Insulin receptor isoform A confers a higher proliferative capability to pancreatic beta cells enabling glucose availability and IGF-I signaling

Escribano, Óscar; Gómez-Hernández, Almudena; Díaz-Castroverde, Sabela; Nevado, Carmen; García, Gema Álvarez; Otero, Yolanda F.; Perdomo, Liliana; Beneit, Nuria; Benito, Manuel

doi:10.1016/j.mce.2015.03.008

Cited by 19 publications

(19 citation statements)

References 41 publications

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“…It seems preferable to search for new agents that will improve insulin sensitivity in the pathway, leading to suppression of hepatic gluconeogenesis, as well as agents able to enhance glucose uptake in order to decrease the hyperglycaemia (Brown and Goldstein, 2008). In this sense, our group reported in vitro that the presence or absence of one or other IR isoform involves changes in the metabolic profile; concisely, that expression of IRA, but not IRB, improves glucose uptake in murine hepatocytes and beta cells by its association with GLUTs (Nevado et al, 2006; Escribano et al, 2015). More recent studies have shown a direct relationship between the metabolic status of individuals with T2DM and the IRA/IRB ratio, suggesting a dynamic regulation of IR splicing depending on the metabolic profile (Besic et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, IRB is predominantly expressed in adult tissues, including the liver, where it triggers the metabolic effects of insulin (Malaguarnera and Belfiore, 2011). Although insulin does not stimulate glucose uptake in the liver, in vitro studies in neonatal hepatocytes and pancreatic beta cells demonstrate that IRA plays a direct role favouring glucose uptake, promoting its specific association with endogenous glucose transporters (GLUT1 and GLUT2) (Nevado et al, 2006; Escribano et al, 2015). Therefore, differences in the capability of glucose uptake can be associated with the presence or absence of IR isoforms or with changes in the ratio between them.…”

Section: Introductionmentioning

confidence: 99%

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Insulin receptor isoform A ameliorates long-term glucose intolerance in diabetic mice

Díaz-Castroverde

Gómez-Hernández

Fernández

et al. 2016

Disease Models &Amp; Mechanisms

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Type 2 diabetes mellitus is a complex metabolic disease and its pathogenesis involves abnormalities in both peripheral insulin action and insulin secretion. Previous in vitro data showed that insulin receptor isoform A, but not B, favours basal glucose uptake through its specific association with endogenous GLUT1/2 in murine hepatocytes and beta cells. With this background, we hypothesized that hepatic expression of insulin receptor isoform A in a mouse model of type 2 diabetes could potentially increase the glucose uptake of these cells, decreasing the hyperglycaemia and therefore ameliorating the diabetic phenotype. To assure this hypothesis, we have developed recombinant adeno-associated viral vectors expressing insulin receptor isoform A (IRA) or isoform B (IRB) under the control of a hepatocyte-specific promoter. Our results demonstrate that in the long term, hepatic expression of IRA in diabetic mice is more efficient than IRB in ameliorating glucose intolerance. Consequently, it impairs the induction of compensatory mechanisms through beta cell hyperplasia and/or hypertrophy that finally lead to beta cell failure, reverting the diabetic phenotype in about 8 weeks. Our data suggest that long-term hepatic expression of IRA could be a promising therapeutic approach for the treatment of type 2 diabetes mellitus.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Insulin receptor isoform A ameliorates long-term glucose intolerance in diabetic mice

Díaz-Castroverde

Gómez-Hernández

Fernández

et al. 2016

Disease Models &Amp; Mechanisms

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“…A recent study demonstrated that the immortalized mouse β-cell line (exclusively expressing IR A isoform) was sensitive to the mitogenic response induced by IGF-1, which further activated β-cell proliferation, primarily through mTORC1 ( Fig. 1 ) ( 25 ). Furthermore, in partial pancreatectomy (60%), mTORC1 exerted a compensatory effect on β-cell mass mainly through the cyclin D2 pathway in early stages ( 26 ).…”

Section: Insulin Signaling Pathwaysmentioning

confidence: 99%

Cellular signaling pathways regulating β‑cell proliferation as a promising therapeutic target in the treatment of diabetes (Review)

2018

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It is established that a decrease in β-cell number and deficiency in the function of existing β-cells contribute to type 1 and type 2 diabetes mellitus. Therefore, a major focus of current research is to identify novel methods of improving the number and function of β-cells, so as to prevent and/or postpone the development of diabetes mellitus and potentially reverse diabetes mellitus. Based on prior knowledge of the above-mentioned causes, promising therapeutic approaches may include direct transplantation of islets, implantation and subsequent induced differentiation of progenitors/stem cells to β-cells, replication of pre-existing β-cells, or activation of endogenous β-cell progenitors. More recently, with regards to cell replacement and regenerative treatment for diabetes patients, the identification of cellular signaling pathways with related genes or corresponding proteins involved in diabetes has become a topic of interest. However, the majority of pathways and molecules associated with β-cells remain unresolved, and the specialized functions of known pathways remain unclear, particularly in humans. The current article has evaluated the progress of research on pivotal cellular signaling pathways involved with β-cell proliferation and survival, and their validity for therapeutic adult β-cell regeneration in diabetes. More efforts are required to elucidate the cellular events involved in human β-cell proliferation in terms of the underlying mechanisms and functions.

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“…In 32D cells, IRA induces mitogenic and antiapoptotic signals in response to IGF-II, whereas IRB tends to send differentiation signals [15]. In mouse beta cell lines, IRA confers a stronger proliferative capacity favoring the mitogenic effects of IGF-I and increasing glucose uptake [16], and it also might provide an explanation for the beta cell hyperplasia induced by liver insulin resistance in iLIRKO mice [17]. Additionally, long-term AAV-mediated hepatic expression of IRA, but not IRB, improves glucose homeostasis in iLIRKO mice, precluding beta cell mass expansion and, therefore, avoiding the final beta cell failure [18].…”

Section: Introductionmentioning

confidence: 99%

Expression of insulin receptor (IR) A and B isoforms, IGF-IR, and IR/IGF-IR hybrid receptors in vascular smooth muscle cells and their role in cell migration in atherosclerosis

Beneit

Fernandez-Garcia

Martı́n-Ventura

et al. 2016

Cardiovasc Diabetol

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BackgroundAbnormal proliferation and migration of vascular smooth muscle cells (VSMCs) is a major contributor to the development of atherosclerotic process. In a previous work, we demonstrated that the insulin receptor isoform A (IRA) and its association with the insulin-like growth factor-I receptor (IGF-IR) confer a proliferative advantage to VSMCs. However, the role of IR and IGF-IR in VSMC migration remains poorly understood.MethodsWound healing assays were performed in VSMCs bearing IR (IRLoxP+/+ VSMCs), or not (IR−/− VSMCs), expressing IRA (IRA VSMCs) or expressing IRB (IRB VSMCs). To study the role of IR isoforms and IGF-IR in experimental atherosclerosis, we used ApoE−/− mice at 8, 12, 18 and 24 weeks of age. Finally, we analyzed the mRNA expression of total IR, IRB isoform, IGF-IR and IGFs by qRT-PCR in the medial layer of human aortas.ResultsIGF-I strongly induced migration of the four cell lines through IGF-IR. In contrast, insulin and IGF-II only caused a significant increase of IRA VSMC migration which might be favored by the formation of IRA/IGF-IR receptors. Additionally, a specific IGF-IR inhibitor, picropodophyllin, completely abolished insulin- and IGF-II-induced migration in IRB, but not in IRA VSMCs. A significant increase of IRA and IGF-IR, and VSMC migration were observed in fibrous plaques from 24-week-old ApoE−/− mice. Finally, we observed a marked increase of IGF-IR, IGF-I and IGF-II in media from fatty streaks as compared with both healthy aortas and fibrolipidic lesions, favoring the ability of medial VSMCs to migrate into the intima.ConclusionsOur data suggest that overexpression of IGF-IR or IRA isoform, as homodimers or as part of IRA/IGF-IR hybrid receptors, confers a stronger migratory capability to VSMCs as might occur in early stages of atherosclerotic process.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0477-3) contains supplementary material, which is available to authorized users.

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Insulin receptor isoform A confers a higher proliferative capability to pancreatic beta cells enabling glucose availability and IGF-I signaling

Cited by 19 publications

References 41 publications

Insulin receptor isoform A ameliorates long-term glucose intolerance in diabetic mice

Insulin receptor isoform A ameliorates long-term glucose intolerance in diabetic mice

Cellular signaling pathways regulating β‑cell proliferation as a promising therapeutic target in the treatment of diabetes (Review)

Expression of insulin receptor (IR) A and B isoforms, IGF-IR, and IR/IGF-IR hybrid receptors in vascular smooth muscle cells and their role in cell migration in atherosclerosis

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