Deficient hippocampal insulin signaling and augmented Tau phosphorylation is related to obesity- and age-induced peripheral insulin resistance : a study in Zucker rats

BACKGROUND: Insulin signaling and Tau protein phosphorylation in the hippocampi of young and old obese Zucker fa/fa rats and their lean controls were assessed to determine whether obesity-induced peripheral insulin resistance and aging are risk factors for central insulin resistance and whether central insulin resistance is related to the pathologic phosphorylation of the Tau protein. RESULTS: Aging and obesity significantly attenuated the phosphorylation of the insulin cascade kinases Akt (protein kinase B, PKB) and GSK-3β (glycogen synthase kinase 3β) in the hippocampi of the fa/fa rats. Furthermore, the hyperphosphorylation of Tau Ser396 alone and both Tau Ser396 and Thr231 was significantly augmented by aging and obesity, respectively, in the hippocampi of these rats. CONCLUSIONS: Both age-induced and obesity-induced peripheral insulin resistance are associated with central insulin resistance that is linked to hyperTau phosphorylation. Peripheral hyperinsulinemia, rather than hyperglycemia, appears to promote central insulin resistance and the Tau pathology in fa/fa rats

Metabolomics Based on MS in Mice with Diet-Induced Obesity and Type 2 Diabetes Mellitus: the Effect of Vildagliptin, Metformin, and Their Combination

Type 2 diabetes mellitus (T2DM) is a major epidemiological problem. Metformin and vildagliptin are well-established antidiabetic drugs. The aim of the study was to evaluate the changes of plasma metabolic profile induced by a high-fat diet (HFD) and subsequent oral administration of metformin, vildagliptin, and their combination in a mouse model of diet-induced obesity (DIO)/T2DM analyzed using quadrupole-time-of-flight mass spectrometry (qTOF-MS). Metformin treatment increased the levels of butyrylcarnitine and acylcarnitine C18:1 concentrations and decreased the levels of isoleucine concentrations compared to untreated HFD mice. Vildagliptin treatment increased levels of butyrylcarnitine and acetylcarnitine. In summary, our metabolomics study revealed multiple differences between obese diabetic HFD mice and lean standard chow diet (SCD) mice, which were partially modifiable by subsequent metformin and vildagliptin treatment