Characterization of bone pathologies in the ins2+/akita mouse, a new model for diabetes insulindependent: contribution for a better understanding of the disease in humans

• Autor(a) principal: Carvalho, Filipe Ricardo Pires de
• Data de Publicação: 2016
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.1/8680
• topic: Bone; Cartilage; Diabetes; Insulin; Leptin

In the past 30 years developed and developing countries faced significant lifestyle changes that made the incidence of diabetes mellitus to reach pandemic proportion worldwide. This increase, seen in both types of the disease, made diabetes mellitus one of the leading causes of morbidity and mortality of our times. Bone is one t of several organs that are affected by diabetes mellitus, being morbidity caused by bone fractures highly correlated to diabetic bone. Alterations in the constituents of bone, microarchitecture changes and bone loss have been pointed as the main reasons for its fragility. This work aimed to contribute to identify the molecular players or the functional changes affecting bone and caused by diabetes mellitus. In chapter 2, using as animal model of type 1 diabetes mellitus the Ins2+/akita mouse, we identified bone growth retardation related to growth plate impairment. These changes were associated to reduced expression of Igf1 and increased expression of cartilage degradation enzymes like Adams-5. We also identified severe microarchitecture changes caused by reduced bone formation and resorption that could be explained by leptin deficiency and/or decreased insulin signaling. In chapter 3, we concluded that paricalcitol (vitamin D analog) and cinacalcet (calcimimetic), two drugs used for the treatment of secondary hyperthyroidism, have beneficial effects in fin regeneration and mineralization in a zebrafish model of diabetes. These results could be explained by the downregulation of pthr suggesting reduced signaling of parathyroid hormone, that is a potent activator of bone remodeling, and increased expression of runx2, indicating increased osteoblast differentiation. Increased expression of the two zebrafish insulin genes, insa and insb, could be observed, suggesting that both drugs promote an increase in insulin signaling. In chapter 4, we suggest that in humans, the insulin paralog gene, INS-IGF2, does not have a redundant function with the insulin gene, in contrast with what is seen in mice and probably in zebrafish. We could also conclude that extrapancreatic expression of insulin is present in human, mouse and zebrafish. In humans this expression results mainly from expression of the ancestral gene while in mice and zebrafish it is due to expression of the insulin paralogues.