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    • Acknowledgments br Introduction Diabetes mellitus DM is a mu

    2020-02-25

    Acknowledgments
    Introduction Diabetes mellitus (DM) is a multifactorial disease [1] associated with serious comorbidities. This condition has recently reached epidemic proportions, as its occurrence has exponentially increased in the general population. Over 400 million people worldwide were estimated to have DM and total mortality increased by 32.1% from 2005 to 2015. Diabetes caused 5 million deaths in 2015, representing the seventh leading cause of death in the United States [[2], [3]]. Moreover, the risk of both microvascular and macrovascular complications has significantly increased, including diabetic kidney disease (DKD), an independent risk factor for coronary artery and peripheral vascular disease. Hyperglycemia triggers many mechanisms resulting in alteration of kidney architecture, oxidative and inflammatory stress, and eventually progressive loss of renal function [[4], [5]]. Strict glucose control through lifestyle changes (i.e., diet, physical exercise, and weight loss) is crucial for slowing DKD progression. However, most type 2 diabetic patients need also medications such as oral hypoglycemic agents and insulin to achieve sustained control of hyperglycemia [6]. Other pharmacological treatments have a positive effect on renal function, retarding the l-name to end-stage renal disease (ESRD) [7]. For instance, renin–angiotensin system (RAS) inhibitors [8] as well as the use of antioxidant agents [9] have demonstrated significant renoprotection, particularly related to their anti-proteinuric activity. Interestingly, the anti-inflammatory and hemorrheologic drug pentoxifylline may also afford renoprotective effects, even though there is still no conclusive evidence supporting its widespread use for improving renal outcomes in subjects with chronic kidney disease (CKD) of various etiology [10]. Some drugs specifically used to treat diabetes, like incretin-based therapies, represent a relatively new tool against the global epidemic of DM. Incretin-based drugs include glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) and inhibitors of dipeptidyl-peptidase-4 (DPP-4). They basically promote a significant decrease in serum glucose that is accompanied by low risk of hypoglycemia and weight loss (with GLP-1RAs) or weight neutrality (with DPP-4 inhibitors) when compared to conventional therapies (metformin monotherapy or combination therapy) [[11], [12]]. However, conflicting results have been obtained with these drugs: some clinical studies, in fact, have shown positive pleiotropic effects in retarding DKD [[13], [14], [15], [16]], whereas others pointed out the possible accumulation of these agents in patients with impaired renal function, thereby exposing them to adverse events [[17], [18], [19], [20], [21], [22]].
    Main pharmacologic features of DPP-4 inhibitors: an overview Drugs that inhibit DPP-4 activity, commonly referred to as gliptins, represent a relatively new class of non-insulin glucose-lowering agents endowed with great ability to improve glycemic control, with a favorable tolerability and safety profile [[23], [24]]. DPP-4 belongs to a family of proteolytic enzymes that are ubiquitously expressed in several tissues where they exert different functions. In particular, the DPP-4 enzyme exists in two forms, a soluble form circulating in the blood and a membrane-bound one present in several cell types [25]. In the kidney, DPP-4 is localized on glomerular visceral epithelial cells, the proximal tubule brush border and on endothelial cells [26] where it usually acts by preferentially cleaving peptide hormones containing a position two alanine or proline at the NH2-terminus [27]. The incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), are the best-studied substrates for the DPP-4 enzyme. These peptide hormones are secreted respectively by L (in the lower gut) and K cells (in the upper gut), in response to food intake. Notably, GLP-1 is mainly involved in post-prandial glucose homeostasis through the stimulation of pancreatic GLP-1 receptor (GLP-1R), thus facilitating insulin secretion from β-cells and inhibiting glucagon secretion from α-cells in a glucose-dependent manner [[28], [29]]. Upon GLP-1 secretion, DPP-4 rapidly breaks down this hormone, inactivating it [30]. Furthermore, the incretin hormones are quickly removed from the bloodstream by the circulating DPP-4 and renal filtration [[31], [32]]. Taking into account the pancreatic effects of GLP-1 and its fast degradation, DPP-4 represents a relevant pharmacological target to manage diabetes. In this setting, DPP-4 inhibitors (DPP-4is) prevent GLP-1 inactivation resulting in the potentiation of pancreatic GLP-1R signaling, which enhances glucose consumption and reduces hepatic glucose production [[28], [29]].