GLP also showed cardioprotective effects i
GLP-1 also showed cardioprotective effects (i.e., infarct size reduction and ejection fraction improvement) in experimental models of myocardial ischemia-reperfusion injury by suppressing caspase-3 activation and preventing apoptosis of cardiomyocytes [, ]. Of note, such a cardioprotection was previously reported to be mediated by both GLP-1R-dependent and GLP-1R-independent mechanisms . More importantly, GLP-1 has been reported to improve ejection fraction of left ventricle and to prevent its ischemic dysfunction in patients with acute myocardial infarction  and coronary artery disease (CAD) , respectively. Besides its beneficial effects in CAD, GLP-1 might improve heart failure by increasing glucose uptake and, therefore, left ventricular function, as suggested by both animal  and human [, ] studies. DPP-4 inhibition resulted in similar cardioprotective effects in preclinical models [, ].
Regarding cerebrovascular function, GLP-1 attenuated cerebral oxidative stress and neuronal cell death by reducing reactive oxygen species (ROS) production and exerting anti-apoptotic effects in both non-diabetic and diabetic animals after cerebral ischemia [, , ]. In accordance, linagliptin afforded neuroprotection in a diabetic mouse model of ischemic brain damage. It is interesting to note that sulfonylurea glimepiride was not able to show similar neuroprotective effects in the same study, suggesting that neuroprotection was independent of lowering glucose levels .
The incretin system also indirectly contributes to improved macrovascular function by regulating lipid metabolism . Dyslipidemia amelioration has been associated with GLP-1 infusion in both experimental animals and humans through the down-regulation of intestinal lipid Ki16425 australia [, , ]. GLP-1 has been also reported to modulate hepatic lipid metabolism by suppressing fatty acid synthesis and promoting fatty acid oxidation [, ]. Based on these mechanisms, vildagliptin and sitagliptin have been shown to suppress postprandial elevation of triglycerides in type 2 diabetic patients, suggesting their potential role in the prevention of macrovascular complications [, ].
Furthermore, some effects of GLP-1 in the peripheral nervous system, eyes, and kidney could be clinically significant in the treatment of diabetes-related microvascular complications .
Consistent with its ability to promote neurite outgrowth of the dorsal root ganglion neurons in diabetic mice, GLP-1 might be useful for ameliorating diabetic polyneuropathy, irrespective of glycemic control . Accordingly, the vildagliptin analogue PKF275-055 partially improved the nerve conduction velocity deficit observed in diabetic rats . Moreover, vildagliptin was shown to provide protection against nerve fiber loss in diabetic animals . Taken together, these findings suggest the potential clinical significance of DPP-4is in the treatment of peripheral neuropathy.
Accruing studies on diabetes animal models have also shown beneficial effects of GLP-1 and DPP-4is on the retina [, , , ]. In particular, sitagliptin was able to decrease the nitrosative stress, IL-1beta production, and cell apoptosis in diabetic rat retinas, thus protecting the blood-retinal barrier . However, the involvement of GLP-1 in these effects needs to be confirmed.
Last but not least, the kidney function is heavily influenced by GLP-1 and DDP-4is  whose effects might be clinically meaningful in the treatment of kidney-related disorders such as diabetic nephropathy (DN), a major cause of kidney failure . Most notably, preclinical studies and meta-analyses of clinical trials have shown that DDP-4is afford direct renoprotective effects that make them potentially effective in acute and chronic renal failure .
Effects of DPP-4 inhibitors on kidney function: physiological settings