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Jaime Guevara-Aguirre Colegio de Ciencias de la Salud, Universidad San Francisco de Quito, Diego de Robles s/n y Pampite, Cumbayá, Quito, Ecuador
Instituto de Endocrinología IEMYR, Quito, Ecuador
Maastricht University, Maastricht, The Netherlands

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Gabriela Peña Colegio de Ciencias de la Salud, Universidad San Francisco de Quito, Diego de Robles s/n y Pampite, Cumbayá, Quito, Ecuador

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Gabriel Pazmiño Colegio de Ciencias de la Salud, Universidad San Francisco de Quito, Diego de Robles s/n y Pampite, Cumbayá, Quito, Ecuador

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William Acosta Colegio de Ciencias de la Salud, Universidad San Francisco de Quito, Diego de Robles s/n y Pampite, Cumbayá, Quito, Ecuador

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Jannette Saavedra Instituto de Endocrinología IEMYR, Quito, Ecuador

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Daniela Lescano Colegio de Ciencias de la Salud, Universidad San Francisco de Quito, Diego de Robles s/n y Pampite, Cumbayá, Quito, Ecuador

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Alexandra Guevara Instituto de Endocrinología IEMYR, Quito, Ecuador

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Antonio W D Gavilanes Maastricht University, Maastricht, The Netherlands

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Meta-analyses from 2018–2022 have shown that obesity increases the risk of various cancers such as acute myeloid lymphoma, chronic myeloid lymphoma, diffuse beta cell lymphoma, Hodgkin's lymphoma, leukemia, multiple myeloma, non-Hodgkin's lymphoma, bladder, breast, cholangiocarcinoma, colorectal, ovarian, esophageal, kidney, liver, prostate, thyroid, and uterus. Contextually, obesity, and its comorbidities, is the largest, most lethal pandemics in the history of mankind; hence, identification of underlying mechanisms is needed to adequately address this global health threat. Herein, we present the metabolic and hormonal mechanisms linked to obesity that might etiologically contribute to neoplasia, including hyperinsulinemia and putative places in the insulin-signaling pathway. Excess insulin, acting as a growth factor, might contribute to tumorigenesis, while abundant ATP and GDP supply the additional energy needed for proliferation of rapidly dividing cells. Our observations in the Ecuadorian cohort of subjects with Laron syndrome (ELS) prove that obesity does not always associate with increased cancer risk. Indeed, despite excess body fat from birth to death, these individuals display a diminished incidence of cancer when compared to their age- and sex-matched relatives. Furthermore, in cell cultures exposed to potent oxidizing agents, addition of ELS serum induces less DNA damage as well as increased apoptosis. ELS individuals have absent growth hormone (GH) counter-regulatory effects in carbohydrate metabolism due to a defective GH receptor. The corresponding biochemical phenotype includes extremely low basal serum concentrations of insulin and insulin-like growth factor-I, lower basal glucose and triglyceride (TG) levels, and diminished glucose, TG, and insulin responses to orally administered glucose or to a mixed meal.

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Jaime Guevara-Aguirre Colegio de Ciencias de la Salud, Universidad San Francisco de Quito, Diego de Robles s/n y Pampite, Cumbayá, Quito, Ecuador
Instituto de Endocrinología IEMYR, Quito, Ecuador
Maastricht University, Maastricht, The Netherlands

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Gabriela Peña Colegio de Ciencias de la Salud, Universidad San Francisco de Quito, Diego de Robles s/n y Pampite, Cumbayá, Quito, Ecuador

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William Acosta Colegio de Ciencias de la Salud, Universidad San Francisco de Quito, Diego de Robles s/n y Pampite, Cumbayá, Quito, Ecuador

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Gabriel Pazmiño Colegio de Ciencias de la Salud, Universidad San Francisco de Quito, Diego de Robles s/n y Pampite, Cumbayá, Quito, Ecuador

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Jannette Saavedra Instituto de Endocrinología IEMYR, Quito, Ecuador

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Lina Soto Colegio de Ciencias de la Salud, Universidad San Francisco de Quito, Diego de Robles s/n y Pampite, Cumbayá, Quito, Ecuador

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Daniela Lescano Colegio de Ciencias de la Salud, Universidad San Francisco de Quito, Diego de Robles s/n y Pampite, Cumbayá, Quito, Ecuador

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Alexandra Guevara Instituto de Endocrinología IEMYR, Quito, Ecuador

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Antonio W D Gavilanes Maastricht University, Maastricht, The Netherlands

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The relationship between growth hormone (GH) excess and cancer is a controversial matter. Until 2016, most studies in patients with acromegaly found links with colon and thyroid neoplasms. However, recent studies found increased risks in gastric, breast, and urinary tract cancer also. Concordantly, clinical situations where GH and insulin-like growth facto-I deficits exist are indeed associated with diminished malignancy incidence. In line with these observations, gain-of-function mutations of various enzymes belonging to the GH and IGF-I signaling pathways have been associated with increased carcinogenesis; similarly, loss-of-function mutations of other enzymes that usually work as tumor repressors are also associated with augmented cancer risk. In a study performed in Ecuador, it was demonstrated that subjects in the Ecuadorian cohort with Laron syndrome (ELS), who have a mutant GH receptor and greatly diminished GH and IGF-I signaling, display diminished incidence of cancer. Along with absent action of GH and IGF-I, ELS individuals also have low serum insulin levels and decreased insulin resistance. Furthermore, hyperglycemia and hyperinsulinemia are indispensable for fast cell mitosis, including that of those cells present in the benign and malignant neoplasms. Notably, and despite their obesity, subjects with the ELS display normoglycemia and hypo-insulinemia, along with diminished incidence of malignancies. We believe that the dual low-IGF-I/low insulin serum levels are responsible for the cancer protection, especially considering that the insulin/INSR signaling is a central site for energy generation in the form of ATP and GDP, which are indispensable for all and every GH/IGF-I physiologic as well as pathologic events.

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