Serum Dipeptidyl Peptidase-4 Research Articles

Association of serum and salivary dipeptidyl peptidase-4 (DPP-4) with oral cancerous and precancerous lesions; an observational diagnostic accuracy study

BackgroundEnhancing the prognosis and treatment outcomes of oral cancer relies heavily on its early detection. This study aims to establish a connection between serum and salivary dipeptidyl peptidase-4 (DPP-4) levels and oral squamous cell carcinoma (OSCC), comparing them with oral potentially malignant lesions (OPMLs) and control subjects and validating salivary DPP-4 as a diagnostic marker for the early detection of oral cancer.MethodologyForty-five systemically healthy individuals were categorized into three groups: Group I consisted of 15 patients diagnosed with OSCC, Group II comprised 15 patients with OPMLs (including leukoplakia and oral lichen planus), and Group III included 15 participants without any oral mucosal lesions. Serum and whole unstimulated salivary samples were collected from all participants to assess DPP-4 levels using an enzyme-linked immunosorbent assay (ELISA) kit. Receiver operating characteristic (ROC) analysis was conducted to determine the area under the curve (AUC), sensitivity, specificity, and diagnostic accuracy of DPP-4.ResultsBoth serum and salivary DPP-4 levels were highest in the healthy group, followed by OPMLs, and lowest in the OSCC group, with statistically significant differences observed. ROC analysis demonstrated excellent diagnostic accuracy of salivary DPP-4 in distinguishing OSCC from healthy individuals, OPMLs from healthy individuals, and OSCC from OPMLs, with accuracies of 100%, 100%, and 96.67%, respectively. Salivary DPP-4 levels also exhibited a statistically significant correlation with OSCC grades.ConclusionsDPP-4 appears to play a protective, anti-oncogenic role in maintaining oral tissue health. The remarkable diagnostic accuracy of both serum and salivary DPP-4 in discriminating between OSCC, OPMLs, and healthy controls suggests its potential utility as a well-established marker for early oral cancer diagnosis. Salivary DPP-4, being non-invasive, could serve as a convenient chair-side diagnostic tool for the early detection of OSCC.Clinical trial registrationThe study was retrospectively registered on clinicaltrial.gov with NCT06087042, date of registration (first posted date): 17/10/2023

Consumption of a Sourdough-Leavened Croissant Enriched with a Blend of Fibers Influences Fasting Blood Glucose in a Randomized Controlled Trial in Healthy Subjects

BackgroundAn incorrect lifestyle, including diet, is responsible for the worldwide dramatic increase in obesity and type 2 diabetes. Increasing dietary fiber consumption may lead to health benefits, and reformulation of bakery products may be a strategy to globally improve the diet. ObjectivesThis study aimed to assess the impact of a 2-wk breakfast consumption with a sourdough-leavened croissant containing a blend of dietary fiber from 10 sources (4.8 g/100 g, croissant enriched with dietary fibers [FIBCRO]), compared with a control croissant (dietary fibers 1.3 g/100 g, CONCRO) on daily energy intake, appetite, metabolic variables, and the gut microbiome. MethodsThirty-two healthy participants were randomly allocated to 2 groups consuming FIBCRO or CONCRO. Participants self-recorded their diet and appetite through 7-d weighted food diaries and visual analog scales every day over the 2 wk. At baseline and after the intervention, fasting blood and urine samples, and fecal samples were collected beside blood pressure, anthropometry, and body composition. Serum glucose, lipids, C-reactive protein, and insulin according to the official methods and serum dipeptidyl peptidase-4 (DPPIV) activity by photometric method were measured. Polyphenols and urolithins in urines were analyzed by Liquid chromatography–tandem mass spectrometry (LC/MS/MS), whereas gut microbiome in feces by shotgun metagenomics. ResultsFIBCRO consumption improved fasting blood glucose compared with CONCRO (mean changes from baseline −2.0 mg/dL in FIBCRO compared with +3.1 mg/dL in CONCRO, P = 0.022), also reducing serum DPPIV activity by 1.7 IU/L (P = 0.01) and increasing urinary excretion of urolithin A-sulfate by 6.9 ng/mg creatinine (P = 0.04) compared with baseline. No further changes in any of the monitored variables or in the gut microbiome were detected. ConclusionsResults suggested that a 2-wk consumption of a sourdough croissant claimed as “source of dietary fiber” improved fasting glycemia compared with a conventional sourdough croissant in healthy subjects. The reduced serum DPPIV activity and increased bioavailability of urolithin likely contributed to determine that effect independently from gut microbiome changes.This trial was registered at clinicaltrials.gov as NCT04999280.

Clinical profile and risk factors for type-2 diabetes – A cross-sectional study

Objectives Type 2 diabetes is a chronic metabolic disorder characterised by elevated blood glucose levels due to insulin resistance or insufficient insulin production. Understanding the prevalence, characteristics, and markers of this disease is essential for effective prevention, management and treatment. The study aims to explore the association between type 2 diabetes and its prevalence, characteristics and markers. Material and Methods Adults with type 2 diabetes and matched healthy controls were enrolled in the study. Statistical calculations were used to establish the sample size. Information on demographics, physical examinations and lab tests were collected. We assessed plasma glucose, glycated haemoglobin (HbA1c), serum lipids and serum DPP4. Results The mean age (SD) of the population under research was 55.7 (6.12) years for the study subjects and 55.7 (6.11) years for the controls. A positive family history of diabetes was present in 34 (or 33%) of the diabetes patients compared to 11 (or 11%) of the non-diabetic patients (p 0.001). The mean HbA1c in the diabetic group was substantially greater than that of the non-diabetic controls (5.47 1.89%), as expected (7.23 2.69%), p 0.001. It’s interesting to note that total cholesterol was markedly higher in the diabetes participants (5.59 2.24 mmol/L) than in the non-diabetic controls (6.48 1.54 mmol/L), p = 0.001. Conclusion Due to common risk factors and underlying mechanisms, type 2 diabetes and hypertension may be related, as suggested by the high prevalence of hypertension in the diabetic group. Type 2 diabetes was substantially related to elevated HbA1c and fasting plasma glucose levels, indicating poor glycaemic control. The higher mean serum Dipeptidyl peptidase-4 (DPP4) level in the group with type 2 diabetes shows a link between high DPP4 levels and the disease, which may have an effect on incretin hormone activity, insulin resistance and therapeutic options.

Exploring serum Dipeptidyl peptidase-4 levels: Associations with diabetes, glucose control and peripheral artery disease

Objectives Elevated serum Dipeptidyl peptidase-4 (DPP4) levels have emerged as a potential diagnostic biomarker for diabetes. This study aimed to investigate the association between serum DPP4 levels and diabetes, explore potential pathophysiological mechanisms and assess the clinical implications. Material and Methods Serum DPP4 levels were measured in participants, and their diabetes status was determined. Statistical analysis was employed to evaluate associations between DPP4 levels and diabetes, as well as their impact on glycaemic control and potential implications for diabetes management. Results Elevated serum DPP4 levels were significantly associated with diabetes. Higher DPP4 levels correlated with poorer glucose control. Notably, individuals with diabetes and peripheral arterial disease (PAD) exhibited markedly elevated DPP4 levels, suggesting a link between DPP4 and PAD in diabetes. Conclusion Serum DPP4 levels hold promise as a diagnostic tool for identifying diabetes and assessing its severity. This finding raises questions about the role of DPP4 in glucose metabolism and vascular complications. Further research may unveil mechanisms and therapeutic opportunities, potentially enhancing personalised diabetes care and preventive strategies for PAD in diabetic populations.

Association of DPP-4 Concentrations with the Occurrence of Gestational Diabetes Mellitus and Excessive Gestational Weight Gain.

Gestational diabetes mellitus (GDM) is considered one of the most common diseases that occur during pregnancy. In addition to increasing the risk of numerous complications throughout gestation, it is also believed to have a long-term potential to impact the risk of developing type 2 diabetes mellitus (T2DM) and cardiovascular disease for the mother and her offspring. While there are clear guidelines for healthy weight gain in pregnancy depending on pre-pregnancy BMI, as well as dietary and training recommendations to achieve this, an increasing number of women are experiencing excessive gestational weight gain (EGWG). Such patients have a higher risk of developing GDM and gestational hypertension, as well as requiring caesarian delivery. Dipeptidyl peptidase-4 (DPP-4) is a glycoprotein that seems to play an important role in glucose metabolism, and inhibition of its activity positively affects glucose regulation. The aim of our study was to compare DPP-4 concentrations in patients with GDM and EGWG with healthy women. DPP-4 levels were assessed in serum and urine samples collected on the day of delivery. The bioelectrical impedance analysis (BIA) method was also used to analyze the body composition of patients on the second day of the postpartum period. DPP-4 serum concentrations were significantly higher in patients in the GDM and EGWG groups compared to healthy women. Urinary DPP-4 concentrations were significantly higher in the control and GDM groups than in the EGWG group. Serum DPP-4 levels were positively correlated with BMI measured before pregnancy, on the delivery day, and in the early postpartum period, among other factors. According to our knowledge, this is the first study to determine DPP-4 levels in EGWG patients. DPP-4 may be related to the occurrence of GDM and EGWG; however, this requires further research.

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.

Dipeptidyl peptidase 4 as a potential serum biomarker for disease activity and treatment response in rheumatoid arthritis.

The treatment of rheumatoid arthritis (RA) related to the disease activity. However, the lack of highly sensitive and simplified markers limits the evaluation of disease activity. We sought to explore potential biomarkers associated with disease activity and treatment response in RA. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomic analysis was performed to determine the differentially expressed proteins (DEPs) in serum collected from RA patients with moderate or high disease activity (determined by DAS28) before and after 24weeks of treatment. Bioinformatic analysis were performed for DEPs and hub proteins. In the validation cohort, 15 RA patients were enrolled. Key proteins were validated by enzyme-linked immunosorbent assay (Elisa), correlation analysis and ROC curve. We identified 77 DEPs. The DEPs enriched in humoral immune response, blood microparticle, and serine-type peptidase activity. KEGG enrichment analysis displayed that the DEPs were significantly enriched in cholesterol metabolism and complement and coagulation cascades. Activated CD4+T cell, T follicular helper cell, natural killer cell, and plasmacytoid dendritic cell significantly increased after treatment. Fifteen hub proteins were screened out. Among them, dipeptidyl peptidase 4 (DPP4) was the most significant protein associated with clinical indicators and immune cells. Serum concentration of DPP4 was testified to significantly increase after treatment and inversely correlate with disease activity indicators (ESR, CRP, DAS28-ESR, DAS28-CRP, CDAI, SDAI). Significant reduction was found in the serum CXC chemokine ligand10 (CXC10) and CXC chemokine receptor 3 (CXCR3) after treatment. Overall, our results suggest that serum DPP4 might be a potential biomarker for disease activity assessment and treatment response of RA.

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 dipeptidyl peptidase-4 levels and DPP4 RS17574 polymorphism in subclinical atherosclerosis individuals with and without fatty liver. The GEA Mexican study

Background and Aims : Dipeptidyl peptidase-4 (DPP4) levels are related to non-alcoholic fatty liver (NAFLD/NASH), and this condition is associated with subclinical atherosclerosis (SA). On the other hand, the association of DPP4 gene polymorphisms with cardiovascular disease has been suggested. The present study aimed to establish whether DPP4 levels and the DPP4 rs17574 polymorphism are associated with fatty liver (FL) in individuals with SA.

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.

Serum dipeptidyl peptidase-4 and eosinophil cationic protein levels in patients of bronchial asthma

Treprostinil, a prostacyclin analogue used in the treatment of pulmonary arterial hypertension (PAH), is available for administration by parenteral, oral, or inhaled routes. Transitioning between routes may be beneficial for appropriate patients; however, there is little published data on transitions between oral and inhaled treprostinil. We used a modified Delphi process to develop expert consensus recommendations on transitions between these formulations. Three questionnaires were used to develop statements about relevant aspects of transition management, which the panelists rated, using a Likert scale, from −5 (strongly disagree) to +5 (strongly agree). Eleven physicians with expertise in PAH treatment modalities, participated in the panel. Of the 492 statements evaluated, consensus was reached on 215 (43.7%). Key consensus recommendations included (1) accurately defining successful transition, as stable or improved PAH with good tolerability and adherence, and (2) patients with stable, low-risk PAH showing insufficient response or tolerability to their existing treprostinil therapy (and due to restrictions in up titration of dosing), as appropriate candidates for transitions between treprostinil formulations. Panelists did not reach consensus for an overall strategy for performing these transitions, mainly because of variability in their practice parameters. Consensus was also achieved on recommendations for adverse event management, including reassurance, administration of oral treprostinil 3 times daily with food, and dosing inhaled treprostinil at intervals ≥3 hours apart. The Delphi process aided in developing expert consensus recommendations that may provide clinically useful guidance for transitioning between treprostinil formulations. However, additional data from centers with high volumes of PAH patients undergoing treprostinil transitions would be optimal for defining more complete and robust strategies to facilitate successful transition.

Fecal Dipeptidyl Peptidase-4: An Emergent Biomarker in Inflammatory Bowel Disease.

INTRODUCTION:Dipeptidyl peptidase-4 (DPP-4) is a membrane-bound glycoprotein that acts as a receptor but also exists in a soluble form. It has been recognized as a mediator of inflammation and considered a biomarker in inflammatory bowel disease (IBD).METHODS:We evaluated a prospectively recruited cohort, consisting of 101 patients with IBD, using validated clinical indexes; 22 patients with ulcerative colitis (UC) underwent endoscopic evaluation. Fecal DPP-4 (fDPP-4) levels were analyzed and correlated with clinical scores, Mayo endoscopic score (in UC patients), serum DPP-4, C-reactive protein, and fecal calprotectin. Immunohistochemical staining for DPP-4 in intestinal biopsies was also performed.RESULTS:When compared with remitters, median fDPP-4 levels were higher in patients with ileal Crohn's disease (CD) (7,584 [1,464–7,816] vs 2,104 [630–2,676] ng/mL, P = 0.015) and lower in patients with UC exhibiting clinical activity (1,213 [559–1,682] vs 7,814 [2,555–7,985] ng/mL, P < 0.001). Patients with UC presenting endoscopic activity also had lower levels than remitters (939 [559–1,420] vs 7,544 [4,531–7,940] ng/mL, P = 0.006). Fecal DPP-4 discriminated clinical activity from remission with areas under the curve of 0.76 (95% confidence interval [CI] 0.58–0.94, P = 0.015) and 0.80 (95% CI 0.68–0.93, P < 0.001) in CD and UC, respectively; it allowed to differentiate endoscopic activity in patients with UC, with areas under the curve of 0.84 (95% CI 0.63–1.00, P = 0.009). Immunohistochemical analysis revealed higher DPP-4 apical expression in UC remitters, but no statistically significant differences were revealed between patients with ileal CD.DISCUSSION:Our results suggest that fDPP-4 can be used as a biomarker of IBD activity, particularly in UC. The expression profiles in intestinal tissue might represent a functional compartmentalization of DPP-4 expression.

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.

710-P: Serum DPP-4 Protein Is Decreased upon Consuming an Isocaloric High Saturated Fat Diet and Genetically Determined in Healthy Human Twins

Obesity is associated with increased levels of soluble Dipeptidyl Peptidase-4 (DPP-4) in serum leading to adipose tissue inflammation and insulin resistance. Animal studies, however, have shown that a high fat diet acutely decreases serum DDP-4 levels. This study investigated the response of serum DDP-4 to a sudden switch from a healthy isocaloric low fat diet to an isocaloric high fat diet (HFD) in healthy human twins. 35 monzyogotic and 11 dizygotic healthy pairs of twins (women and men, age 18 - 70) were investigated for 12 weeks. An isocaloric diet rich in carbohydrates (55% carbohydrates, 30% fat, 15% protein, LF) was applied for 6 weeks, followed by an isocaloric diet rich in saturated fat (40% carbohydrates, 45% fat, 15% protein, HF) for another 6 weeks. Body weight (BW) and serum concentrations of DPP-4, tumor necrosis factor α (TNFα) and insulin were analyzed after the LF period, after one week (HF1w) and at the end (HF6w) of the HF period. Total body fat and lean mass were determined by DEXA-Scan at LF and HF6w. BW was constant over the time of intervention. Serum DPP-4 protein was decreased by 15% at HF1w and by 18% at HF6w, respectively, compared to LF (both P&amp;lt;0.001). At HF1w DPP-4 and TNFα serum levels were positively correlated (r=0.299, P=0.004) however, this correlation was lost at HF6w. Serum DPP-4 was positively correlated with lean mass at LF (r=0.357, P&amp;lt;0.001) and HF6w (r=0.218, P&amp;lt;0.05), however not with body fat content. DPP-4 serum protein was strongly positively correlated within monzogotic twins at LF, HF1w and HF6w (for all P&amp;lt;0.01), but not within dizygotic twins. Insulin was increased 1.20-fold and 1.12-fold at HF1w and HF6w, respectively, compared to LF (both P&amp;lt;0.001). These data indicate that serum DPP-4 protein responds to nutritional stimuli and is decreased upon consuming a HFD under isocaloric conditions in healthy human subjects which is in contrast to overt adiposity. Moreover, expression of serum DPP-4 protein is genetically determined. Disclosure M. Kruse: None. A. Ost: None. S. Hornemann: None. D. Hoffmann: None. T. Frahnow: None. A. Busjahn: None. A.F. Pfeiffer: None. Funding German Federal Ministry of Education and Research (0315424)

Serum Dipeptidyl peptidase-4 level is related to adiposity in type 1 diabetic adolescents

BackgroundInsulin resistance (IR) plays a great role in type 1 diabetes (T1DM) disease process than is commonly recognized. Dipeptidyl peptidase-4 (DPP-4) is an enzyme that deactivates many bioactive peptides involved in glucose regulation. AimsThis study evaluates DPP-4 level in adolescent patients with T1DM compared to controls and investigates the relationship between DPP-4 level and IR in these patients. Materials and methodsWe measured serum DPP-4 level in 50 patients with T1DM recruited from the Diabetes Endocrine Metabolism Pediatric Unit, and in 80 healthy controls. IR was assessed by the equation for estimated glucose disposal rate (eGDR). Biochemical evaluation including glycated haemoglobin (HbA1C) and lipid profile were included. ResultsIR was found in 80% of patients with T1DM. DPP-4 was significantly higher in control group than patients with T1DM. Patients with T1DM were classified into 3 groups according to DPP-4 tertiles showing significant increase in BMI SDS and total cholesterol across the 3 groups. Significant correlation was found between DPP-4 levels and insulin dose. DPP-4 was significantly higher in patients with T1DM with good glycemic control. ConclusionIn sample of individuals researched by us, serum DPP-4 was related to adiposity and not to the hyperglycemia in patients with T1DM. Larger sample should be researched to make firm conclusions.

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.

Decreased shedding dipeptidyl peptidase 4 from membrane in Hashimoto's thyroiditis

AimsThis study aimed to determine the concentration and enzymatic activity of dipeptidyl peptidase 4 (DPP4) in serum and peripheral blood mononuclear cells (PBMCs) from patients with Hashimoto’s thyroiditis (HT) and to explore the potential mechanism of the abnormal DPP4 in HT development. MethodsA total of 33 newly diagnosed HT patients and 31 age- and sex-matched healthy controls were enrolled. Clinical characteristics and thyroid function data were collected for all participants. Serum DPP4 and kallikrein-related peptidase 5 (KLK5) concentrations were measured by sandwich enzyme-linked immunosorbent assay. DPP4 enzymatic activities in serum and PBMCs were determined by enzymatic assay. DPP4, KLK5 and interferon (IFN)-γ mRNA expression levels in PBMCs were evaluated by quantitative real-time polymerase chain reaction. ResultsSerum DPP4 level and activity were significantly lower in the HT group compared with the control group. However, DPP4 mRNA expression was significantly increased and both serum KLK5 concentration and KLK5 mRNA expression in PBMCs were significantly decreased in HT patients. Correlation analyses revealed that DPP4 concentration was positively correlated with DPP4 enzymatic activity in serum. No significant difference in DPP4 activity was found in PBMCs. DPP4 enzymatic activity in PBMCs was negatively correlated with DPP4 enzymatic activity in serum. IFN-γ mRNA expression in PBMCs was significantly increased in HT patients. ConclusionsDPP4 is involved in the development and pathological process of HT. Decreased cleavage of membrane-anchored DPP4 by KLK5 may be responsible for the decreased serum DPP4 levels in HT patients.