Altered expression of insulin receptor types A and B in the skeletal muscle of non-insulin-dependent diabetes mellitus patients.

Mosthaf, Luitgard; Vogt, Beate; Häring, Hans Ulrich; Ullrich, Axel

doi:10.1073/pnas.88.11.4728

Cited by 99 publications

(73 citation statements)

References 30 publications

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“…Furthermore, IGF-II binds to IR-A but not to IR-B, with an affinity close to that of insulin, whereas the affinity for IGF-I for both receptors is similar (Mosthaf et al, 1991;Yamaguchi et al, 1991;Yamaguchi et al, 1993;Frasca et al, 1999;Pandini et al, 2002;Benyoucef et al, 2007). Contradictory results were reported in mouse 3T3 cells using a targeted ablation of the IGF-1R gene (Denley et al, 2004).…”

Section: Introductionmentioning

confidence: 52%

“…In embryos, IR-A promotes growth owing to its ability to bind insulin and IGF-II; in adults, IR-B is expressed predominantly in insulin-sensitive tissues regulating glucose homeostasis. Misregulation of IR alternative splicing is involved in some diseases and has important consequences for insulin and IGF-II sensitivity and responsiveness (Mosthaf et al, 1990;Mosthaf et al, 1991;Kellerer et al, 1993;Savkur et al, 2001;Sen et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Differential endocytosis and signaling dynamics of insulin receptor variants IR-A and IR-B

Giudice

Leskow

Arndt‐Jovin

et al. 2011

Journal of Cell Science

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Insulin signaling comprises a complex cascade of events, playing a key role in the regulation of glucose metabolism and cellular growth. Impaired response to insulin is the hallmark of diabetes, whereas upregulated insulin activity occurs in many cancers. Two splice variants of the insulin receptor (IR) exist in mammals: IR-A, lacking exon 11, and full-length IR-B. Although considerable biochemical data exist on insulin binding and downstream signaling, little is known about the dynamics of the IR itself. We created functional IR transgenes fused with visible fluorescent proteins for use in combination with biotinamido-caproyl insulin and streptavidin quantum dots. Using confocal and structured illumination microscopy, we visualized the endocytosis of both isoforms in living and fixed cells and demonstrated a higher rate of endocytosis of IR-A than IR-B. These differences correlated with higher and sustained activation of IR-A in response to insulin and with distinctive ERK1/2 activation profiles and gene transcription regulation. In addition, cells expressing IR-B showed higher AKT phosphorylation after insulin stimulation than cells expressing IR-A. Taken together, these results suggest that IR signaling is dependent on localization; internalized IRs regulate mitogenic activity, whereas metabolic balance signaling occurs at the cell membrane.

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Section: Introductionmentioning

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Differential endocytosis and signaling dynamics of insulin receptor variants IR-A and IR-B

Giudice

Leskow

Arndt‐Jovin

et al. 2011

Journal of Cell Science

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“…It is appealing to speculate that alterations in mRNA splicing may be responsible, at least in part, for insulin resistance and NIDDM. In fact, others have shown both at the mRNA and protein levels that the exon 11 + receptor isoform is markedly increased in the muscles of subjects with NIDDM, compared with nondiabetic controls (22)(23)(24)(25)(26). These findings could not be substantiated by other groups (27,28).…”

Section: Introductioncontrasting

confidence: 44%

“…For example, the observations of Mosthaf et al (22) and Kellerer et al (23), that diabetic subjects have less of the exon 11-mRNA variant, may be explained if they were comparing normoglycemic subjects with high insulin levels (this study's prediabetic group) to diabetics (this study's late NIDDM group) (Fig. 6 B).…”

Section: ----------------------------------------760 Rat :--N----t---mentioning

confidence: 98%

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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“…While the biological significance of the two alternative spliced transcripts is yet to be established, it may be possible that disorders with alternative INSR transcript assembly leading to changes in both forms ratio in different tissues may lead to the development of various severe diseases in human [65,70,95,104,106,126], though, the differences in both insulin receptor mRNA expression level has not been observed yet in patients suffering from various forms of insulin resistance in comparison to healthy ones [130].…”

Section: Insulin Receptor Transcript's Characteristicsmentioning

confidence: 99%

Insulin Receptor and its Relationship with Different Forms of Insulin Resistance

Rojek¹,

Niedziela²

2010

Advances in Cell Biology

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Summary:Insulin plays an important role in maintaining the whole organism's homeostasis. The presence of insulin receptors in all vertebrates and invertebrates cells reflects the diversity of regulatory processes in which this hormone is involved. Furthermore, many different factors may influence the level of insulin receptor expression. These factors include e.g. the sole insulin or stage of development. Mutations in the receptor may lead to the development of insulin resistance. These mutations differ in the level of severity and are frequently associated with diabetes mellitus, hypertension, cardiovascular disorders, heart failure, metabolic syndrome and infertility in women. More than 50 mutations in insulin receptor gene have already been characterized. These mutations are associated with rare forms of insulin resistance like leprechaunism, insulin resistance type A or Rabson-Mendenhall syndrome. Molecular analysis of insulin receptor gene may lead to a better understanding of molecular mechanisms underlying various types of insulin resistance and help to develop more efficient treatment.

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Altered expression of insulin receptor types A and B in the skeletal muscle of non-insulin-dependent diabetes mellitus patients.

Abstract: The human insulin receptor exists in two isoforms, HIR-A and HIR-B, which are generated by alterna-

Cited by 99 publications

References 30 publications

Differential endocytosis and signaling dynamics of insulin receptor variants IR-A and IR-B

Differential endocytosis and signaling dynamics of insulin receptor variants IR-A and IR-B

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

Insulin Receptor and its Relationship with Different Forms of Insulin Resistance

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