ARHGAP21 controls multiple cellular functions, such as migration, proliferation, differentiation and vesicles intracellular traffic. Our ARHGAP21-heterozygous animal model (Het, 50% of the protein expression) treated with the high fat diet (HFD) have higher content of triglycerides in the liver, compared to C57BL/6 animals fed on the same diet. The HFD favored the accumulation of lipids in the Het animal. The liver of our model fed with HFD is more sensitive to insulin than the control animal, which may have led to increased degradation of the proteins involved in the assembly of VLDL, such as MTP, preventing this molecule from being secreted and consequently has became the animal's liver steatotic. In addition, there is a greater gene expression of GLUT2 in het animals, this more glucose reaches the hepatocytes, this overload of glucose may be converted in lipids, and it collaborates with the steatotic state found in this animal.

Artigo 1 (Manuscrito submetido): "Cholesterol reduction ameliorates glucose-induced ca 2+ handling and insulin secretion in islets from low-density lipoprotein receptor knockout mice"……………………………………………………………………………...

No abstract

A prática do exercício físico é fortemente recomendada para indivíduos diabéticos do tipo 1 (DT-1), especialmente por melhorar o controle glicêmico desses pacientes. Entretanto, a prescrição do exercício físico para este grupo de indivíduos apresenta desafios importantes, pois estes apresentam risco aumentado de crises hipoglicêmicas. Neste sentido, os inibidores da proteína dipeptidil peptidase-IV parecem ter potencial terapêutico importante, uma vez que esta droga é capaz de aumentar a secreção de glucagon durante clamp hiperinsulinêmico-hipoglicêmico. Entretanto, o potencial desta droga em prevenir crises hipoglicêmicas, durante o exercício físico e recuperação em modelo animal de DT-1 tratado com insulina ainda não foi explorado. Assim, este projeto tem como objetivo induzir o DT-1 em camundongos C57BL-6, tratá-los com insulina e avaliar o possível efeito da administração da vildagliptina (um inibidor da dipeptidil peptidase-IV) sobre a secreção de glucagon e prevenção da hipoglicemia durante e após a prática do exercício físico. Como o esperado, os animais que receberam a administração da droga vildagliptina apresentaram índices glicêmicos maiores do que os animais DT-1 durante e após o exercício físico em relação aos animais controles, indicando que a vildagliptina apresenta potencial terapêutico importante na prevenção de hipoglicemia induzida por exercício físico associado a administração de insulina exógena.

Obesity and type 2 diabetes affects million peoples around the world, and is characterized by hyperinsulinemia state which impairs many tissues function and insulin action. The hyperinsulinemic is due to enhanced insulin secretion by pancreatic islets and a reduced liver insulin clearance and IDE expression. The Tauroursodeoxycholic acid is secreted mainly after meal ingestion and have an important function in digestion. Previous studies have been demonstrated that TUDCA improves glucose tolerance, insulin sensitivity and insulin secretion in insulin resistant models. However the effect of this bile acid on insulin clearance have not been explored yet. Here, we acessed insulin clearance and liver IDE expression in C57BL6 mice fed high fat diet (HFD) and treated with TUDCA (HFD + TUDCA). As expected the mice fed on HFD presents impaired glucose tolerance, insulin sensitivity, and increased insulinemia and c-peptide, and reduction in insulin clearance and IDE expression. The impairments of HFD upon glucose tolerance, insulin sensitivity, and insulin clearance were improved by TUDCA administration. Interestingly, the reestablishment of insulinemia in HFD + TUDCA was associated with an augmented IDE expression on liver. So, we conclude that the bile acid TUDCA, in addition to regulates insulin secretion and signaling in HFD fed mice, also recovery the plasma insulin levels probably due to an increased in IDE expression in the liver which also may contributes to the improvement of glucose homeostasis.