DPP-4 Inhibitors as Therapeutic Modulators of Immune Cell Function and Associated Cardiovascular and Renal Insulin Resistance in Obesity and Diabetes

Abstract

The prevalence of obesity and diabetes continues to rise in the United States and worldwide. These findings parallel the expansion of childhood obesity and diabetes. Obesity is a central component of the cardiorenal metabolic syndrome (CRS) which increases the risk for cardiovascular disease (CVD) and chronic kidney disease (CKD). The hallmark of obesity, CRS, and early type 2 diabetes is insulin resistance, a result of decreased insulin metabolic signaling due, in part, to enhanced serine phosphorylation and/or proteasome-mediated degradation of the insulin receptor substrate. Cardiovascular and renal insulin resistance significantly contributes to endothelial dysfunction, impaired cardiac diastolic and vascular relaxation, glomerular injury, and tubular dysfunction. In this context, multiple factors including oxidative stress, increased inflammation, and inappropriate activation of the renin-angiotensin-aldosterone and the sympathetic nervous system contribute to overweight- and obesity-induced systemic and tissue insulin resistance. One common link between obesity and the development of insulin resistance appears to be a low-grade inflammatory response resulting from dysfunctional innate and adaptive immunity. In this regard, there has been recent work on the role of dipeptidyl peptidase-4 (DPP-4) in modulating innate and adaptive immunity. The direct effects of DPP-4 on immune cells and the indirect effects through GLP-1-dependent and -independent pathways suggest effects of DPP-4 inhibition may have beneficial effects beyond glycemic control in improving CVD and renal outcomes. Accordingly, this review addresses new insights into the role of DPP-4 in immune modulation and the potential beneficial effects of DPP-4 inhibitors in insulin resistance and associated CVD and CKD prevention.

Effect of sitagliptin on epicardial fat thickness in subjects with type 2 diabetes and obesity: a pilot study

“…Interestingly, a decrease in inflammatory macrophage accumulation has been observed in adipose tissue and atherosclerotic lesions following treatment with DPP-4 inhibitors [38,39]. It is thus possible to suggest that sitagliptin might exert an anti-inflammatory effect on EAT as recently found with other anti-inflammatory drugs [40,41].…”

Effect of Sleeve Gastrectomy Plus Side-to-Side Jejunoileal Anastomosis for Type 2 Diabetes Control in an Obese Rat Model

“…The hindgut hypothesis states that food will stimulate L cells in the ileum to secrete GLP-1, which can improve glucose homeostasis [7]. The role of GLP-1 in improving insulin sensitivity has been confirmed [28], and GLP-1 analogs have been proposed for patients with type 2 diabetes [29]. Previous studies have also shown that SG and RYGB procedures increase GLP-1 secretion [30].…”

Pleiotropic effects of the dipeptidylpeptidase-4 inhibitors on the cardiovascular system

“…However, it is also expressed in other immune cells and nonimmune cells/tissues (5,202). Tissues/ organs expressing DPP-4 include blood vessels, adipose tissue, kidney, liver, pancreas, lymph nodes, spleen, bone, brain, lung, prostate, thymus, and uterus (109,202).…”

“…Vascular dysfunction is the critical factor in progression to CVD and CKD and the associated vasculopathies that constitute early derangements mediating progression to end organ damage (5,8,137,138). Vascular dysfunction is independently associated with CVD complications, including stroke, atherosclerosis, and heart and kidney disease (8,135).…”

“…In the setting of obesity/T2DM, endothelial dysfunction and arterial stiffness may result from multiple factors including insulin resistance, oxidative stress, dyslipidemia, adipose tissue dysfunction (e.g., visceral and perivascular inflammation), and dysfunctional immunity (Fig. 3) (5,27,189). Endothelial dysfunction, altered vascular tone, extracellular matrix remodeling, and adventitial dysfunction contribute to arterial stiffness (6,110); however, arterial stiffness also contributes to endothelial dysfunction (6).…”