*5.4. Adiponectin and Type 2 Diabetes Medications*

Several studies have suggested that AD and T2DM are related to each other; thus, T2DM drugs and their potential to be used as AD treatment are drawing attention [131,132]. There are several types of type 2 diabetes drugs, such as biguanide derivatives (metformin), PPARγ agonists (thiazolidinedione [TZD] derivatives), glucagon-like peptide-1 receptor (GLP-1R) agonists, dipeptidyl peptidases 4 (DPP-4) inhibitors, sodium-glucose transport protein 2 inhibitors, and second-generation sulfonylureas [133]. In addition to these drugs' ability to improve cognitive function, some of these drugs are capable of increasing adiponectin levels.

Metformin, the drug used as first-line pharmacologic therapy in T2DM, has been shown to attenuate AD-like pathology in both in-vitro and in-vivo studies [134–136]. An improvement in cognitive function has been observed in many studies on mild cognitive function and dementia patients [60,137,138]. Many studies have shown that metformin increases serum adiponectin levels in various conditions [139–141]. Furthermore, like adiponectin, metformin plays a neuroprotective role by activating AMPK signaling [142,143].

TZD derivatives, including rosiglitazone and pioglitazone, act as PPARγ agonists and are used for T2DM treatment because of their insulin sensitization activity [144,145]. They have also been researched as alternative AD treatments [146,147]. Increased adiponectin by TZD might play a key role in the insulin sensitization activity induced by TZD [132,148]. Thus, TZD's beneficial effect on AD might be related to the increased adiponectin levels.

An insulin-releasing hormone in hyperglycemic conditions, GLP-1, has been found to have a neuroprotective effect [149–151]. GLP-1 receptors are responsible for controlling food intake and body weight and are widely distributed in the brain and special neurons (pyramidal neurons of the hippocampus and neocortex), which means that it plays an important role in neural function and synaptic transmission [149,151–154]. In an AD mice model, Val(8)GLP-1, liraglutide, and exidin-4 (GLP-1 analogs, well known for the upregulation of adiponectin) treatments rescued synaptic plasticity by preventing synaptic degradation, which is also correlated with the increased learning ability of new spatial tasks [155–158]. Several studies have also shown the beneficiary effect of GLP-1 analogs for AD [159–161].

Inhibitors of DPP-4 also increase GLP-1 signaling activation by inhibiting the degradation of GLP-1 [162]. Therefore, they potentially act on AD, like other GLP-1 analogs [163]. They also lead to increased adiponectin and are thought to be alternative medications for AD [164–167]. Accordingly, the GLP-1 functional facilitator, GLP-1 analogs, and DPP-4 inhibitors might be good candidates for AD treatment because of their ability to increase adiponectin.
