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  • br Materials and methods br Results br Discussion


    Materials and methods
    Discussion Plg plays important roles in various physiological processes, such as fibrinolysis, proteolysis, cell migration, differentiation, tissue remodeling, and inflammation [6], [7], [8]. We herein found that Plg deficiency enhanced insulin secretion, and was associated with improved glucose tolerance in mice (Fig 1). The incretin hormones, such as GLP-1, are major regulators of post-prandial insulin secretion, and DPP-4 cleaves the incretin hormones [4]. It has been reported that Plg can interact with DPP-4 [5]. Next, we showed that Plg deficiency was associated with lower DPP-4 activity, and elevated the levels of GLP-1 (Fig. 2). Plg can interact with various cell surface proteins, and the lysine Pomalidomide of Plg are associated with some of the interaction [9]. We showed that the blocking of lysine binding by a lysine analogue had no effect in the glucose tolerance and DPP-4 activity (Fig. 3). These data suggest that Plg regulates DPP-4 activity without accompanying lysine binding, and preserves active incretin hormones. Plg deficiency also reduces fat accumulation in mice [10]. Plg-mediated obesity and glucose metabolism may play a critical role in the progression of type 2 diabetes.
    Because of their ease of use and tolerability, dipeptidyl peptidase (DPP)-4 inhibitors are commonly prescribed to lower blood glucose in patients with type 2 diabetes, particularly as an adjunct to first-line therapy with metformin , . Unlike other agents that signal through the incretin pathway (i.e., long-acting glucagon-like peptide[GLP]-1 analogs), DPP-4 inhibitors do not require parenteral administration, and their use is associated with fewer gastrointestinal adverse effects . Unlike older antidiabetic drugs, the use of DPP-4 inhibitors is not accompanied by weight gain and carries a low risk of hypoglycemia . In contrast to sodium-glucose transporter 2 (SGLT2) inhibitors, DPP-4 inhibitors do not increase the risk of genitourinary infections or have adverse effects on lipid metabolism. Taken together, these features have contributed to the popularity of DPP-4 inhibitors among practitioners who treat patients with type 2 diabetes. However, DPP-4 inhibitors may precipitate heart failure in patients at increased cardiovascular risk or may worsen the clinical course in patients with pre-existing left ventricular dysfunction. Heart failure is the most important and preventable macrovascular complication of diabetes; diabetes and heart failure frequently coexist, and the clinical courses of the 2 disorders often progress in parallel . Given the clinical overlap between these 2 disorders, it is relevant to ask, Is worsening heart failure a class effect of DPP-4 inhibitors? Can patients with both diabetes and heart failure be treated safely with this class of drugs? In this article I describe the pathophysiological pathways that may be relevant to the use of DPP-4 inhibitors in patients with known or clinically inapparent left ventricular dysfunction, critically examine the findings of randomized clinical trials and community-based observational studies, and identify important concerns that warrant urgent attention in future research. Experimental Actions of DPP-4 Inhibitors That Are Relevant to Heart Failure DPP-4 inhibitors are incretins that lower blood glucose because of their ability to augment the release of insulin from the pancreas (1). Experimentally, potentiation of insulin signaling can cause adverse cardiac remodeling, deleterious effects on vascular structure and function, and sodium retention by the kidney 4, 5, 6. These pathophysiological responses likely explain why antidiabetic medications that enhance hyperinsulinemia or augment insulin signaling are associated with an increased risk of heart failure in clinical trials (7). The action of DPP-4 inhibitors Pomalidomide as insulin secretagogues results from their ability to potentiate of GLP-1 and glucose-dependent insulinotropic polypeptide (1). Endogenous GLP-1 is wholly responsible for the hypoglycemic actions of DPP-4 inhibitors (8). However, DPP-4 inhibitors also act to enhance the effects of many other substrates that rely on DPP-4 for their degradation, particularly stromal cell–derived factor (SDF)-1 9, 10. Many of the nonhypoglycemic actions of DPP-4 inhibitors are mediated by their effect to potentiate endogenous SDF-1. SDF-1 is a stem cell chemokine that acts to channel mesenchymal cells to sites of tissue injury, thereby promoting inflammation, regeneration, and repair 11, 12. Conventional incretins (i.e., long-acting GLP-1 analogs) do not potentiate the actions of SDF-1 (1).