Search

Background: It is not known which type 2 diabetes mellitus (T2DM) patients would most benefit from dipeptidyl peptidase-4 (DPP-4) inhibitor treatment. We aimed to investigate the predictors of response to DPP-4 inhibitors considering degree of DPP-4 inhibition.Methods: This study is a post hoc analysis of a 24-week, randomized, double-blind, phase III trial that compared the efficacy and safety of a DPP-4 inhibitor (gemigliptin vs. sitagliptin) in patients with T2DM. Subjects were classified into tertiles of T1 2=0.281, B=–0.014, P=0.024).Conclusion: This study showed that HbA1c reduction by DPP-4 inhibitor was associated with increasing age, and this association was linked with higher DPP-4 inhibition.

Free fatty acid (FFA) deposition in non-adipose tissues such as the heart is a characteristic of insulin resistant states which feature hyperinsulinemia and dipeptidyl peptidase-4 (DPP-4) activation. Estrogen–progestin oral contraceptives (OC) treatment reportedly increased DPP-4 activity in rat tissue, and DPP-4 inhibitors have anti-diabetic and anti-inflammatory properties. This study aims to investigate the effects of DPP-4 inhibition on cardiac FFA deposition in estrogen–progestin-treated female rats. From our data, estrogen–progestin OC exposure in female rats led to elevated plasma insulin, cardiac DPP-4 activity, FFA and triglyceride (TG) accumulation, TG/high-density lipoprotein cholesterol (TG/HDL-C) ratio, adenosine deaminase/xanthine oxidase/uric acid pathway (ADA/XO/UA), lipid peroxidation, glycogen synthase activity, and alanine phosphatase; whereas cardiac glucose-6-phosphate dehydrogenase, Na+/K+-ATPase and nitric oxide (NO) were decreased. However, DPP-4 inhibition resulted in decreased plasma insulin, cardiac DPP-4 activity, FFA, TG, TG/HDL-C ratio, and alkaline phosphatase. These were accompanied by reduced ADA/XO/UA pathway, lipid peroxidation, and augmented NO and Na+/K+-ATPase in estrogen–progestin OC-treated rats. DPP-4 inhibition attenuated cardiac lipid deposition accompanied by reduced activity in the ADA/XO/UA pathway in estrogen–progestin OC-treated female rats. DPP-4 is therefore a plausible therapeutic target in cardiometabolic disorders.

BACKGROUND Portal hypertension is a pathophysiological abnormality with distinct vascular derangements associated with liver cirrhosis. Dipeptidyl peptidase-4 (DPP-4) inhibitors are anti-diabetic agents which exert pleiotropic vascular effects, but their relevant impact on portal hypertension and liver cirrhosis remains unclear. This study aims to clarify this issue. METHODS Rats receiving partial portal vein-ligation (PVL) and common bile duct-ligation (BDL) served as experimental models for portal hypertension and cirrhosis, respectively. After linagliptin (a DPP-4 inhibitor) treatment, the survival rate, hemodynamics, biochemistry parameters and liver histopathology were evaluated. In addition, the collateral vascular responsiveness and severity of portal-systemic shunting were examined. mRNA and protein expression in the vasculature and liver were also examined. RESULTS Linagliptin significantly reduced portal pressure (control vs. linagliptin: 12.9±1.2 vs. 9.1±2.0 mmHg, p=0.001) and up-regulated nitric oxide synthase expression in the collateral vessel, superior mesentery artery and liver of PVL rats. However, the portal hypotensive effect was insignificant in BDL rats. Glucose plasma levels, liver and renal biochemistry parameters were not significantly altered by linagliptin. The degree of portal-systemic shunting and collateral vascular responsiveness were also not significantly altered by linagliptin treatment. Linagliptin did not improve liver fibrosis and hepatic inflammation in BDL rats. CONCLUSION DPP-4 inhibition by linagliptin reduced portal pressure in portal hypertensive rats but not in cirrhotic rats. It may act by decreasing intra-hepatic resistance via up-regulation of hepatic nitric oxide synthase in portal hypertensive rats.

Andrographis paniculata Nees, disebut juga sambiloto adalah tanaman yang berkhasiat sebagai terapi alternatif diabetes melitus (DM). Sambiloto merupakan tanaman multi-compounds yang memiliki kandungan senyawa antara lain: diterpenoid, flavonoid dan polifenol. Studi ini bertujuan menjelaskan aktivitas senyawa kimia yang terkandung di dalam batang dan daun sambiloto terhadap lima target molekular terapi DM, yaitu Dipeptidyl Peptidase 4 (DPP4), Protein Tyrosine Phosphatase (PTP1B), α-glukosidase, Glucose Transporter (GLUT) dan glukokinase. Studi ini menggunakan metode systematic review, yakni dengan membuat PRISMA checklist dan diagram flow, menetapkan kriteria inklusi-eksklusi, search engine serta kata kunci untuk mendapatkan data yang relevan. Data yang diperoleh berupa hasil penelitian primer yang disajikan dalam tabel ekstraksi data, selanjutnya ditelaah secara komprehensif. Hasil studi menunjukkan bahwa golongan senyawa diterpenoid dan flavonoid yang terkandung dalam batang dan daun sambiloto dapat memberikan aktivitas terhadap target molekular, seperti senyawa 19-trifenil isoandrografolid dapat menghambat DPP4, α-glukosidase dan mengaktivasi glukokinase; senyawa andrografolakton dapat menghambat PTP1B; senyawa deoksiandrografolid meningkatkan translokasi dan akselerasi GLUT4; senyawa 15-p-metoksibenziliden 14-deoksi-11,12-didehidroandrografolid menghambat α-glukosidase; dan Golongan flavonoid seperti senyawa apigenin mampu menghambat DPP4, PTP1B, serta mengaktivasi glukokinase.

BACKGROUND Dipeptidyl peptidase-4 (DPP4) is associated with cognitive dysfunction in patients with type 2 diabetes. AIM To assess a possible relationship between serum DPP4 and cognitive function in perinatal pregnant women with gestational diabetes mellitus (GDM). METHODS The study subjects were divided into three groups: GDM group (n = 81), healthy pregnant (HP) group (n = 85), and control group (n = 51). The Montreal Cognitive Assessment (MoCA) was used to assess the cognitive status of each group. Venous blood samples were collected to measure blood lipids, glycated hemoglobin, and glucose levels. For each participant, a 3-mL blood sample was collected and centrifuged, and the serum was collected. Blood samples were stored at -80 ℃, and DPP4, interleukin-6 (IL-6), and 8-iso-prostaglandin F2α (8-iso-PGF2α), and brain-derived neurotrophic factor (BDNF) were detected using ELISA. RESULTS The MoCA scores in the GDM and HP groups were significantly different from those in the control group in terms of visuospatial/executive function and attention (P < 0.05); however, the scores were not significantly different between the GDM and HP groups (P > 0.05). In terms of language, the GDM group had significantly different scores from those in the other two groups (P < 0.05). In terms of memory, a significant difference was found between the HP and control groups (P < 0.05), as well as between the GDM and HP groups. The levels of DPP4, IL-6, and 8-iso-PGF2α in the GDM group were significantly higher than those in the HP and control groups (P < 0.05); however, the differences between these levels in the HP and control groups were not significant (P > 0.05). The level of BDNF in the GDM group was significantly lower than that in the HP and control groups (P < 0.05), although the difference in this level between the HP and control groups was not significant (P > 0.05). CONCLUSION Cognitive dysfunction in perinatal pregnant women with GDM mainly manifested as memory loss, which might be associated with elevated DPP4 levels.

Dipeptidyl peptidase IV inhibitor (DPP-4i) has been shown to act either as a promoter or as a suppressor for cancer. Although epidemiologic studies suggest that DPP-4i does not correlate with the development of malignancies, its effects on cancer metastases are controversial. We evaluated the impact of DPP-4i on postoperative outcomes of the diabetic patients with colorectal cancer and microscopic features of the resected tumors. In 260 consecutive patients with type 2 diabetes mellitus (T2DM) who underwent curative resection of colorectal cancer, the correlation between DPP-4i use and prognosis was retrospectively examined. Expression of Zeb1 on tumor cells and density of infiltrating immune cells were quantitatively evaluated with multicolor IHC in 40 tumors from DPP-4i users, 40 tumors from propensity score–matched users, and 40 tumors from nonusers. Postoperative disease-free survival (DFS) was significantly lower in 135 patients treated with DPP-4i compared with 125 nontreated patients [5-year DFS, 73.7% vs. 87.4%; HR, 1.98; 95% confidence interval (CI), 1.05–3.71; P = 0.035]. IHC revealed that the number of Zeb1+ tumor cells increased in tumors from DPP-4i–treated patients than tumors from nonusers (P < 0.01). The densities of CD3+ and CD8+ T cells were significantly lower in tumors from DPP-4i users (P < 0.01) with decreased density of tertiary lymphoid structures (P < 0.001). However, the density of M2-type tumor-associated macrophages with CD68+ CD163+ phenotypes was significantly higher (P < 0.01) in tumors from DPP-4i users. Exposure of colorectal cancer to DPP-4i may accelerate epithelial-to-mesenchymal transition (EMT) creating a tumor-permissive immune microenvironment, which might impair the outcomes of the patients with colorectal cancer and T2DM. Significance: DPP-4i has been shown to enhance the antitumor effects of immunotherapy. However, we found that DPP-4i significantly impairs the outcomes of patients with colorectal cancer who underwent curative resection, possibly through acceleration of EMT and creation of a tumor-permissive immune microenvironment. This suggests that DPP-4i must be used with caution until its safety is fully confirmed by further studies of the mechanistic effects on existing cancers in humans.

Alzheimer’s disease (AD) is the most common reason for progressive dementia in the elderly. It has been shown that disorders of the mammalian/mechanistic target of rapamycin (mTOR) signaling pathways are related to the AD. On the other hand, diabetes mellitus (DM) is a risk factor for the cognitive dysfunction. The pathogenesis of the neuronal impairment caused by diabetic hyperglycemia is intricate, which contains neuro-inflammation and/or neurodegeneration and dementia. Glucagon-like peptide-1 (GLP1) is interesting as a possible link between metabolism and brain impairment. Modulation of GLP1 activity can influence amyloid-beta peptide aggregation via the phosphoinositide-3 kinase/AKT/mTOR signaling pathway in AD. The GLP1 receptor agonists have been shown to have favorable actions on the brain such as the improvement of neurological deficit. They might also exert a beneficial effect with refining learning and memory on the cognitive impairment induced by diabetes. Recent experimental and clinical evidence indicates that dipeptidyl-peptidase-4 (DPP4) inhibitors, being currently used for DM therapy, may also be effective for AD treatment. The DPP-4 inhibitors have demonstrated neuroprotection and cognitive improvements in animal models. Although further studies for mTOR, GLP1, and DPP4 signaling pathways in humans would be intensively required, they seem to be a promising approach for innovative AD-treatments. We would like to review the characteristics of AD pathogenesis, the key roles of mTOR in AD and the preventive and/ or therapeutic suggestions of directing the mTOR signaling pathway.

BACKGROUND Dipeptidyl peptidase-4 (DPP-4) inhibitors are a generally safe and well tolerated antidiabetic drug class with proven efficacy in type 2 diabetes mellitus (T2DM). Recently, a series of large, randomized controlled trials (RCTs) addressing cardiovascular outcomes with DPP-4 inhibitors have been published. AIM To pool data from the aforementioned trials concerning the impact of DPP-4 inhibitors on surrogate cardiovascular efficacy outcomes and on major cardiac arrhythmias. METHODS We searched PubMed and grey literature sources for all published RCTs assessing cardiovascular outcomes with DPP-4 inhibitors compared to placebo until October 2020. We extracted data concerning the following “hard” efficacy outcomes: fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, hospitalization for heart failure, hospitalization for unstable angina, hospitalization for coronary revascularization and cardiovascular death. We also extracted data regarding the risk for major cardiac arrhythmias, such as atrial fibrillation, atrial flutter, ventricular fibrillation and ventricular tachycardia. RESULTS We pooled data from 6 trials in a total of 52520 patients with T2DM assigned either to DPP-4 inhibitor or placebo. DPP-4 inhibitors compared to placebo led to a non-significant increase in the risk for fatal and non-fatal myocardial infarction [risk ratio (RR) = 1.02, 95%CI: 0.94-1.11, I2 = 0%], hospitalization for heart failure (RR = 1.09, 95%CI: 0.92-1.29, I2 = 65%) and cardiovascular death (RR = 1.02, 95%CI: 0.93-1.11, I2 = 0%). DPP-4 inhibitors resulted in a non-significant decrease in the risk for fatal and non-fatal stroke (RR = 0.96, 95%CI: 0.85-1.08, I2 = 0%) and coronary revascularization (RR = 0.99, 95%CI: 0.90-1.09, I2 = 0%), Finally, DPP-4 inhibitors demonstrated a neutral effect on the risk for hospitalization due to unstable angina (RR = 1.00, 95%CI: 0.85-1.18, I2 = 0%). As far as cardiac arrhythmias are concerned, DPP-4 inhibitors did not significantly affect the risk for atrial fibrillation (RR = 0.95, 95%CI: 0.78-1.17, I2 = 0%), while they were associated with a significant increase in the risk for atrial flutter, equal to 52% (RR = 1.52, 95%CI: 1.03-2.24, I2 = 0%). DPP-4 inhibitors did not have a significant impact on the risk for any of the rest assessed cardiac arrhythmias. CONCLUSION DPP-4 inhibitors do not seem to confer any significant cardiovascular benefit for patients with T2DM, while they do not seem to be associated with a significant risk for any major cardiac arrhythmias, except for atrial flutter. Therefore, this drug class should not be the treatment of choice for patients with established cardiovascular disease or multiple risk factors, except for those cases when newer antidiabetics (glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors) are not tolerated, contraindicated or not affordable for the patient.

AIMS/INTRODUCTION We assessed the association between dipeptidyl peptidase-4 inhibitors (DPP-4is) and bullous pemphigoid (BP) and time-dependent changes in the risk for developing BP after DPP-4i initiation. MATERIALS AND METHODS The present population-based, real-world study was carried out using the Japanese National Database dataset collected between 2013 and 2018. To assess independent correlations between DPP-4is and the development of BP, the self-controlled case series method was used. RESULTS Among the cohort followed up for a median of 1,540 days, 53,027 patients were likely to develop BP. The possible incidence rate of BP in all 150,328,339 patients was 10.4/100,000 person-years. Among the 9,705,814 patients with type 2 diabetes, 15,634 were likely to develop BP. The possible incidence rate of BP in patients with type 2 diabetes was 38.1/100,000 person-years, whereas that in patients with type 2 diabetes who did and did not use DPP-4is was 40.7 and 30.0/100,000 person-years, respectively. Analysis of the 28,705 patients with type 2 diabetes likely to develop BP after initial DPP-4i use showed a risk ratio of 2.15 (95% confidence interval [CI] 1.75-2.63), 1.70 (95% CI 1.37-2.11), 1.44 (95% CI 1.15-1.82), 1.25 (95% CI 0.98-1.59), 0.84 (95% CI 0.63-1.10), 0.84 (95% CI 0.64-1.11) and 1.05 (95% CI 0.92-1.20), for the risk period of ≤30, 31-60, 61-90, 91-120, 121-150, 151-180 and 181-365 days, respectively. CONCLUSIONS Although DPP-4is were associated with increased risk for BP, the risk was particularly significant within 3 months from first use.

Background Coronavirus disease 2019 (COVID-19) is a recent pandemic infectious disease caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2). COVID-19 may lead to acute kidney injury (AKI). Main text SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) and dipeptidyl peptidase 4(DPP4) as entry point receptors in the alveolar type II cell of the lung. However, the expression of ACE2 is 100-fold higher in kidney tissue than the lung, though the potential entry point of SARS-CoV-2 for renal tissue and induction of AKI remains undefined. Therefore, reduction of ACE2 and high circulating angiotensin II in COVID-19 may together participate in the induction of AKI. Thereby, direct ACE2 activator is under investigation to be used as an effective therapy in the management COVID-19-induced AKI. Besides, the direct effect via invasion of SARS-CoV-2 may lead to glomerulopathy and renal proximal tubular necrosis. Conclusion COVID-19 may associate with AKI due to direct effect of SARS-CoV-2 through ACE2 and DPP4 receptors or indirectly through the development of cytokine storm. Both ACE2 and DPP4 are interacted mutually in the pathogenesis of AKI. Thus, DPP4 inhibitors or ACE2 activators could reverse early AKI in COVID-19. Therefore, emerging of clinical trials is warranted to confirm the role of ACE2 and DPP4 modulators in COVID-19-induced AKI.

CONTEXT Inflammatory and immune pathways play a crucial role in the pathophysiology of non-alcoholic fatty liver disease (NAFLD). Sitagliptin blocks the dipeptidyl peptidase-4 (DPP-4) enzyme, mechanisms that alter inflammatory pathways and the innate immune system, and by which Sitagliptin affects the pathogenesis of NAFLD weren't previously discussed. OBJECTIVE This study aims to understand the interaction between Sitagliptin and innate immune response in order to meliorate NAFLD. METHODS Thirty- two Wistar male albino rats were categorised into four groups. Rats have received a standard diet or a high-fat diet either with or without Sitagliptin. Serum HMGB1, protein and mRNA expressions of hepatic TLR4 and NF-κB, inflammatory cytokines, and histopathological changes were analysed. RESULTS An ameliorative action of Sitagliptin in NAFLD was demonstrated via decreasing HMGB1-mediated TLR4/NF-κB signalling in order to suppress inflammation and reduce insulin resistance. CONCLUSION Sitagliptin may in fact prove to be a beneficial therapeutic intervention in NAFLD.

Introduction The aim of this study was to assess the efficacy and safety of switching to teneligliptin from other dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes mellitus (T2DM) inadequately controlled despite treatment with a stable dose of other DPP-4 inhibitors. Methods Patients with glycosylated hemoglobin (HbA1c) ≥ 7% despite taking DPP-4 inhibitors other than teneligliptin, with or without other antidiabetic agents, for at least 3 months were enrolled in this study. Patients on DPP-4 inhibitors administered prior to participation in this study were switched to 20 mg teneligliptin once daily and the dose was maintained for the 52-week study period. The primary endpoint was the change in HbA1c at week 12. Fasting plasma glucose (FPG) and the blood lipid profile were also evaluated. Adverse events were monitored for safety assessment. Results At weeks 12, 24, and 52, the HbA1c values significantly decreased by − 0.39, − 0.44, and − 0.52%, respectively, compared to the baseline value (p

As a common chronic metabolic disease, the development of diabetes mellitus (DM) may also be accompanied by liver damage and inflammatory disorders. Sitagliptin is an inhibitor of dipeptidyl peptidase-4 (DPP4, also known as CD26), which is clinically used for DM treatment. However, the mechanism of sitagliptin’s efficiency in liver diseases is largely unknown. In this study, mice suffering from streptozotocin (STZ) exhibit elevated liver DPP4 expression and activity, as well as inflammatory and chronic liver injury phenotype, whereas specifically inhibiting the activity of DPP4 in mouse liver tissues and hepatocytes by sitagliptin contributes to decreased cytokines, oxidative stress, cell apoptosis, and inflammation in STZ-induced diabetic mice. Moreover, sitagliptin reduced TNFα or LPS-induced cellular reactive oxygen species (ROS) level, cell apoptosis, and protein expression in the NFκB signaling pathway in HepG2 cells or primary mouse hepatocytes. Altogether, our study confirms that sitagliptin may protect liver tissue by alleviating ROS production and NFκB signaling activation, providing a putative mechanism for preventing the development of diabetic liver disease.

The cardiovascular (CV) safety of glucagon-like peptide 1 (GLP-1) receptor agonists has been established in robust cardiovascular outcomes trials (CVOTs) in patients with type 2 diabetes at high CV risk. The GLP-1 receptor agonists liraglutide, dulaglutide, and injectable semaglutide demonstrated a significant CV benefit in these trials and now have indications to reduce the risk of major adverse CV events, including CV death, myocardial infarction, and stroke in adult patients with type 2 diabetes and established cardiovascular disease or high CV risk (dulaglutide). The dipeptidyl peptidase 4 inhibitors have also demonstrated CV safety in dedicated CVOTs but have not been associated with any CV benefit. Guidelines for the treatment of type 2 diabetes have evolved from a glucocentric focus to one that now focuses on reducing overall CV risk by personalizing therapy and using drugs such as GLP-1 receptor agonists with proven CV benefits.

Dipeptidyl peptidase 4 inhibitors (DPP-4i) are associated with an increased risk of developing bullous pemphigoid (BP) in patients with diabetes. Autoantibodies targeting epitopes on the processed BP180, 120-kDa (LAD-1), and 97-kDa (LABD97) linear immunoglobulin (Ig)A dermatosis antigens are the major autoantibodies in DPP-4i-associated BP. However, no case of mucous membrane pemphigoid (MMP) developing during treatment with DPP-4i has been reported. We report a case of MMP associated with DPP-4i. A man in his late 70s presented with oral mucous membrane erosion and a few blisters on his upper chest and back. He had used linagliptin for diabetes for over 1 year when he presented. The immunological characteristics were similar to DPP4i-associated BP: higher reactivity to LAD-1 and LABD97 than to the full-length BP180. The aphthae achieved remission after oral linagliptin was replaced with sitagliptin. However, 6 months later, the aphthae relapsed and any DPP-4i was discontinued. The aphthae disappeared, and now he is completely free from lesions associated with MMP. This case suggests that the DPP-4i may have shared roles in the production of IgG antibodies to LAD-1 or to LABD97 in the pathogenesis of DPP-4i-associated BP and MMP. Our case highlights the possibility of overlooking the mild MMP in DPP-4i-treated diabetes patients with mucosal lesions.

The leaves and fruits of Aegle marmelos (L.) have antidiabetic activity. However, the mode of action and molecules having antidiabetic activity are not known. Hence, we conducted molecular docking of phytochemicals with various molecular antidiabetic targets to find the same. Docking prioritized Dipeptidyl peptidase-4 (DPP-4) as the main target for phytochemicals of Aegle marmelos. DPP-4 inactivates intestinal peptides, glucagon-like peptide-1 (GLP-1), and Gastric inhibitory polypeptide (GIP). GLP-1 and GIP stimulate a decline in blood glucose levels, but DPP-4 inhibits their functions resulting high level of glucose. Hence inhibiting the activity of DPP-4 is a well-known strategy to treat Type 2 diabetes. Therefore, to find a mechanism that may be involved to act as a natural inhibitor of DPP-4, we screened five phytochemicals out of seventy-three based on Virtual Screening, ADMET Drug-likeness analysis, and PAINS filtering. Further, all five phytochemicals, i.e. Aegeline, Citral, Marmesinin, Auraptene, β-Bisabolene, and reference compound subjected MDS for analyzing the stability of docked complexes to assess the fluctuation and conformational changes during protein-ligand interaction. The values of RMSD, RG, RMSF, SASA, and Gibbs energy revealed the good stability of these phytochemicals in the active site pocket of DPP-4 in comparison to reference. Additionally, we have done the pharmacophore analysis, which revealed many common pharmacophore features between screened phytochemicals of A. marmelos and reference molecule. Our results show that these phytochemicals are potential antidiabetic candidates and can be further modified and evaluated to develop more effective antidiabetic drugs against DPP-4 to treat Type 2 Diabetes. Communicated by Ramaswamy H. Sarma.

Aims Studies examining the prevalence of and factors associated with switching from sulphonylureas (SUs) to dipeptidyl peptidase 4 (DPP-4) inhibitors in real-world settings are lacking. We assessed the factors associated with switching from SUs to DPP-4 inhibitors in the United States. Materials and methods This retrospective cohort study was conducted using the Optum Clinformatics® Data Mart (2009-2018). Adults with type 2 diabetes and newly prescribed at least two SUs were included and were followed for 2 years after the initiation of SU (index date). We compared the characteristics of those who switched from SUs to DPP-4 inhibitors (only; no additional antidiabetic drugs) with those who continued with SUs (without adding other antidiabetic drugs) using multivariate logistic regression. Multinomial regression analyses were also conducted to assess the factors associated with switching to different drug classes versus continuation with SUs. Results In a sample of 119 107 new SU users, 2.2% (2633) switched to DPP-4 inhibitors, 3.8% (4542) switched to antidiabetic drugs other than DPP-4 inhibitors, 68.3% (81 394) discontinued SUs but did not switch to another antidiabetic drug, 12.9% (15 345) continued with SUs and added other antidiabetic drugs, and 12.8% (15 193) continued with SUs only. Multivariate logistic regression showed that those who had significantly higher likelihood of switching were younger, female [vs. males; adjusted odds ratio (AOR) = 0.70], and living in the south; had previous use of DPP-4 inhibitors (AOR = 1.71); were not using antidiabetic drugs at baseline; had more baseline diabetes-related emergency room visits (AOR = 1.13), depression (AOR = 1.34), post-index hypoglycaemia (AOR = 2.20), and an earlier index year; and were glyburide users (vs. glimepiride users; AOR = 1.29). Conclusions The discontinuation rate for SUs is high. Factors associated with switching from SUs to DPP-4 inhibitors included age, sex, geographic region, baseline antidiabetic drug use, type of SU, baseline diabetes-related emergency room visits, hypoglycaemia and depression.

Introduction Metformin has demonstrated favorable effects on glycemic control in patients with type 2 diabetes (T2D), regardless of the body mass index (BMI). On the contrary, dipeptidyl peptidase-4 inhibitors (DPP-4is) are reportedly less effective in patients having high BMI values (≥ 25 or ≥ 30). The aim of this study was to compare metformin and DPP-4is as first-line treatment for their effects on glycemic control and improvement of other health outcomes among obese and non-obese Japanese patients with T2D. Methods A Japanese health insurance claims database that also included annual medical checkup data was used. This database included data on company employees who were members of health insurance societies and their family members. Most patients were aged 6.5%; primary outcome) and changes in fasting plasma glucose, BMI, triglyceride, cholesterol, and abdominal circumference (secondary outcomes) at 12 months from baseline were compared between treatments. Results When evaluated relative to the baseline BMI, the mean reduction rate in excessive HbA1c tended to be higher in the metformin group than in the DPP-4i group, especially in patients with BMI ≥ 25. Similarly, significant improvement was observed in most outcomes in obese patients prescribed metformin compared to those prescribed a DPP-4i. In contrast, in patients with BMI

Medications used to treat diabetes mellitus are heterogeneous, with widely differing safety profiles in therapeutic use and in overdose. Insulin overdose may produce severe and prolonged hypoglycemia. Sulfonylurea poisoning should be treated with octreotide, sparing intravenous dextrose where possible. Acute metformin overdose may lead to life-threatening acidosis with elevated lactate concentrations, which may require hemodialysis. Glucagon-like peptide 1 agonists and dipeptidyl peptidase 4 inhibitors are benign in overdose in diabetic patients but may produce profound hypoglycemia in nondiabetic patients. Euglycemic diabetic ketoacidosis may develop in critically ill patients taking sodium-glucose co-transporter 2 inhibitors.

Exposure to chronic psychosocial stress is a risk factor for various pulmonary diseases. In view of the essential role of dipeptidyl peptidase 4 (DPP4) in animal and human lung pathobiology, we investigated the role of DPP4 in stress-related lung injury in mice. Eight-week-old male mice were randomly divided into a non-stress group and a 2-week immobilization stress group. Non-stress control mice were left undisturbed. The mice subjected to immobilized stress were randomly assigned to the vehicle or the DPP4 inhibitor anagliptin for 2 weeks. Chronic stress reduced subcutaneous and inguinal adipose volumes and increased blood DPP4 levels. The stressed mice showed increased levels in the lungs of genes and/or proteins related to oxidative stress (p67phox, p47phox, p22phox and gp91phox), inflammation (monocyte chemoattractant protein-1, vascular cell adhesion molecule-1, and intracellular adhesion molecule-1), apoptosis (caspase-3, -8, -9), senescence (p16INK4A, p21, and p53) and proteolysis (matrix metalloproteinase-2 to -9, cathepsin S/K, and tissue inhibitor of matrix metalloproteinase-1 and -2), and reduced levels of eNOS, Sirt1, and Bcl-2 proteins; and these effects were reversed by genetic and pharmacological inhibitions of DPP4. We then exposed human umbilical vein endothelial cells in vitro to hydrogen peroxide; anagliptin treatment was also observed to mitigate oxidative and inflammatory molecules in this setting. Anagliptin can improve lung injury in stressed mice, possibly by mitigating vascular inflammation, oxidative stress production, and proteolysis. DPP4 may become a new therapeutic target for chronic psychological stress-related lung disease in humans and animals.

Affecting the vast majority of the population, diabetes has become one of the major causes of death in India and the world. With the growing number of diabetic people in India, one in six people in the world with diabetes is from India. Bacopa monnieri is a wonder herb having many pharmacological applicaions. Traditionally, Brahmi is used to improve memory and concentration. Asthma, bronchitis, gastric ulcers, irritable bowel syndrome, anxiety, etc. DDP-4 inhibitors cause antihyperglycemic effect and regulates blood glucose. PPARs effectively regulates blood glucose levels and reduce triglycerides. The isoform of PPARs i.e., PPARγ plays a vital role in insulin sensitivity. The role of these protein receptors in treating T1DM is under research. Though few instances prove their effectiveness to treat T1DM, its efficacy is questionable and requires more research input. Branched chain and aromatic amino acids like tyrosine and glutamine have their functional role in regulating blood glucose level and onset of diabetic conditions. Bioactive ligands like Jujubogenin, bacogenin and luteolin are selected based on their interactions and binding affinity. T1DM mainly affects children and prediabetic period before the onset of T1DM provides us the golden opportunity to treat or suppress the condition through medical interventions. Thus, the ligand-macromolecule interaction and their efficacy in controlling Type-1 diabetes mellitus is the basis of this study.

Background Sodium glucose co-transporter 2 inhibitors (SGLT2is) prevent hospitalization resulting from heart failure (HHF). However, patients with type 2 diabetes mellitus use multiple antihyperglycemic drugs to achieve glycosylated hemoglobin (HbA1c) targets. In these drug combinations, the risk of HHF is unpredictable and so is the parallel effect of glucose-lowering. Purpose To examine the impact of antihyperglycemic drugs and their association on HHF. Data Sources Forty randomized controlled trials (RCTs) reporting HHF. Study Selection Published RCTs were the data source. Data Extraction Incidence rates of HHF. Data Synthesis Random additive-effects network meta-analysis showed that metformin (P = 0.55), sulfonylureas (P = 0.51), glucagon-like peptide-1 receptor-agonist (P = 0.16), and dipeptidyl peptidase 4 inhibitors (DPP4is; P = 0.54) were neutral on the risk of HHF. SGLT2is and SGLT2is + DPP4is reduced the risk of HHF with a hazard ratio (HR) of 0.68 (95% CI, 0.60-0.76; P Limitations There are no data to verify drug combinations available for clinical use and to discriminate the effect of drugs within each of the therapeutic classes. Conclusions The risk of HHF is reduced by SGLT2is as monotherapy or in combination with DPP4is and increased by TZDs as monotherapy or in combination. Glucose-lowering provides an additive effect of reducing HHF.

Dipeptidyl-peptidase 4 (DPP4) is a multifunctional type II transmembrane glycoprotein that is expressed on various cell surfaces. While DPP4 inhibitors have a therapeutic role in the treatment of diabetes mellitus, they are an independent risk factor in the development of bullous pemphigoid. Contrarily, there are reports of improvement in psoriasis with DPP4 inhibition. We investigated the effect of DPP4 inhibition on primary human keratinocytes to determine whether DPP4 modulates keratinocyte inflammatory signaling and keratinocyte homeostasis. We performed RNA sequencing of primary adult human keratinocytes treated with DPP4 inhibitor, identifying 424 differentially expressed genes. Gene ontology analysis revealed significant enrichment of epidermal differentiation and cornified envelope genes. Using three-dimensional organotypic cultures and a pan-late cornified envelope 2 (LCE2) antibody, we demonstrate a dose dependent relationship between DPP4 inhibition and increased expression of LCE2 during epidermal development. The late cornified envelope gene clusters are expressed at the late stages of epithelial development, responding to stimuli such as calcium and ultraviolet light. While its biologic function is not fully understood, mutations in LCE3B/LCE3C confer a 40% increased risk in the development of plaque psoriasis. While we did not identify significant modulation of keratinocyte inflammatory markers, DPP4 inhibition increased expression of the late cornified envelope may offer a potential alternative therapeutic mechanism in psoriasis.

Visual Abstract, Highlights • Treatment with linagliptin, a DPP-4 inhibitor, alleviates not only EAM but also ICIM. • DPP-4 physically interacts with cathepsin G and enhances its activity. • Linagliptin promotes SerpinA3N activity, thereby suppressing cathepsin G activity. • Cathepsin G aggravates EAM through upregulating angiotensin II. • Linagliptin suppresses oxidative stress in EAM hearts., Summary This study sought to show the mechanism of how to ameliorate experimental autoimmune myocarditis (EAM) by administering dipeptidyl peptidase (DPP)-4 inhibitor linagliptin. The number of RAR-related orphan nuclear receptor gamma–positive Th17 cells infiltrated to the EAM myocardium was significantly attenuated by linagliptin treatment. Tandem mass spectrometry–based analysis demonstrated that DPP-4 binds to cathepsin G in EAM hearts, thereby protecting cathepsin G activity through inhibiting SerpinA3N activity. Linagliptin suppresses oxidative stress in EAM hearts as well. Thus, we found that DPP-4 plays a detrimental role in the progression of EAM by interacting with cathepsin G, which, in turn, suppresses SerpinA3N activity.

The global high prevalence of diabetes mellitus has resulted into the development of several oral hypoglycemic agents. However, these drugs have limited efficacy and harmful side effects, which call for the search for alternatives from natural sources. The inhibition of dipeptidyl peptidase‐4 (DPP‐4) activity increases the level of glucagon‐like peptide‐1 and glucose‐dependent insulinotropic polypeptide, which in turn reduces hyperglycemia by activating insulin secretion and inhibiting glucagon secretion. Some studies have reported the in vitro DPP‐4 inhibitory potential of functional foods, but there is no repository of information on these reports. This article is an attempt to present in concise form, reports of functional foods with DPP‐4 inhibitory potentials in vitro. This will guide the use of these foods as well as in antidiabetic drug development.

The current study aimed to investigate the molecular mechanisms of metformin and vitamin D3-induced nephroprotection in a metabolic syndrome (MetS) rat model, evaluating the capacity of vitamin D3 to potentiate metformin action. MetS was induced by 10% fructose in drinking water and 3% salt in the diet. After 6 weeks, serum lipid profile and uric acid were measured, an oral glucose tolerance test (OGTT) was performed, and kidney function was investigated. In conjunction with the same concentrations of fructose and salt feeding, MetS rats with significant weight gain, dyslipidemia, hyperuricemia, and dysglycemia were treated orally with metformin (200 mg/kg), vitamin D3 (10 µg/kg), or both daily for 6 weeks. At the end of the study period, anthropometrical parameters were recorded, OGTT was reperformed, urine and blood samples were collected, and tissue samples were harvested at sacrifice. MetS rats showed dramatically declined renal function, enhanced intrarenal oxidative stress and inflammation, and extravagant renal histopathological damage with interstitial fibrosis. Metformin and vitamin D3 significantly reversed all the aforementioned deleterious effects in MetS rats. The study has verified the nephroprotective effects of metformin and vitamin D3 in MetS, accentuating the critical role of AMP-activated protein kinase/sirtuin-1 activation and dipeptidyl peptidase-4 inhibition. Given the synergistic effects of the combination, vitamin D3 is worth being investigated as an additional therapeutic agent for preventing MetS-induced nephropathy.