Growth effects of insulin and insulin analogues

Sandow, J.

doi:10.1080/13813450902835690

Cited by 36 publications

(31 citation statements)

References 85 publications

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“…The MAPK and PI3K pathways are canonical signaling pathways downstream of IR and IGF1R activation [6]. Ovarian organoids cultured with inhibitors of the insulin/IGF pathway appeared to have more MIS expression in the granulosa cells indicating that the ovary has endogenous production of IGF that in ex vivo 3D culture is detrimental to the tissue.…”

Section: Discussionmentioning

confidence: 99%

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Insulin and insulin-like growth factor signaling increases proliferation and hyperplasia of the ovarian surface epithelium and decreases follicular integrity through upregulation of the PI3-kinase pathway

et al. 2013

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BackgroundThe ovarian surface epithelium responds to cytokines and hormonal cues to initiate proliferation and migration following ovulation. Although insulin and IGF are potent proliferative factors for the ovarian surface epithelium and IGF is required for follicle development, increased insulin and IGF activity are correlated with at least two gynecologic conditions: polycystic ovary syndrome and epithelial ovarian cancer. Although insulin and IGF are often components of in vitro culture media, little is known about the effects that these growth factors may have on the ovarian surface epithelium morphology or how signaling in the ovarian surface may affect follicular health and development.MethodsOvaries from CD1 mice were cultured in alginate hydrogels in the presence or absence of 5 μg/ml insulin or IGF-I, as well as small molecule inhibitors of IR/IGF1R, PI 3-kinase signaling, or MAPK signaling. Tissues were analyzed by immunohistochemistry for expression of cytokeratin 8 to mark the ovarian surface epithelium, Müllerian inhibiting substance to mark secondary follicles, and BrdU incorporation to assess proliferation. Changes in gene expression in the ovarian surface epithelium in response to insulin or IGF-I were analyzed by transcription array. Extracellular matrix organization was evaluated by expression and localization of collagen IV.ResultsCulture of ovarian organoids with insulin or IGF-I resulted in formation of hyperplastic OSE approximately 4–6 cell layers thick with a high rate of proliferation, as well as decreased MIS expression in secondary follicles. Inhibition of the MAPK pathway restored MIS expression reduced by insulin but only partially restored normal OSE growth and morphology. Inhibition of the PI 3-kinase pathway restored MIS expression reduced by IGF-I and restored OSE growth to a single cell layer. Insulin and IGF-I altered organization of collagen IV, which was restored by inhibition of PI 3-kinase signaling.ConclusionsWhile insulin and IGF are often required for propagation of primary cells, these cytokines may act as potent mitogens to disrupt cell growth, resulting in formation of hyperplastic OSE and decreased follicular integrity as measured by MIS expression and collagen deposition. This may be due partly to altered collagen IV deposition and organization in the ovary in response to insulin and IGF signaling mediated by PI 3-kinase.

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Section: Discussionmentioning

confidence: 99%

“…Activation of IR or IGF1R by ligand binding activates downstream signaling pathways including the phosphatidylinositiol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways. In turn, proliferative and anti-apoptotic pathways are activated, including Akt, glycogen synthase kinase 3 β (GSK3β), Bcl2, and Bad [6]. …”

Section: Introductionmentioning

confidence: 99%

Insulin and insulin-like growth factor signaling increases proliferation and hyperplasia of the ovarian surface epithelium and decreases follicular integrity through upregulation of the PI3-kinase pathway

et al. 2013

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“…There are several uncertainties which make it very difficult to answer the question decisively (Hansen 2008). There seems to be a consensus that insulin and insulin analogues have growth-promoting activity (Sandow 2009). Moreover, insulin and insulin analogues have no carcinogenic activity (cell transformation) and are not a co-carcinogen when evaluated in special toxicology (Sandow 2009).…”

Section: In Vitro/ex Vivo Cell Culture Systemsmentioning

confidence: 99%

“…There seems to be a consensus that insulin and insulin analogues have growth-promoting activity (Sandow 2009). Moreover, insulin and insulin analogues have no carcinogenic activity (cell transformation) and are not a co-carcinogen when evaluated in special toxicology (Sandow 2009). Although Giorgino et al (1991) found that supraphysiological overexpression of IRs does favour ligand-dependent cell transformation in vitro, which underlines the potency of insulin to do so, it certainly does not mean that this occurs in vivo.…”

Section: In Vitro/ex Vivo Cell Culture Systemsmentioning

confidence: 99%

Insulin and its analogues and their affinities for the IGF1 receptor

Varewijck¹,

Janssen²

2012

Endocrine-Related Cancer

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Insulin analogues have been developed in an attempt to achieve a more physiological replacement of insulin and thereby a better glycaemic control. However, structural modification of the insulin molecule may result in altered binding affinities and activities to the IGF1 receptor (IGF1R). As a consequence, insulin analogues may theoretically have an increased mitogenic action compared to human insulin. In view of the lifelong exposure and large patient populations involved, insulin analogues with an increased mitogenic effect in comparison to human insulin may potentially constitute a major health problem, since these analogues may possibly induce the growth of pre-existing neoplasms. This hypothesis has been evaluated extensively in vitro and also in vivo by using animal models. In vitro, all at present commercially available insulin analogues have lower affinities for the insulin receptor (IR). Although it has been suggested that especially insulin analogues with an increased affinity for the IGF1R (such as insulin glargine) are more mitogenic when tested in vitro in cells expressing a high proportion of IGF1R, the question remains whether this has any clinical consequences. At present, there are several uncertainties which make it very difficult to answer this question decisively. In addition, recent data suggest that insulin (or insulin analogues)-mediated stimulation of IRs may play a key role in the progression of human cancer. More detailed information is required to elucidate the exact mechanisms as to how insulin analogues may activate the IR and IGF1R and how this activation may be linked to mitogenesis.

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“…It is, however, difficult to predict results in vivo on the basis of in vitro data [23], and in vitro studies do not conclusively support IGFR activation as the mechanism of increased mitogenic activity. The mitogenic action of insulin glargine is increased in certain cell lines with high IGFR:IR ratios [6, 7, 24–28], but other cell lines with high IGFR:IR ratios do not respond to insulin glargine treatment with increased proliferation [4, 5, 7, 24, 25, 29–34].…”

Section: Discussionmentioning

confidence: 99%

Differences in metabolic and mitogenic signalling of insulin glargine and insulin aspart B10 in rats

et al. 2013

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Aims/hypothesisIn vitro, insulin glargine (A21Gly,B31Arg,B32Arg human insulin) has an insulin receptor (IR) profile similar to that of human insulin, but a slightly higher affinity for the IGF-1 receptor (IGF1R). Insulin aspart B10 (B10Asp human insulin) (AspB10), the only insulin analogue with proven carcinogenic activity, has a greater affinity for IGF1R and IR, and a prolonged IR occupancy time. The pharmacological and signalling profile of therapeutic and suprapharmacological doses of glargine were analysed in different tissues of rats, and compared with human insulin and AspB10.MethodsMale Wistar rats were injected s.c. with human insulin or insulin analogue at doses of 1 to 200 U/kg, and the effects on blood glucose and the phosphorylation status of IR, IGF1R, Akt and extracellular signal-regulated protein kinase 1/2 in muscle, fat, liver and heart samples were investigated.ResultsGlargine, AspB10 and human insulin lowered blood glucose, with the onset of action delayed with glargine. Glargine treatment resulted in phosphorylation levels of IR and Akt that were comparable with those achieved with human insulin, although delayed in time in some tissues. AspB10 treatment resulted in at least twofold higher phosphorylation levels and significantly longer duration of IR and Akt phosphorylation in most tissues. None of the insulin treatments resulted in detectable IGF1R phosphorylation in muscle or heart tissue, whereas intravenous injection of IGF-1 increased IGF1R phosphorylation.Conclusions/interpretationThe IR signalling pattern of AspB10 in vivo is distinctly different from that of human insulin and insulin glargine, and might challenge the notion that activation of IGF1R plays a role in the observed carcinogenic effect of AspB10.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-013-2923-z) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Growth effects of insulin and insulin analogues

Cited by 36 publications

References 85 publications

Insulin and insulin-like growth factor signaling increases proliferation and hyperplasia of the ovarian surface epithelium and decreases follicular integrity through upregulation of the PI3-kinase pathway

Insulin and insulin-like growth factor signaling increases proliferation and hyperplasia of the ovarian surface epithelium and decreases follicular integrity through upregulation of the PI3-kinase pathway

Insulin and its analogues and their affinities for the IGF1 receptor

Differences in metabolic and mitogenic signalling of insulin glargine and insulin aspart B10 in rats

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