Serum Levels of Soluble CD26/Dipeptidyl Peptidase-IV in Type 2 Diabetes Mellitus and Its Association with Metabolic Syndrome and Therapy with Antidiabetic Agents in Malaysian Subjects

Abstract

BackgroundA soluble form of CD26/dipeptidyl peptidase-IV (sCD26/DPP-IV) induces DPP-IV enzymatic activity that degrades incretin. We investigated fasting serum levels of sCD26/DPP-IV and active glucagon-like peptide-1 (GLP-1) in Malaysian patients with type 2 diabetes mellitus (T2DM) with and without metabolic syndrome (MetS), as well as the associations between sCD26/DPP-IV levels, MetS, and antidiabetic therapy.MethodsWe assessed sCD26/DPP-IV levels, active GLP-1 levels, body mass index (BMI), glucose, insulin, A1c, glucose homeostasis indices, and lipid profiles in 549 Malaysian subjects (including 257 T2DM patients with MetS, 57 T2DM patients without MetS, 71 non-diabetics with MetS, and 164 control subjects without diabetes or metabolic syndrome).ResultsFasting serum levels of sCD26/DPP-IV were significantly higher in T2DM patients with and without MetS than in normal subjects. Likewise, sCD26/DPP-IV levels were significantly higher in patients with T2DM and MetS than in non-diabetic patients with MetS. However, active GLP-1 levels were significantly lower in T2DM patients both with and without MetS than in normal subjects. In T2DM subjects, sCD26/DPP-IV levels were associated with significantly higher A1c levels, but were significantly lower in patients using monotherapy with metformin. In addition, no significant differences in sCD26/DPP-IV levels were found between diabetic subjects with and without MetS. Furthermore, sCD26/DPP-IV levels were negatively correlated with active GLP-1 levels in T2DM patients both with and without MetS. In normal subjects, sCD26/DPP-IV levels were associated with increased BMI, cholesterol, and LDL-cholesterol (LDL-c) levels.ConclusionSerum sCD26/DPP-IV levels increased in T2DM subjects with and without MetS. Active GLP-1 levels decreased in T2DM patients both with and without MetS. In addition, sCD26/DPP-IV levels were associated with Alc levels and negatively correlated with active GLP-1 levels. Moreover, metformin monotherapy was associated with reduced sCD26/DPP-IV levels. In normal subjects, sCD26/DPP-IV levels were associated with increased BMI, cholesterol, and LDL-c.

Improved glycaemia in high-fat-fed neprilysin-deficient mice is associated with reduced DPP-4 activity and increased active GLP-1 levels

“…To determine whether neprilysin directly inhibits DPP-4 activity, recombinant neprilysin was treated with the inhibitor dl -thiorphan and then incubated with recombinant DPP-4 in vitro at a neprilysin:DPP-4 molar ratio of 1:5 or 1:10, to match proportions found in plasma from lean and obese humans [3, 16, 17]. Measurement of DPP-4 activity showed that dl -thiorphan treatment resulted in 75±2% ( n =3, p <0.05) and 84±4% ( n =3, p <0.05) inhibition of neprilysin activity in samples containing neprilysin:DPP-4 molar ratios of 1:5 and 1:10, respectively, but had no effect on DPP-4 activity (Fig.…”

“…Recombinant human DPP-4 (R&D Systems, Minneapolis, MN, USA) was then added at a final concentration of 0.01, 0.05 or 0.1 µmol/l, and incubated for 1 h at 37°C. When 1:1, 1:5 and 1:10 molar ratios of neprilysin to DPP-4 were tested, the 1:5 and 1:10 ratios approximated those documented in plasma from lean and obese humans [3, 16, 17]. Samples were assayed for neprilysin and DPP-4 activities as described above.…”

Quercetin and Coumarin Inhibit Dipeptidyl Peptidase-IV and Exhibits Antioxidant Properties: In Silico, In Vitro, Ex Vivo

“…The active principles of some plants, such as phytochemicals, inhibit DPP-IV enzyme activity [29]. Based on some findings, it is believed that DPP-IV level increased in diabetic condition and associated with long-term exposure to high levels of glucose [30]. The significant reduction in the incretin effect has been known to decrease the circulation level of GLP-1, which may be due to an increase in degradation by DPP-IV that leads to a decline in the mass and size of β-cell in the pancreas [31].…”

Circulating Levels of Soluble Dipeptidyl Peptidase-4 Are Dissociated from Inflammation and Induced by Enzymatic DPP4 Inhibition

“…Furthermore, the demonstration that selective inhibition of DPP-4 enzymatic activity leads to robust induction of circulating sDPP4 without concomitant changes in inflammation raises further questions about the experimental and pathophysiological context linking changes in levels of sDPP4 to pro-inflammatory pathways. Intriguingly, DPP-4 inhibitors are widely used in conjunction with metformin, an agent associated with (1) reduced levels of circulating sDPP4 (Ahmed et al, 2015;Zhong et al, 2015) and (2) decreased numbers of major cardiovascular events, relative to DPP-4 inhibitors alone, in cardiovascular outcome studies (Crowley et al, 2017). Given the widespread use of DPP-4 inhibitors in human subjects with diabetes and inflammatory co-morbidities, including cardiovascular disease (Mulvihill and Drucker, 2014), it seems prudent to further elucidate the circumstances and co-factors linking changes in soluble and tissue DPP-4 with ambient DPP-4 activity, and sDPP4-mediated regulation of inflammation.…”