No abstract

Type 2 diabetes mellitus is characterized by insulin resistance and loss of pancreatic b-cell mass. b-cells are located in the pancreatic islets and secrete insulin. Though many therapies exist that address insulin resistance and to augment b-cell insulin secretion, there is a critical need to find therapies to preserve b-cell mass in order to decrease the incidence and severity of diabetes. In non-diabetic obesity, an early adaptive response to insulin resistance is increased b-cell proliferation. This compensatory mechanism leads to increased b-cell mass and increased insulin secretion from b-cells. This increase in b-cell mass is seen in as little as 4 days of high fat diet (HFD) feeding in murine models. A promising therapeutic for the preservation of b-cell mass is glucagon-like peptide-1 receptor (Glp-1r) agonists. The ability of GLP-1 to stimulate b-cell proliferation and inhibit apoptosis is largely based on studies using pharmacologic treatment, but the importance of GLP-1 in b-cell mass regulation in normal physiology or pathophysiology has not been well studied. Notably, GLP-1 is secreted from alpha cells in the local islet environment and this paracrine signaling pathway is important for islet function. The goal of this work is to investigate the contribution of b-cell Glp-1r signaling to b-cell mass regulation in the metabolic stress condition of a one-week HFD. We hypothesize that b-cell Glp-1r signaling is necessary for the compensatory mechanisms needed to maintain glucose homeostasis during metabolic stress conditions and that lack of b-cell Glp-1r will lead to decreased proliferation of b-cells. Understanding the role of β-cell Glp-1r signaling in adaptive b-cell mass expansion will allow for development of new strategies to augment β-cell mass in type 2 diabetes. We used a newly generated murine model with a b-cell specific knockout of Glp-1r, where the Ins1-Cre knock-in transgene drives recombination in b-cells. Glp-1r fl/fl mice (WT) and Glp-1r fl/fl – Ins1Cre mice (KO) were fed a HFD for one week. There was a trend toward elevated fasting (171+/-29 mg/dl vs 205+/-36 mg/dl, p=0.0475, n=9) and non-fasting blood glucose (195+/-24 mg/dl vs 216+/-40 mg/dl, p=0.0537, n=18) and impaired glucose tolerance in the KO mice. Notably, we found that insulin secretion in response to intraperitoneal glucose is impaired in KO mice. KO mice have a blunted proliferation response to a 1-week HFD stress, as measured by Ki67 mRNA levels (1.5-fold induction of Ki67 in WT vs. 0.6-fold induction in KO, p=0.0167, n=8-10). b-cell proliferation will also be measured by immunofluorescent image analysis of whole pancreas sections. These data suggest there is a critical role for b-cell Glp-1r signaling in the early proliferative response of b-cells in response to metabolic stress. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Agradeço à Beatriz, minha esposa, pela compreensão e apoio em todos os momentos. Ao meu filho Lorenzo por sua maravilhosa presença e seu grandioso sorriso, que me cativa todo o tempo. Aos meus pais, Arnaldo e Neiva, às minhas irmãs Angélica e Caroline, ao meu cunhado André Luiz, ao meu sogro Luiz Afonso. Agradecimentos a toda família.Agradeço ao meu professor Paulo pela atenção dispensada e conselhos efetuados. E, sobretudo, agradeço àquela Força que por vezes não ouso nominar. EPÍGRAFE "Não sabendo que era impossível, foi lá e fez" Jean Cocteau RESUMOCom o intuito de investigar a prática e a pesquisa científica em biologia evolutiva, esta dissertação faz uso da filosofia da ciência de Imre Lakatos, aplicada à pesquisa de Mary Schweitzer e equipe, com base em dois artigos sobre a descoberta de um T-Rex com tecidos moles e, posteriormente, sobre a detecção de colágeno.Deste modo, este trabalho visa ressaltar as partes do programa de pesquisa no qual Mary Schweitzer trabalha, bem como a possível aplicabilidade desta filosofia geral da ciência na prática científica em biologia evolutiva.Palavras-chave: Filosofia da ciência. Lakatos. Prática científica. Teoria da Evolução.