Background and objectives Evidence suggests that circulating IGF-I levels increase mammographic density (a breast cancer risk factor) and breast cancer risk in premenopausal women. The objective of this thesis was to examine the association of genetic variation at the IGF1 gene with IGF-I concentration, mammographic density, breast cancer risk, and related anthropometric measures in premenopausal women. Methods Three IGF1 CA repeat polymorphisms (at the 5′ and 3′ ends, and in intron 2) were genotyped. A cross-sectional design was used to investigate their associations with IGF-I levels, mammographic density, BMI, weight, and height. Families from registries in Ontario and Australia were used to investigate associations with breast cancer risk and also BMI, weight and height. Results In the cross-sectional study, greater number of copies of the 5′ 19 allele were associated with lower circulating IGF-I levels. Greater number of 3′ 185 alleles were associated with greater percentage breast density, smaller amount of non-dense tissue, and lower BMI. Including BMI in regression models removed the association of the 3′ 185 allele with percentage breast density. In the family based study, nominally significant associations (5′ 21 allele, intron 2 212 allele, intron 2 216 allele) with breast cancer risk were observed, but significance was lost after multiple comparison adjustment. There was a stronger association between the intron 2 216 allele and risk under a recessive model, and 5′ allele groupings of length 18 to 20 and 20 or more repeats produced significant positive and negative associations respectively. These associations were not strongly supported in analyses stratified by registry. Results from the family based study did not support an association between genetic variation at IGF1 with BMI, weight or height. Conclusions No specific IGF1 variant influenced each of circulating IGF-I levels, mammographic density, and breast cancer risk. The failure to replicate the association of the 3′ 185 allele with BMI in the family based study suggests that the association of the 3′ 185 allele with percentage breast density is spurious, since this association was mediated through the relationship with BMI (suggesting IGF-I action on body fat). Evidence for an association between IGF1 and breast cancer risk was limited.

The developing chick retina is an extrapituitary site of growth hormone (GH) synthesis and action. GH, GH receptor (GHR) and their mRNAs are present in the neural retina when the neural cells are undergoing proliferation and differentiation during early embryogenesis. It is thus likely that GH acts as an autocrine or paracrine in this location. The present study shows that intra-vitreal injection of a chick GH (cGH) small interfering RNA (siRNA) into the eyes of early embryos [embryonic day (ED) 4] suppresses GH expression in the neural retina and increases the incidence of spontaneous retinal cell death. Our current work also demonstrates a reduction of local IGF-1 expression after retinal GH gene knockdown, suggesting that GH action in retinal cells is regulated through IGF-1 signalling. These results demonstrate that retinal GH is an autocrine/paracrine hormone that acts as a neuroprotective factor in the retina of chick embryos.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2005. / Härtill 7 uppsatser.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20798号 / 医博第4298号 / 新制||医||1025(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 辻川 明孝, 教授 清水 章, 教授 戸口田 淳也 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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京都大学 / 新制・課程博士 / 博士(医学) / 甲第24091号 / 医博第4867号 / 新制||医||1059(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 林 康紀, 教授 髙橋 良輔, 教授 渡邉 大 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

The pathological hallmark of Alzheimer's disease (AD) is the accumulation of amyloid β (Aβ) plaques, present in the majority of clinically diagnosed cases. Treatment options, such as the FDA-approved Lecanemab, target early-stage AD by promoting Aβ clearance via microglial (MG) phagocytosis, but no effective therapy exists for late-stage AD. Hyperhomocysteinemia (HHcy), prevalent in the elderly, is an established risk factor for AD, with previous studies linking it to various pathologies but not to Aβ dynamics or MG function. This study examined the hypothesis that HHcy-induced epigenetic changes impair MG clearance of Aβ, potentially exacerbating AD. It also investigated the role of IGF-1 (Insulin-like growth factor 1) in MG phagocytosis, considering the established influence of hypomethylation on both IGF-1 expression and AD progression. In this study, we probed the interplay among HHcy, Aβ accumulation, and MG phagocytosis in AD using Cbs-/- mice as a model. Our approach delineated an HHcy-induced hypomethylation status in both plasma and brain cortex. HHcy increased Aβ deposition without a corresponding rise in Aβ production in the 5xFAD x Cbs-/- mouse brains. This was characterized by elevated levels of soluble Aβ40 and insoluble Aβ42, alongside unaltered the β-secretase and s-APPβ expression. Single-nucleus multiomic profiling unveiled five distinct MG subclusters (MG_0 to MG_4) in the hippocampi of both Cbs-/- and control mice. MG_0, specific to control mice, involved activated MG phagocytosis. Subclusters MG_2 and MG_3, predominantly identified in Cbs-/- mice, exhibited decreased migration and phagocytosis. Subcluster MG_4, unique to Cbs-/- mice, displayed impaired cytoskeleton organization and dendritic development. HHcy suppressed MG Aβ phagocytosis activity in the mouse MG cell line SIM-A9 (ex vivo phagocytosis), freshly isolated MG from HHcy mice with Cbs-/- or a high-methionine (HM) diet (ex vivo phagocytosis), and in 3xTg-AD mice with an HM diet (in vivo phagocytosis). Through meta-analysis over transcriptomes of Cbs-/- mouse MG, human and mouse AD MG, Aβ phagocytosis model, and human AD methylome, we identified 5 differentially expressed genes (DEGs) (Flt1, Calponin 3, Igf1, Cacna2d4, and Celsr) in HHcy-suppressed phagocytic AD MG. All of them have been reported to regulate the migration and Aβ phagocytosis of MG and macrophages (MΦ). IGF-1 expression changes are the most significant between liver-specific Ahcy-/- (model of hypomethylation) and HHcy-altered phagocytic AD MG. In both AD and non-AD mice, the HHcy group exhibited significantly lower IGF-1 levels in the brain, plasma, and MG than the non-HHcy group. Additionally, a negative correlation was observed between Igf1 levels and MG Aβ phagocytosis. Our study underscored the critical role of HHcy in AD progression, particularly through its detrimental impact on MG Aβ phagocytosis and altered MG subclusters, leading to reduced Aβ clearance. We identified key genes, such as IGF-1, essential for MG function. These findings indicated that HHcy may exacerbate AD and potentially diminish the efficacy of treatments like Lecanemab, highlighting the importance of HHcy-targeted strategies in AD therapy. / Biomedical Sciences

Os hormônios do eixo GH-sistema IGF são conhecidos pelo seu papel anabólico e melhora nos ganhos de força. Alguns estudos sugerem que suplementação com o composto Zinco, Magnésio e Piridoxina (\"ZMA\") poderia aumentar os níveis dos hormônios do eixo GH/IGF e na testosterona em jovens. Este hipotético aumento, poderia causar alterações significativas na composição corporal. O ZMA é um suplemento muito popular, facilmente encontrado em lojas especializadas, e tem como premissa causar este aumento nos níveis dos hormônios do eixo GH/IGF, além da testosterona. Contudo, os estudos são divergentes acerca de sua eficácia. Assim sendo, o presente projeto objetivou verificar os efeitos do treinamento físico associado à suplementação de 8 semanas do composto ZMA sobre as concentrações de IGF-1, IGFBP-3 e testosterona em jovens do sexo masculino. Participaram do estudo 18 sujeitos saudáveis, do sexo masculino, atletas amadores de futebol americano. Eles foram divididos em dois grupos: ZMA (grupo suplementado) e placebo. Os resultados mostraram elevação das concentrações de IGF-1, IGFBP-3 e de Testosterona entre a avaliação inicial e a avaliação após 8 semanas. Essa elevação foi semelhante nos dois grupos, não havendo diferenças entre o grupo suplementado e o grupo placebo. Nos dois grupos foi observado de forma semelhante aumento nos parâmetros antropométricos que atestam ganho de massa magra, acompanhado de diminuição naqueles que indicam redução da gordura corporal. Assim sendo, os resultados sugerem que em indivíduos com dieta adequada, doses extras dos micronutrientes presentes no ZMA não trazem quaisquer benefícios adicionais, seja na composição corporal ou nos níveis hormonais. / The GH-IGF system has several anabolic effects and plays an important role in strength gain. Some studies suggest that Zinc, Magnesium and Pyridoxine (\"ZMA\") supplementation could increase GH/IGF and testosterone levels in young subjects. This hypothetical increase could lead to significant changes in body composition. ZMA is a very popular supplement, easily found in specialty stores, and it is presumed to cause increasing in GH/IGF and testosterone levels. However, studies are divergent regarding its efficacy. Therefore, the present study aimed to verify the effects of physical training associated with 8-week ZMA supplementation on the IGF-1, IGFBP-3 and testosterone levels in young males. Eighteen healthy male amateur football players were included in the study. They were divided into two groups: ZMA (supplemented group) and placebo. IGF-1, IGFBP-3 and testosterone concentrations were higher in the final evaluation (8 weeks) than at the beginning of the study. The increase was similar in the supplemented and in the placebo group. Both groups showed similar changes in anthropometric parameters attesting for lean mass gain and decrease in body fat mass. The findings suggest that extra doses of the micronutrients present in the ZMA do not bring any additional benefits, either in the body composition or in the hormonal levels in subjects under adequate diet.