Insulin receptor isotype expression correlates with risk of non-insulin-dependent diabetes.

Mosthaf, Luitgard; Eriksson, Johan G.; Häring, Hans‐Ulrich; Groop, Leif; Widén, Elisabeth; Ullrich, Axel

doi:10.1073/pnas.90.7.2633

Cited by 47 publications

(30 citation statements)

References 28 publications

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“…Furthermore, this increase was positively correlated with plasma insulin concentration and negatively correlated with in vivo insulin sensitivity [58]. The results of this study may provide a key to the interpretation of the discordant data reported by the different studies [50][51][52][53][54][55]. In these latter reports, the metabolic state of the subjects studied ranged from glucose intolerance to overt diabetes and since this progression is usually paralleled by the decline in plasma insulin levels which accompany increases in glycemia, the differences in relative abundance of the two insulin receptor isoforms between normoglycemic and diabetic subjects may have been minimal or absent due to similar plasma insulin concentrations.…”

Section: Ir In Type 2 Diabetes 367mentioning

confidence: 51%

“…Studies on the relative expression of the two mRNA transcripts have led to divergent observations [50][51][52][53][54][55]. Thus, three studies have reported that expression of the two mRNA species measured by polymerase chain reaction (PCR) is altered in skeletal muscle of both type 2 diabetic and pre-diabetic insulin-resistant subjects as compared to normal insulin-sensitive controls [50][51][52].…”

Section: Insulin Receptor Isoforms In Type 2 Diabetesmentioning

confidence: 99%

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Molecular mechanism of insulin resistance in type 2 diabetes mellitus: role of the insulin receptor variant forms

Sesti

Federici

Lauro

et al. 2001

Diabetes Metabolism Res

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Type 2 diabetes is a heterogeneous and polygenic disorder resulting from interaction of genetic factors with environmental influences. Numerous candidate genes for insulin signaling proteins have been screened, but no single major susceptibility gene for type 2 diabetes has been identified. Due to its pivotal role in insulin action, the insulin receptor was considered a plausible candidate gene. The insulin receptor exists in two isoforms differing by the absence (Ex11(-)) or presence (Ex11(+)) of a 12 amino acid sequence in the COOH-terminus of the alpha-subunit, as a consequence of alternative splicing of exon 11. The Ex11(-) binds insulin with two-fold higher affinity than the Ex11(+). This difference is paralleled by a decreased sensitivity for metabolic actions of insulin. Some, but not all, studies have reported that expression of the low-affinity Ex11(+) is increased in target tissues from type 2 diabetic patients, thus suggesting that alterations in abundance of the two isoforms might contribute to insulin resistance. Insulin and type 1 IGF receptors have been shown to form hybrid receptors in tissues co-expressing both molecules. Hybrid receptors bind IGF-I, but not insulin, with high affinity, and behave as IGF-I holoreceptors, rather than insulin receptors, in terms of receptor autophosphorylation, and hormone internalization. It has been shown that the abundance of hybrid receptors is increased in skeletal muscle and adipose tissue from type 2 diabetic patients, and is negatively correlated with in vivo insulin sensitivity. Mutations in the insulin receptor gene have been identified in studies which examined an appropriately sized population of patients with type 2 diabetes. The prevalence of mutations in the insulin receptor gene ranged from 0.4%-7.8%. This review will focus on the structural and functional heterogeneity of the insulin receptor, and will discuss the pathogenetic role of insulin receptor variant forms and polymorphisms in the development of the common form of type 2 diabetes.

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Section: Ir In Type 2 Diabetes 367mentioning

confidence: 51%

Section: Insulin Receptor Isoforms In Type 2 Diabetesmentioning

confidence: 99%

Molecular mechanism of insulin resistance in type 2 diabetes mellitus: role of the insulin receptor variant forms

Sesti

Federici

Lauro

et al. 2001

Diabetes Metabolism Res

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“…Studies on humans and animal models of insulin resistance have demonstrated defects in the insulin signalling cascade at levels as proximal as the insulin receptor expression level and its tyrosine kinase activity [48,49,50]. If insulin resistance is a result of such a proximal signalling defect, what is the physiological relevance of an additional breakage point further downstream, like the one described in this study ? We believe that the literature to date does not rule out a role for insulin signalling defect(s) downstream of PI 3-kinase.…”

Section: Discussionmentioning

confidence: 65%

Nelfinavir-induced insulin resistance is associated with impaired plasma membrane recruitment of the PI 3-kinase effectors Akt/PKB and PKC-?

et al. 2004

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Aims/hypothesis. Chronic exposure of 3T3-L1 adipocytes to the HIV protease inhibitor nelfinavir induces insulin resistance, recapitulating key metabolic alterations of adipose tissue in the lipodystrophy syndrome induced by these agents. Our goal was to identify the defect in the insulin signal transduction cascade leading to nelfinavir-induced insulin resistance. Methods. Fully differentiated 3T3-L1 adipocytes were exposed to 30 µmol/l nelfinavir for 18 h, after which the amount, the phosphorylation and the localisation of key proteins in the insulin signalling cascade were evaluated.Results. Insulin-induced interaction of phosphatidylinositol 3′-kinase (PI 3-kinase) with IRS proteins was normal in cells treated with nelfinavir, as was IRS-1-associated PI 3-kinase activity. Yet insulin-induced phosphorylation of Akt/protein kinase B (PKB), p70S6 kinase and extracellular signal-regulated kinase 1/2 was significantly impaired. This could not be attributed to increased protein phosphatase 2A activity or to increased expression of phosphoinositide phosphatases (SHIP2 or PTEN). However, insulin failed to induce translocation of the PI 3-kinase effectors Akt/PKB and protein kinase C-ζ (PKC-ζ) to plasma membrane fractions of nelfinavir-treated adipocytes. Conclusions/interpretation. We therefore conclude that nelfinavir induces a defect in the insulin signalling cascade downstream of the activation of PI 3-kinase. This defect manifests itself by impaired insulin-mediated recruitment of Akt/PKB and PKC-ζ to the plasma membrane.

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“…It has been recently reported by some [22][23][24], but not all authors [16] that muscle tissue from insulin-resistant subjects (both diabetic and non-diabetic) has an increased proportion of the insulin receptor isoform exon 11+. This receptor isoform has a twofold lower affinity for the insulin molecule [25][26][27] and, consequently, a twofold lower sensitivity to insulin stimulation of its tyrosine-kinase activity [26,27], a decrease that is similar to the one we observed in the present study in muscle tissue of insulin-resistant subjects.…”

Section: Discussionmentioning

confidence: 97%

Insulin receptor tyrosine-kinase activity is altered in both muscle and adipose tissue from non-obese normoglycaemic insulin-resistant subjects

et al. 1995

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We performed i.v. insulin tolerance test in 30 non-obese (BMI < 30 male and < 28 female) non-diabetic (by oral glucose tolerance test) subjects and subdivided them into three groups of 10 subjects each, according to their insulin sensitivity (K(itt) values). Then we compared the tyrosine-kinase activity of immunopurified insulin receptors (using 32P-ATP and poly-glu-tyr (4:1) from both muscle and adipose tissue in 7 of the most insulin-sensitive and 7 of the most insulin-resistant subjects. No difference was observed between the two groups in the basal (no insulin) receptor tyrosine-kinase activity from both tissues. In contrast, tyrosine-kinase activity response to insulin was significantly higher (p < 0.05 by 2-way ANOVA test) in receptors from both tissues of insulin-sensitive subjects. In addition, a decreased tyrosine-kinase sensitivity to insulin was observed in muscle, but not adipose, tissue of insulin-resistant subjects (insulin ED50 being 0.87 +/- 0.05 nmol/l vs 2.03 +/- 0.07, p < 0.05 in insulin-sensitive and -resistant subjects). Insulin ED50 of muscle receptor tyrosine-kinase significantly (p = 0.001) correlated to both K(itt) values (r = -0.79) and plasma insulin values at 120 min during OGTT (r = + 0.80). Insulin receptor content, as assessed by radioimmunoassay, was similar in both muscle (7.9 +/- 1.3 and 9.2 +/- 1.9 ng/mg protein) and adipose tissue (8.2 +/- 1.3 and 7.5 +/- 1.4) of insulin-sensitive and -resistant subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

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Insulin receptor isotype expression correlates with risk of non-insulin-dependent diabetes.

Abstract: Skeletal muscle insulin resistance plays a pivotal role in the pathogenesis of non-insulin-dependent dia-

Cited by 47 publications

References 28 publications

Molecular mechanism of insulin resistance in type 2 diabetes mellitus: role of the insulin receptor variant forms

Molecular mechanism of insulin resistance in type 2 diabetes mellitus: role of the insulin receptor variant forms

Nelfinavir-induced insulin resistance is associated with impaired plasma membrane recruitment of the PI 3-kinase effectors Akt/PKB and PKC-?

Insulin receptor tyrosine-kinase activity is altered in both muscle and adipose tissue from non-obese normoglycaemic insulin-resistant subjects

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