Serum Dipeptidyl Peptidase-4 Activity Research Articles

Decreased circulating dipeptidyl peptidase-4 activity after short-term intensive insulin therapy predicts clinical outcomes in patients with newly diagnosed type 2 diabetes.

This study aims to investigate the changes in circulating dipeptidyl peptidase-4 (DPP-4) activity following short-term intensive insulin therapy (SIIT) in newly diagnosed type 2 diabetes (T2D) patients and to assess its potential in predicting long-term remission. Ninety-five patients underwent SIIT for 2-3 weeks to attain and sustain near-normal glycemia. Insulin was then discontinued, and patients were followed for a year to evaluate glycemic outcomes. Biochemical tests, serum DPP-4 activity, and mixed meal tolerance tests were conducted at baseline, post-SIIT, and the 3-month follow-up. DPP-4 activity decreased from 44.08 ± 9.58 to 40.53 ± 8.83 nmol/min/mL after SIIT (P<0.001). After three months post-SIIT, DPP-4 activity remained stable in the remission group (39.63 ± 8.53 nmol/L) but increased in the non-remission group (42.34 ± 6.64 nmol/L). This resulted in a more pronounced decrease in DPP-4 activity from baseline in the remission group (-3.39 ± 8.90 vs.-1.10 ± 8.95, P = 0.035). Logistic regression analyses showed that patients with greater DPP-4 activity reduction had a higher likelihood of 1-year remission (70% vs. 51.1%, OR: 7.939 [1.829, 34.467], P = 0.006 in the fully adjusted model). A non-linear relationship between △DPP-4 and 1-year remission rate was observed, with a clear threshold and saturation effect. Circulating DPP-4 activity significantly decreases after SIIT. The change in circulating DPP-4 activity during the 3-month post-treatment phase has the potential to predict long-term remission.

Diabetic individuals with COVID-19 exhibit reduced efficacy of gliptins in inhibiting dipeptidyl peptidase 4 (DPP4). A suggested explanation for increased COVID-19 susceptibility in patients with type 2 diabetes mellitus (T2DM)

AimsDipeptidyl peptidase 4 (DPP4) has been proposed as a coreceptor for SARS-CoV-2 cellular entry. Considering that type 2 diabetes mellitus (T2DM) has been identified as the most important risk factor for SARS-CoV-2, and that gliptins (DPP4 inhibitors) are a prescribed diabetic treatment, this study aims to unravel the impact of DPP4 in the intersection of T2DM/COVID-19. Materials and methodsWe analyzed 189 serum human samples, divided into six clinical groups (controls, T2DM, T2DM + gliptins, COVID-19, COVID-19 + T2DM, and COVID-19 + T2DM + gliptins), measuring DPP4 protein concentration and activity by Western blot, ELISA, and commercial activity kits. The obtained results were verified in Huh-7 cellular models. Key findingsBoth DPP4 concentration and activity were decreased in COVID-19 patients, and as in T2DM patients, compared to controls. Despite these lower levels, the ratio of DPP4 activity/concentration in COVID-19 sera was the highest (0.782 ± 0.289 μU/ng vs. 0.547 ± 0.050 μU/ng in controls, p < 0.0001), suggesting a compensating mechanism in these patients. Supernatants of Huh-7 cells incubated with COVID-19 serum showed a consistent and significantly lower DPP4 concentration and activity. Furthermore, COVID-19 + T2DM + gliptins patients showed a higher serum DPP4 concentration and activity than T2DM + gliptin subjects (p < 0.05), indicating that sera from COVID-19 convalescents interfere with gliptins. SignificanceEither SARS-CoV-2 or some metabolites present in the sera of COVID-19-convalescent patients interact with soluble DPP4 or even gliptins themselves since the inhibitory effect of gliptins on DPP4 activity is being prevented. The interactions between DPP4, gliptins, and SARS-CoV-2 should be further elucidated to reveal the mechanism of action for these interesting observations.

Acute Effects of Breakfast Fruits Meal Sequence and Postprandial Exercise on the Blood Glucose Level and DPP4 Activity among Type 2 Diabetes Mellitus Patients: A Pilot Study.

Objectives Type 2 diabetes mellitus (T2DM) is a major global public health issue. Diet and physical exercise are modifiable factors that influence the glycaemic status of patients with T2DM. We aimed to investigate the acute effects of breakfast fruits meal sequence and postprandial exercise on the blood glucose level and dipeptidyl peptidase 4 (DPP4) activity among type 2 diabetes mellitus patients. Methods A randomized pilot study recruited patients with T2DM who attended two primary health care centres in Tasikmadu District, Karanganyar Regency, and Kartasura District, Sukoharjo Regency, Central Java, Indonesia, from July to October 2016. Eligible patients (4 men and 32 women) were randomly divided into four treatment groups. Venous blood samples were analyzed for fasting and one-hour postprandial blood glucose (FBG and 1 h PPG) levels and DPP4 activity. Blood glucose levels were measured using a routine hexokinase method, and serum DPP4 activity was determined spectrophotometrically after incubation with the Gly-Pro-p-nitroanilide substrate. Results Fruits last meal decreased FBG level whilst fruits first meal did not significantly decrease 1 h PPG level. Both treatments had no acute effects on DPP4 activity but the addition of postprandial exercise helped lower DPP4 activity. Fruit last and first meals showed significant opposite effects on mean changes of FBG level (p < 0.05). Conclusions This preliminary report of fruits meal sequence is potentially involved in acute regulation of blood glucose levels and that it might be independent of DPP4 activity in Indonesian patients with T2DM. Moreover, postprandial exercise may be an important intervention for T2DM through the mediation of DPP4 but has no acute effects on the regulation of blood glucose levels. Further studies are required to investigate whether or not different types of fruits and longer treatment intervals can affect blood glucose levels and DPP4 activity differently. This study also gives an insight into the feasibility of conducting food order modification with or without the combination of postprandial exercise in a primary health setting for our next studies.

Serum and Adipose Dipeptidyl Peptidase 4 in Cardiovascular Surgery Patients: Influence of Dipeptidyl Peptidase 4 Inhibitors.

Dipeptidyl peptidase 4 (DPP-4) is a novel adipokine and may be involved in the association between adipose tissue and metabolic syndrome. We investigated DPP-4 and adiponectin levels in the serum, subcutaneous adipose tissue (SAT), and epicardial adipose tissue (EAT), and their relationship with preoperative factors, as well as comparing the DPP-4 levels in SAT and EAT with and without DPP-4 inhibitors. This study included 40 patients (25 men, age 67.5 ± 13.8 years). The serum adipokine, DPP-4, and adiponectin levels in SAT and EAT were measured using ELISA and Western blotting. The DPP-4 and adiponectin levels were significantly higher in the SAT than in the EAT. The serum DPP-4 and DPP-4 activity levels had no correlation with the DPP-4 levels in the SAT and EAT, but the DPP-4 levels in the SAT and EAT had a positive correlation. The DPP-4 levels in the SAT were positively correlated with atherosclerosis, diabetes mellitus, DPP-4-inhibitor use, and fasting blood glucose. The DPP-4 levels in the EAT showed a negative correlation with eGFR and a positive correlation with atrial fibrillation. The DPP-4 activity in the serum had a lower tendency in the group taking DPP-4 inhibitors than in the group not taking them. DPP-4 inhibitors may suppress angiogenesis and adipose-tissue hypertrophy.

Unraveling the interplay between dipeptidyl peptidase 4 and the renin-angiotensin system in heart failure

AimsEmerging evidence suggests the existence of a crosstalk between dipeptidyl peptidase 4 (DPP4) and the renin-angiotensin system (RAS). Therefore, combined inhibition of DPP4 and RAS may produce similar pharmacological effects rather than being additive. This study tested the hypothesis that combining an inhibitor of DPP4 with an angiotensin II (Ang II) receptor blocker does not provide additional cardioprotection compared to monotherapy in heart failure (HF) rats. Main methodsMale Wistar rats were subjected to left ventricle (LV) radiofrequency ablation or sham operation. Six weeks after surgery, radiofrequency-ablated rats who developed HF were assigned into four groups and received vehicle (water), vildagliptin, valsartan, or both drugs, for four weeks by oral gavage. Key findingsVildagliptin and valsartan in monotherapy reduced LV hypertrophy, alleviated cardiac interstitial fibrosis, and improved systolic and diastolic function in HF rats, with no additional effect of combination treatment. HF rats displayed higher cardiac and serum DPP4 activity and abundance than sham. Surprisingly, not only vildagliptin but also valsartan in monotherapy downregulated the catalytic function and expression levels of systemic and cardiac DPP4. Moreover, vildagliptin and valsartan alone or in combination comparably upregulate the components of the cardiac ACE2/Ang-(1-7)/MasR while downregulating the ACE/Ang II/AT1R axis. SignificanceVildagliptin or valsartan alone is as effective as combined to treat cardiac dysfunction and remodeling in experimental HF. DPP4 inhibition downregulates classic RAS components, and pharmacological RAS blockade downregulates DPP4 in the heart and serum of HF rats. This interplay between DPP4 and RAS may affect HF progression and pharmacotherapy.

Serum dipeptidyl peptidase-4 activity and progranulin level in polycystic ovary syndrome patients.

Background:Evidence showed that abnormal alteration of adipokines level may perform a key role in polycystic ovary syndrome (PCOS) pathogenesis. Dipeptidyl peptidase-4 (DPP4) and progranulin (PGRN) are two novel adipokines related to insulin resistance (IR). Thus, we aimed to determine the serum DPP4 activity and PGRN level in PCOS patients with and without IR, and non-PCOS women.Methods:Ninety women were recruited in the present study including 60 PCOS patients (divided into two groups of 30 IR and 30 non-IR) and 30 non-PCOS women. Serum levels of insulin, fasting blood glucose, PGRN, and DPP4 activity were measured, and IR indices were calculated.Results:DPP4 activity was significantly higher in PCOS-IR and PCOS-NIR patients than non-PCOS women (p<0.001, P=0.011, respectively), whereas no significant variation was detected between two groups of PCOS subjects. There was no significant difference in the level of PGRN in the three groups of the present study.Conclusion:The present study suggests that increasing DPP4 activity may be associated with PCOS.

Emerging Roles of Dipeptidyl Peptidase-4 Inhibitors in Delaying the Progression of Type 1 Diabetes Mellitus.

Type 1 diabetes mellitus (T1DM) results from the immune cell-mediated destruction of functional pancreatic β-cells. In the presymptomatic period, T1DM is characterized by the presence of two or more autoantibodies against the islet cells in patients without glycemic decompensation. Therapeutic strategies that can modify the autoimmune process could slow the progression of T1DM. Dipeptidyl peptidase-4 (DPP-4) or CD26, a multifunctional serine protease with a dual function (regulatory protease and binding protein), can modulate inflammation and immune cell-mediated β-cell destruction. CD26 is involved in T-cell co-stimulation, migration, memory development, thymic maturation, and emigration patterns. DPP-4 degrades the peptide hormones GLP-1 and GIP. In addition to regulating glucose metabolism, DPP-4 exerts anti-apoptotic, regenerative, and proliferative effects to promote β-cell mass expansion. GLP-1 receptor signaling may regulate murine lymphocyte proliferation and maintenance of peripheral regulatory T-cells. In patients with T1DM, the serum DPP-4 activity is upregulated. Several studies have suggested that the upregulated DPP-4 activity is correlated with T1DM pathophysiology. DPP-4, which is preferentially expressed on the Th1 surface, can promote the polarization of Th1 immunity, a prerequisite for T1DM development. CD26 inhibition can suppress T-cell proliferation and Th1 cytokine production and stimulate tumor growth factor beta-1 (TGF-β1) secretion, which plays an important role in the regulation of autoimmunity in T1DM. Studies on humans or animal models of T1DM have suggested that DPP-4 inhibitors can improve β-cell function and attenuate autoimmunity in addition to decreasing insulin dependence. This review summarizes the emerging roles of DPP-4 inhibitors in potentially delaying the progression of T1DM.

Postprandial increase in glucagon-like peptide-1 is blunted in severe heart failure.

The relationship between disturbances in glucose homeostasis and heart failure (HF) progression is bidirectional. However, the mechanisms by which HF intrinsically impairs glucose homeostasis remain unknown. The present study tested the hypothesis that the bioavailability of intact glucagon-like peptide-1 (GLP-1) is affected in HF, possibly contributing to disturbed glucose homeostasis. Serum concentrations of total and intact GLP-1 and insulin were measured after an overnight fast and 15 min after the ingestion of a mixed breakfast meal in 49 non-diabetic patients with severe HF and 40 healthy control subjects. Similarly, fasting and postprandial serum concentrations of these hormones were determined in sham-operated rats, and rats with HF treated with an inhibitor of the GLP-1-degrading enzyme dipeptidyl peptidase-4 (DPP4), vildagliptin, or vehicle for 4 weeks. We found that HF patients displayed a much lower increase in postprandial intact and total GLP-1 levels than controls. The increase in postprandial intact GLP-1 in HF patients correlated negatively with serum brain natriuretic peptide levels and DPP4 activity and positively with the glomerular filtration rate. Likewise, the postprandial increases in both intact and total GLP-1 were blunted in HF rats and were restored by DPP4 inhibition. Additionally, vehicle-treated HF rats displayed glucose intolerance and hyperinsulinemia, whereas normal glucose homeostasis was observed in vildagliptin-treated HF rats. We conclude that the postprandial increase in GLP-1 is blunted in non-diabetic HF. Impaired GLP-1 bioavailability after meal intake correlates with poor prognostic factors and may contribute to the establishment of a vicious cycle between glucose disturbance and HF development and progression.

Nitrothiadiazolo[3,2-a]pyrimidines as promising antiglycating agents

Managing the advanced glycation end-products (AGEs) concentration is a reliable approach to achieve control over the pathogenesis of diabetic vascular complications. Inhibition of dipeptidyl peptidase-4 (DPP-4) is also an attractive way to tackle type 2 diabetes mellitus (T2DM). We showed previously that azoloazine heterocycles have the potential to prevent the formation of AGEs and in this work, we conducted docking studies with DPP-4 of 5-alkylamino-6-nitro-1,3,4-thiadiazolo[3,2-a]pyrimidines. Consequently, we have developed a synthetic approach to these structures by chlorodeoxygenation and amination reactions. Antidiabetic properties of obtained compounds were studied by evaluating DPP-4 (ex vivo/in vitro) and AGEs formation inhibition (in vitro). It was shown that the nitrothiadiazolopyrimidines exhibit a higher antiglycation activity than reference compound aminoguanidine, but only moderate inhibition of DPP-4. The most active DPP-4 inhibitor 1l had IC50 of 55.87 μM and showed the ability to inhibit serum DPP-4 activity in rats after 10 mg/kg oral administration but with the less and shorter effect than vildagliptin. At the same time, 1l was the most active antiglycating compound in the series (IC50 134.4 μM). Copper chelation properties of synthesized compounds were also investigated since the formation of AGEs is catalyzed by the transition metal cations. A noticeable correlation between antiglycation activity and metal chelation was revealed. Both activities (antiglycation and copper chelation) correlated with quantum-chemical properties (calculated with ab initio) of the tested compounds. These findings will allow us to predict both activities in the future, without the need to model multiple steps of glycation reaction.

Serum activities of dipeptidyl peptidase-4 and adenosine deaminase in polycystic ovary syndrome: association with obesity

Dipeptidyl peptidase-4 (DPP-4) plays a role in metabolic and inflammatory diseases. Increased adenosine deaminase (ADA) has been suggested to induce insulin resistance and inflammation. We measured serum DPP-4 and ADA activities. Serum ADA activity was significantly higher in PCOS group (p = .006), whereas there was no difference in serum DPP-4 activity between the groups (p > .05). When the study subjects were divided into four groups in terms of obesity; an increasing trend in serum ADA activity between the groups was observed and ADA activity was significantly higher in overweight and obese patients with PCOS than nonobese controls (p = .016), there were no significant differences between the other groups (p > .05). A positive correlation was found between ADA and BMI in the whole group (p = .022). Multivariate regression analyses revealed that significant determinants were diastolic blood pressure, ADA, and the presence of PCOS for DPP-4 (R2 = 0.344, F = 9.079, p < .001); the presence of PCOS and DPP-4 for ADA (R2 = 0.123, F = 6.302, p = .003). We demonstrated increased serum ADA activity as well as its association with obesity in PCOS, while there was no change in serum DPP-4 activity in women with PCOS.

Serum adipocytokines are associated with microalbuminuria in patients with type 1 diabetes and incipient chronic complications

AimsRecent studies have implicated possible contribution of adipocytokines in development and progression of microvascular complications in patients with type 1 diabetes (T1DM). The aim of our study was to investigate relationship between adipocytokines, namely leptin, resistin, adiponectin and dipeptidyl peptidase-4 (DPP-4) activity, with albuminuria in T1DM. MethodsThis study included 202 T1DM without or with incipient microvascular complications. Urinary albumin excretion rate (UAE) was measured from at least two 24-h urine samples. Serum DPP-4 activity was measured by a colorimetric assay, and the level of adiponectin, leptin, and resistin was determined by the ELISA method. ResultsSerum DPP-4 activity and adiponectin were significantly higher in patients with normoalbuminuria compared to patients with microalbuminuria (47 vs 36 U/L, and 10.9 vs 7.3 μg/mL, respectively, p ≤ 0.02). In multivariate logistic regression analysis adiponectin and serum DPP-4 activity were significantly associated with risk of microalbuminuria in our subjects (p ≤ 0.04), with odds ratios of 0.72–0.99. However, after adjustment for age, sex, HbA1c, duration of diabetes and BMI, only serum DPP-4 activity was significantly associated with risk of microalbuminuria (p = 0.008). ConclusionThe results of our study suggest that serum DPP-4 activity is lower in T1DM with microalbuminuria. Prospective studies are warranted to evaluate the relationship between serum DPP-4 activity and progression and development of albuminuria and nephropathy in T1DM.

Dipeptidyl Peptidase 4 Inhibitors Reduce Hepatocellular Carcinoma by Activating Lymphocyte Chemotaxis in Mice.

Background & AimsCD26, a multifunctional transmembrane glycoprotein, is expressed in various cancers and functions as dipeptidyl peptidase 4 (DPP4). We investigated whether CD26 expression is associated with hepatocellular carcinoma (HCC) progression and whether DPP4 inhibitors exert antitumor effects against HCC.MethodsCD26 expression was examined in 41 surgically resected HCC specimens. The effects of DPP4 inhibitors on HCC were examined by using HCC cell lines (Huh-7 and Li-7), xenograft tumors in nude mice, and a nonalcoholic steatohepatitis–related HCC mouse model.ResultsCD26 expression in HCC specimens was associated with increased serum DPP4 activity, as well as a more advanced stage, less tumor immunity, and poorer prognosis in HCC patients. The HCC cell lines and xenograft tumors exhibited CD26 expression and DPP4 activity. The DPP4 inhibitors did not exhibit antitumor effects in vitro, but natural killer (NK) and/or T-cell tumor accumulation suppressed growth of xenograft tumor and HCC in vivo. The antitumor effects of DPP4 inhibitors were abolished by the depletion of NK cells or the neutralization of CXCR3, a chemokine receptor on NK cells. EZ-TAXIScan, an optical horizontal chemotaxis apparatus, identified enhanced NK and T-cell chemotaxis by DPP4 inhibitors ex vivo in the presence of Huh-7 cells and the chemokine CXCL10, which binds to CXCR3. The DPP4 inhibitors prevented the biologically active form of CXCL10 from being truncated by Huh-7 cell DPP4 activity. DPP4 inhibitors also suppressed tumor angiogenesis.ConclusionsThese results provide a rationale for verifying whether DPP4 inhibitors clinically inhibit the progression of HCC or augment the antitumor effects of molecular-targeting drugs or immunotherapies against HCC.

DPP4 inhibition by sitagliptin attenuates LPS-induced lung injury in mice.

Acute respiratory distress syndrome (ARDS) is a severe clinical condition marked by acute respiratory failure and dysregulated inflammation. Pulmonary vascular endothelial cells (PVECs) function as an important pro-inflammatory source in ARDS, suggesting that modulation of inflammatory events at the endothelial level may have a therapeutic benefit. Dipeptidyl peptidase-4 (DPP4) inhibitors, widely used for the treatment of diabetes mellitus, have been reported to have possible anti-inflammatory effects. However, the potential anti-inflammatory effects of DPP4 inhibition on PVEC function and ARDS pathophysiology are unknown. Therefore, we evaluated the effects of sitagliptin, a DPP4 inhibitor in wide clinical use, on LPS-induced lung injury in mice and in human lung ECs in vitro. In vivo, sitagliptin reduced serum DPP4 activity, bronchoalveolar lavage protein concentration, cell number, and proinflammatory cytokine levels after LPS and alleviated histological findings of lung injury. LPS decreased the expression levels of CD26/DPP4 on pulmonary epithelial cells and PVECs isolated from mouse lungs, and the effect was partially reversed by sitagliptin. In vitro, human lung microvascular ECs (HLMVECs) expressed higher levels of CD26/DPP4 than human pulmonary arterial ECs. LPS induced the release of TNFα, IL-6, and IL-8 by HLMVECs that were inhibited by sitagliptin. LPS promoted the proliferation of HLMVECs, and sitagliptin suppressed this response. However, sitagliptin failed to reverse LPS-induced permeability in cultured ECs or lung epithelial cells in vitro. In summary, sitagliptin attenuates LPS-induced lung injury in mice and exerts anti-inflammatory effects on HLMVECs. These novel observations indicate DPP4 inhibitors may have potential as therapeutic drugs for ARDS.

Inhibition of dipeptidyl peptidase IV prevents high fat diet-induced liver cancer angiogenesis by downregulating chemokine ligand 2

Obesity is a major risk factor for hepatocellular carcinoma (HCC) and is typically accompanied by higher levels of serum dipeptidyl peptidase 4 (DPP4). However, the role of DPP4 in obesity-promoted HCC is unclear. Here, we found that consumption of a high-fat diet (HFD) promoted HCC cell proliferation and metastasis and led to poor survival in a carcinogen-induced model of HCC in rats. Notably, genetic ablation of DPP4 or treatment with a DPP4 inhibitor (vildagliptin) prevented HFD-induced HCC. Moreover, HFD-induced DPP4 activity facilitated angiogenesis and cancer cell metastasis in vitro and in vivo, and vildagliptin prevented tumor progression by mediating the pro-angiogenic role of chemokine ligand 2 (CCL2). Loss of DPP4 effectively reversed HFD-induced CCL2 production and angiogenesis, indicating that the DPP4/CCL2/angiogenesis cascade had key roles in HFD-associated HCC progression. Furthermore, concomitant changes in serum DPP4 and CCL2 were observed in 210 patients with HCC, and high serum DPP4 activity was associated with poor clinical prognosis. These results revealed a link between obesity-related high serum DPP4 activity and HCC progression. Inhibition of DPP4 may represent a novel therapeutic intervention for patients with HCC.

The dual DPP4 inhibitor and GPR119 agonist HBK001 regulates glycemic control and beta cell function ex and in vivo

Glucagon like peptide-1 (GLP-1) plays a vital role in glucose homeostasis and sustaining β-cell function. Currently there are two major methods to enhance endogenous GLP-1 activity; inhibiting dipeptidyl peptidase-4 (DPP4) or activating G protein-coupled receptor 119 (GPR119). Here we describe and validate a novel dual-target compound, HBK001, which can both inhibit DPP4 and activate GPR119 ex and in vivo. We show that HBK001 can promote glucose-stimulated insulin secretion in mouse and human primary islets. A single administration of HBK001 in ICR mice can increase plasma incretins levels much more efficiently than linagliptin, a classic DPP4 inhibitor. Long-term treatment of HBK001 in KKAy mice can ameliorate hyperglycemia as well as improve glucose tolerance, while linagliptin fails to achieve such glucose-lowing effects despite inhibiting 95% of serum DPP4 activity. Moreover, HBK001 can increase first-phase insulin secretion in KKAy mice, suggesting a direct effect on islet β-cells via GPR119 activation. Furthermore, HBK001 can improve islet morphology, increase β-cell proliferation and up-regulate genes involved in improved β-cell function. Thus, we have identified, designed and synthesized a novel dual-target compound, HBK001, which represents a promising therapeutic candidate for type 2 diabetes, especially for patients who are insensitive to current DPP4 inhibitors.

Dipeptidyl peptidase-4 activity is associated with urine albumin excretion in type 1 diabetes

AimsThe inability of kidneys to prevent urinary protein leakage represents the earliest sign of renal damage in diabetic kidney disease (DKD). Recent data suggest the possible nephroprotective role of the dipeptidyl peptidase-4 (DPP-4) inhibitors. We aimed to investigate whether serum DPP-4 activity is associated with urine albumin excretion (UAE) in patients with type 1 diabetes (type 1 DM). MethodsDPP-4 activity and UAE measurement were performed in 113 patients with type 1 DM and glomerular filtration rate (GFR) within normal range. They were divided into three groups according to UAE tertiles. ResultsWorse lipid profile and higher waist circumference were observed in the group with highest DPP-4 activity. Patients within lowest UAE tertile group had lowest DPP-4 activity value (p<0.001) compared to group within second and third tertile of UAE. DPP-4 activity correlated with systolic blood pressure (ρ=0.142; p=0.001), HbA1c (ρ=0.133; p=0.013) and UAE (ρ=0.349; p<0.001). In the linear regression analysis when DPP-4 activity was adjusted for age, gender, disease duration, HbA1c, waist circumference, the use of ACEI and hypolipemic agents the association remained significant; UAE increased for 8.136mg/24h by each increase of DPP-4 activity of 1U/L (p<0.008). ConclusionOur results indicate that serum DPP-4 activity is associated with albuminuria in type 1 diabetes. This arises the question whether the use of DPP-4 inhibitors might serve as an additional therapeutic strategy to prevent proteinuria in patients with DKD.

Plasma Incretin Levels and Dipeptidyl Peptidase-4 Activity in Patients with Obstructive Sleep Apnea.

Incretin hormones, namely glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide/glucose-dependent insulinotropic polypeptide (GIP), and dipeptidyl peptidase-4 (DPP-4) activity are important factors in glucose metabolism and have not been investigated in patients with obstructive sleep apnea (OSA). The objective of this study was to investigate the association between OSA and incretin and DPP-4 activity. This study included 96 consecutive patients without diabetes who were suspected of having OSA. We investigated the fasting and post-prandial incremental area under the curve (IAUC) of GLP-1, GIP serum levels, and serum DPP-4 activity levels, as well as their association with OSA. Changes in clinical variables were evaluated in the 43 patients who continued continuous positive airway pressure therapy for 3 months. Apnea-hypopnea index was an independent determining factor for fasting GLP-1 (β = 0.31; P = 0.0019) and IAUC GIP (β = -0.21; P = 0.037) after adjusting for known confounding factors. In those with very severe OSA (apnea-hypopnea index ≥50), the IAUCs for GLP-1 and GIP were significantly decreased, while fasting GLP-1 and fasting GIP were significantly increased. DPP-4 activity had no relation to OSA parameters or severity, while body mass index was significantly higher in those with severe OSA. Although significant changes in incretin secretion were not seen for 3 months after onset of continuous positive airway pressure therapy, the fasting GLP-1 level in the treated patients with severe OSA decreased to the same level as in untreated patients with normal to moderately severe OSA. OSA is associated with elevated serum levels of the incretin hormones GLP-1 (fasting) and GIP (post-prandial) in patients without diabetes. A significant association between body mass index and DPP-4, which is said to exist in healthy persons, was not found in the patients with OSA. Fasting GLP-1 in patients without diabetes with OSA may influence fasting glucose levels.

Anagliptin, a dipeptidyl peptidase-4 inhibitor, decreases macrophage infiltration and suppresses atherosclerosis in aortic and coronary arteries in cholesterol-fed rabbits

IntroductionSeveral studies have demonstrated suppression of aortic atherosclerosis by dipeptidyl peptidase-4 (DPP-4) inhibitors in hypercholesterolemic mice. However, it remains unknown whether DPP-4 inhibitors also exert anti-atherogenic effects in coronary arteries. We examined the effect of anagliptin, a DPP-4 inhibitor, on atherosclerosis development in the aorta and coronary arteries in a high-cholesterol diet-fed rabbits. MethodsJapanese white rabbits were fed either normal chow (n=8) or a diet containing 0.5% cholesterol (n=34) for 14weeks. Cholesterol-fed rabbits were given 0.3% anagliptin or not in drinking water (each n=16 and 18) for 12weeks. ResultsDietary cholesterol intake markedly increased serum total cholesterol (TC) levels (1464±150mg/dL, mean±SE), and the most striking increase was observed among the major lipoproteins in very low-density lipoprotein (VLDL) as determined by high-performance liquid chromatography. No significant changes were observed in body weight, water intake, hemoglobin A1c, or glucose response to intravenous glucose loading following anagliptin administration. Anagliptin decreased TC and VLDL-cholesterol as well as cholesterol absorption markers sitosterol and campesterol slightly, although not significantly. Serum DPP-4 activity was suppressed by 82%, and active glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide levels were increased 2- to 3-fold by anagliptin treatment. Severe hypercholesterolemia resulted in the development of atherosclerosis in the aorta, and the ratio of atherosclerotic lesions to the total aortic surface area was 22±2%. Anagliptin suppressed the lesion ratio to 9±2% (p<0.001). Atherosclerotic lesions were clearly observed in the coronary arteries, where the mean intima-media area was enlarged, and intimal formation was developed. Anagliptin treatment attenuated the intima-media area and the intimal area by 43%. Alpha-smooth muscle actin-positive and macrophage-positive areas in the coronary arteries were suppressed by 66 and 75%, respectively, after anagliptin treatment. The aortic lesion ratio and the coronary intima area were correlated with each other (r=0.506, p<0.01), and each lesion correlated with TC in the whole cholesterol-fed rabbits. Gene expression of the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6 in the carotid arteries was markedly reduced by approximately 90%, and vascular DPP-4 activity was reduced by 66% after anagliptin treatment. ConclusionsWe demonstrated for the first time that a DPP-4 inhibitor can substantially suppress plaque formation in coronary arteries with a marked reduction in macrophage accumulation likely via its anti-inflammatory properties.

Significant elevation of serum dipeptidyl peptidase-4 activity in young-adult type 1 diabetes

AimsCurrently, inhibition of dipeptidyl peptidase-4 (DPP-4) is widely used in the treatment of type 2 diabetes. Application of this strategy is awaited as a new therapeutic approach for type 1 diabetes, but the scientific basis is still lacking. This report describes the evaluation of serum DPP-4 activity in type 1 diabetes compared with control subjects, and assessment of relationships between DPP-4 activity and diabetic complication markers and metabolic variables in type 1 diabetes. MethodsWe examined serum DPP-4 activity in Japanese young-adult type 1 diabetes (n=76, females 69.7%, age 30.9±6.2 years, duration of diabetes 16.5±11.1 years; mean±SD) and healthy controls (n=22). Association of the enzymatic activity with diabetic micro- and macro- vascular complication markers and clinical parameters was also assessed. ResultsSubjects with type 1 diabetes displayed significantly higher serum DPP-4 activity than healthy controls (relative value, control: 1.00±0.28, T1D, 1.29±0.38; p=0.0011) independent of other clinical parameters. In type 1 diabetes, DPP-4 activity was positively correlated with duration of diabetes (r=0.248, p=0.031), while not correlated with HbA1c level. In univariate correlation analysis of diabetic complication markers and other metabolic parameters, coefficient of variation of R-R intervals (CVR-R) and gamma (γ)-glutamyltransferase (GGT) levels were correlated with DPP-4 activity. GGT was extracted as an independent variable of DPP-4 activity in multivariate analysis (β=0.213, p=0.035). ConclusionsSerum DPP-4 activity is significantly elevated in Japanese type 1 diabetes, suggesting pathophysiological significance of the enzyme in type 1 diabetes.

Altered crosstalk in the dipeptidyl peptidase-4-incretin-immune system in type 1 diabetes: A hypothesis generating pilot study

Both GLP17–36 (via GLP1 receptor) and the dipeptidyl peptidase-4 (DPP4) cleaved form of GLP1 (GLP19–36, independently of GLP1R) may modulate the response of lymphocytes to cytokine stimuli. The incretin axis, CXCR3 (receptor of DPP4 ligand cytokines CXCL9–11) expression on Tregs and hematologic parameters were assessed in 34 patients with long standing type 1 diabetes (T1DM) and in 35 healthy controls. Serum DPP4 (sDPP4) activity, plasma total GLP1 and GLP17–36 concentrations were determined. GLP19–36 concentrations were calculated. CXCR3 expression (flow cytometry) was higher on the CD25−/lowFoxp3+ than on the CD25+Foxp3+ Tregs independently from T1DM, suggesting that CD25−/lowFoxp3+ Tregs are possibly waiting for orientational chemotactic stimuli in a “standby mode”. The higher sDPP4 activities in T1DM were inversely correlated with GLP17–36 levels and GLP19–36 levels directly with lymphocyte counts in controls. Our results might indicate an altered DPP4-incretin system and altered immunoregulation including a potentially dysfunctional GLP19–36 signaling in T1DM.