This study was designed to investigate the effect of eight-week HIIT on adiponectin signaling and AD risk factors in the hippocampus of male rats with T2D. Our results showed that diabetes reduced both insulin and adiponectin levels in serum and hippocampus. Diabetes also reduced the expression of adiponectin and insulin receptors and AMPK and increased dephosphorylated GSK3-β and Tau in the hippocampus. HIIT recovered these impairments fully or partially. HOMA-IR, HOMA-β, and QUICKI (i.e. indices of insulin resistance, β cells function, and insulin sensitivity, respectively) were also improved by HIIT. In line with our results, Ghiasi et al.  reported that while HOMA-IR increases and QUICKI and HOMA-β are decrease in diabetes, HIIT returned these indices to the normal ranges.
It has been suggested that diabetes-induced peripheral IR could finally lead to central IR. This can explain the decrease in hippocampal insulin and insulin receptor expression in the T2D group, consistent with Biessels et al. results .
One study suggested that hypoadiponectinemia is associated with a decrease in hippocampus volume in patients with T2D  and adiponectin levels are critical for brain function. Pousti et al.  revealed that adiponectin modulates synaptic plasticity in the hippocampal dentate gyrus. Furthermore, Weisz et al.  demonstrated that adiponectin signaling could regulate hippocampal synaptic transmission. The recovery of adiponectin level and its receptors in hippocampus of diabetic rats through exercise, reported in the present study, shows that HIIT may be used as a non-pharmacological strategy for prevention and treatment of hippocampus function impairments induced by diabetes/AD. At the behavioral level, diabetes can adversely affect cognitive-related function such as the results of Morris water maze  and adiponectin improved animal performance in this test [36, 37]. Our results also showed a negative effect of diabetes on adiponectin levels and its receptors in the hippocampus, which are in agreement with other studies [38, 39].
In line with our results, many studies have shown that exercise can improve HOMA indices and IR [40, 41]. In addition, it has been suggested that HIIT can improve insulin sensitivity and increase insulin secretion . Our observations also confirmed the positive effects of HIIT on insulin sensitivity and insulin secretion. Hemmatinafar et al.  reported that HIIT is a time-efficient method for increasing adiponectin levels and reducing body fat considering the point that exercise intensity is the vital variable in affecting adiponectin. It means that the more exercise intensity the more increase in adiponectin. Added to this, the interval nature of HIIT allows to repeat several bouts of high intensity exercises, reinforcing the HIIT associate advantages .
In addition, we saw increased Tau levels in the hippocampus in T2D which is in line with Hobday et al.  results. AMPK/GSK-3β pathway dysfunction is considered as the main reason for increased Tau accumulation because of increased GSK-3β activity which finally leads to its hyper-phosphorylation . Adiponectin could also stimulates AMPK in the hypothalamus and increases food intake . This may justify the weight loss we saw in diabetic animals.
Our results also showed that the hippocampus level of adiponectin, adiponectin receptors and AMPK are reduced in diabetic rats but HIIT seems to recover these changes. In peripheral tissue, adiponectin activates AMPK through AdipoR1. Furthermore, AMPK promotes Akt phosphorylation and GSK-3β inhibition, both of which increase insulin sensitivity. Activating this signaling pathway also suppresses apoptosis, oxidative stress, and neuro inflammation and it could reduce neurodegeneration. It has been shown that adiponectin could improve memory and synaptic plasticity in a rat model of dementia, and AMPK is essential for the memory-improving effect of adiponectin . Barone et al.  showed that the interplay between oxidative stress, brain IR and AMPK dysfunction contribute to neurodegeneration in T2D and AD. They reported a decrease in AMPK in the hippocampus of diabetic patients and consider decrease adiponectin, increase oxidative stress and inflammation, and increase GSK3B activity as the main players in this scenario . Many studies [50, 51] have shown that HIIT can increase AMPK levels and expression in the skeletal muscle. Exercise has long been known to activate AMPK/Sirtuin1 (AMPK/SIRT1) pathway and enhance brain-derived neurotrophic factor (BDNF) production. The activation of AMPK/SIRT1 and BDNF play an important role in exercise-related mitigation of dementia pathology. AMPK/SIRT1 and BDNF can directly affect intracellular Aβ production, Tau phosphorylation, and neurogenesis via regulating α-, β-,γ-secretases, and GSK3 . Activated GSK-3, phosphorylates and thereby inactivates glycogen synthase, an enzyme that converts glucose to glycogen for storage  (Fig. 11).
Insulin activates AKT/protein kinase B through a well-defined mechanism mediated by the IRS1/PI3K pathway. This leads to the phosphorylation of GSK3B at serin9 residual, resulting in its inactivation . Our results showed increased expression of GSK3B in the hippocampus following T2D. Adiponectin can modulates the GSK3B signaling pathway  and evidence supports GSK3's role in producing some of AD's characteristic hallmarks, such as extracellular accumulation of amyloid-β protein (Aβ) and intra neuronal neurofibrillary tangles composed of hyper-phosphorylated tau and inflammatory markers. These effects contribute to synaptic and neuronal loss and memory decline . GSK3β was recognized as a primary kinase involved in tau phosphorylation, as was apparent from the first study termed tau protein kinase-I. Thus, GSK3β has been identified as one of the major enzymes mediating Tau hyper-phosphorylation at the residues implicated in neurodegenerative Tauopathies, including AD . Our results, showed its increased expression in the hippocampus following T2D. Thota et al.  results are consistent with our data. The recovery of adiponectin levels and reduction of GSK3B expression towards normal by HIIT in diabetic rats, imply that this type of exercise would benefit patients with diabetes to prevent the progression of their memory loss during the course of disease.