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Insulin and Brain Reward Systems
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Brian C. Liu, Qingchen Zhang, Emmanuel N. Pothos
Knockouts of IRs in various areas of the brain also result in increased depressive- and anxiety- like behavior through dopamine signaling. Neuron- specific IR knockout induced depressive- and anxiety-like behaviors in mice. Furthermore, these mice showed decreased dopamine signaling in the dorsal striatum and NAcc compared to controls. IR knockout was associated with increased levels of Monoamine Oxidase (MAO) A and B, which are important for the degradation of monoamines (78). Astrocyte-specific IR knockout also resulted in increased depressive- and anxiety-like behavior in mice. This effect was due to decreased ATP exocytosis, which in turn decreased purinergic signaling on dopaminergic neurons in the nucleus accumbens, medial prefrontal cortex, and dorsal caudate putamen (115). Similarly, the lack of IRs and the related insulin-like growth factor-1 receptor (IGF1R) in the hippocampus and amygdala resulted in increased anxiety-like behavior (116).
Diabetic Retinopathy
Published in Jahangir Moini, Matthew Adams, Anthony LoGalbo, Complications of Diabetes Mellitus, 2022
Jahangir Moini, Matthew Adams, Anthony LoGalbo
Along with the causative cellular defects, there is pathophysiological progression from severe nonproliferative to high-risk proliferative retinopathy. The microglia are activated, there are resident immune cells from the nervous system, and the pigment epithelium degenerates. Leakage of the perifoveal capillaries is believed to cause macular thickening. Histology reveals loss of retinal neurons and foveal cysts. Diabetes affects the eyes by causing chronic inflammation, diffuse vascular dilation, leakage, neovascularization, tortuosity, atrophy of the retinal neural parenchyma, macular edema, and eventually, fibrosis. There are often microaneurysms, microhemorrhages, and exudates that may be hard or described as “cotton-wool” exudates (see Figure 5.3). A maladaptive response occurs, with inflammation damaging the tissues because of edema, and invasion of circulating immune cells. In the retina, the insulin receptor is expressed in every cell, forming heterodimers with the insulin-like growth factor 1 receptor.
The Role of Growth Factor Signaling in the Development and Treatment of Necrotizing Enterocolitis
Published in David J. Hackam, Necrotizing Enterocolitis, 2021
Rita D. Shelby, Terrence M. Rager, Barrett P. Cromeens, Gail E. Besner
Lastly, studies have shown that GLP-2–mediated effects on the intestines involve an incompletely defined collection of downstream mediators, including vasoactive intestinal peptide (VIP), insulin-like growth factors 1 and 2 (IGF-1, IGF-2), keratinocyte growth factor (KGF), and NO (75, 91–95). VIP is thought to be important in affecting GLP-2–mediated effects on the intestines through the ENS (92). GLP-2 administration increases the expression and secretion of IGF-1 in murine intestinal cells, with concomitant increases in intestinal growth and crypt/villus cell proliferation (96, 97). Additionally, the insulin-like growth factor-1 receptor (IGF-1) has been implicated in GLP-2–mediated enhancement of gut barrier function (41). The relationship between GLP-2 and VIP, IGF-1, and other mediators of GLP-2 signaling are areas of ongoing research.
The Prognostic Significance of IGF-1R and the Predictive Risk Value of Circulating IGF-1 in Tunisian Patients with Laryngeal Carcinoma
Published in Cancer Investigation, 2020
Mariem Ben Elhadj, Aida Goucha, Asma Fourati, Olfa Adouni, Sawsen Dhambri, Mohamed Hsairi, Michèle-Veronique El May, Nehla Mokni Baizig
The majority of IGF-1, produced by the liver under the control of growth hormone GH (6) is present in the circulation in combination, in most of the time, with IGFBP-3 (7). To stimulate cell growth, IGF-1 binds to IGF-1R (Insulin-like growth factor 1 receptor). This transmembrane receptor with tyrosine kinase (8) is widely expressed in normal human tissues except hepatocytes and mature B-cells. It is involved in embryonic development and postnatal growth (9). Therefore, both experimental and clinical studies have demonstrated that the IGF-1R is over-expressed in tumors compared to normal tissues (10). Indeed, it’s considered as important effector of neoplastic transformation in various malignancies including non small-cell lung cancer (11), thyroid cancer (12), esophageal cancer (13) and oral cancer (1,14). Furthermore, epidemiological prospective studies have identified high plasma levels of IGF-1 as a potential risk factor for several malignancies (15,16). However, the role of IGF-1/IGF-1R in the development of larynx carcinoma is not so far fully elucidated. Moreover, the incidence of laryngeal cancer is increasing annually worldwide (17). In Tunisia, the standardized incidence rate of this neoplasia is 6.1 for men and 0.4 for women per 100,000 inhabitants (18). The major pathological type of laryngeal cancers is squamous cell carcinoma, accounting for 90–95% of the laryngeal malignant tumors (19). This disease is much more common in the male gender (19), and the most important risk factors are tobacco and alcohol (20).
Co-delivery of insulin-like growth factor 1 receptor specific siRNA and doxorubicin using chitosan-based nanoparticles enhanced anticancer efficacy in A549 lung cancer cell line
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Hajar Shali, Mahdi Shabani, Fatemeh Pourgholi, Mahsa Hajivalili, Leili Aghebati-Maleki, Farhad Jadidi-Niaragh, Behzad Baradaran, Ali Akbar Movassaghpour Akbari, Vahid Younesi, Mehdi Yousefi
The insulin-like growth factor-1 receptor (IGF-1R) is composed of two α subunits that bind to IGFs ligands and two intracellular β subunits with the tyrosine kinase activity [30]. IGF-1R signalling is a complex pathway because activated receptor requite different adapter proteins and start a wide network of signalling pathways in cells such as two major cellular cascade, the RAS/RAF/MEK/MAPK and the PI3K/AKT/mTOR that mediate multiple mechanisms and implicate in numerous features in malignancy including tumor cell growth, resistance to apoptosis, angiogenesis also degradation of the extracellular matrix, and promote tumor migration and invasion [22]. In addition, activation of IGF-1R is one of the mechanisms of resistance to anti-epidermal growth factor receptor (EGFR) therapy in several type of tumor including lung cancer [31]. Numerous studies demonstrated that role of IGF-1R signalling in initiation and progression of lung cancer and has been reported that down-regulation of IGF-IR inhibits cell proliferation and increase response to chemotherapy and radiotherapy [32–34]. These data suggested that IGF-1R is attractive therapeutic targets for NSCLC. On the basis of inhibition of IGF-1R, several therapeutic approaches including antibodies against IGF-IR, small-molecule inhibitors or siRNA used in different cancer cell line. In the current decade, because of the features of siRNA such as stability, versatility and specific gen silencing enhanced the potential for cancer treatment [35–37]. On the other hand, targeted delivery of drugs or siRNA can increase the selective death of cancer cells.
An evaluation of fulvestrant for the treatment of metastatic breast cancer
Published in Expert Opinion on Pharmacotherapy, 2019
Mohsin Soleja, Ganesh V. Raj, Nisha Unni
Insulin-like growth factor 1 receptor (IGF-1R) plays an important role in promoting cell survival and facilitating metastasis in breast cancer cell lines. IGF-1R regulates endocrine resistance through its interaction with ERα as well as an irreversible ERα-independent resistance through rapid and sustained IGF-1R/MAPK or IGF-1R/PI3K signaling (Figure 1). IGF-1R and ERα are often concomitantly expressed in hormone receptor positive breast cancers thereby leading to anti-estrogen therapy resistance including fulvestrant [60].