor's tyrosine kinase.…”

Section: Introductionmentioning

confidence: 99%

Hyperinsulinemia is associated with altered insulin receptor mRNA splicing in muscle of the spontaneously obese diabetic rhesus monkey.

Huang¹,

Bodkin²,

Ortmeyer³

et al. 1994

J. Clin. Invest.

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The human insulin receptor has two isoforms derived from alternative splicing of exon 11 of the insulin receptor gene. The type B (containing exon 11, or exon 11 + ) isoform binds insulin with twofold lower affinity than the type A (lacking exon 11, or exon 11-) isoform. In efforts to resolve the controversy over whether altered splicing is involved in the development of insulin resistance and non-insulin-dependent diabetes mellitus (NIDDM), the spontaneously obese diabetic rhesus monkey, a unique model that is extraordinarily similar to human NIDDM, was used. Cross-sectional studies of insulin receptor mRNA splicing variants in vastus lateralis muscle were performed on 19 rhesus monkeys. When monkeys were divided into four groups based upon the known stages of progression to NIDDM: normal (normoglycemic/normoinsulinemic), prediabetic (normoglycemic/hyperinsulinemic), early NIDDM (hyperglycemic/hyperinsulinemic), and late NIDDM (hyperglycemic/ hypoinsulinemic), both hyperinsulinemic groups had significantly higher percentages of the exon 11-mRNA splicing variant compared to the normal (74.8±1.7 vs 59.0 ±2.3%; P < 0.005) and late NIDDM groups (74.8±1.7 vs 64.2±3.9%; P < 0.05). Our findings provide the first direct evidence linking hyperinsulinemia to alterations in insulin receptor mRNA splicing, and suggest that alterations of insulin receptor mRNA splicing in muscle is an early molecular marker that may play an important role in NIDDM.

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The two isotypes of the human insulin receptor (HIR-A and HIR-B) follow different internalization kinetics

Cited by 103 publications

References 6 publications

Insulin receptor and cancer

Insulin receptor and cancer

Differential gene expression of insulin receptor isoforms A and B and insulin receptor substrates 1, 2 and 3 in rat tissues: modulation by aging and differentiation in rat adipose tissue

Hyperinsulinemia is associated with altered insulin receptor mRNA splicing in muscle of the spontaneously obese diabetic rhesus monkey.

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