Docking Study of Naphthalene Compounds from Eleutherine Bulbosa as Antidiabetic Agents on Multiple Receptors

New Glucose-Lowering Agents for Diabetic Kidney Disease.

Benefit-risk assessment of incretin and other anti-diabetic agents in type 2 diabetes using a stochastic multicriteria acceptability analysis model.

Sabino-Silva R. Na+/glucose cotransporter SGLT1 in the salivary glands of diabetic and hypertensive rats: role of sympathetic outflow and protein kinase A activity [PhD. thesis]. Sao Paulo: Instituto de Ciencias Biomedicas, Universidade de Sao Paulo; 2010. Salivary dysfunctions have been described in diabetic and hypertensive subjects. The stoichiometric relationship of transport capacity of the sodium glucose cotransporter 1 (SGLT1) protein is 2 Na:1 glucose:264 H2O molecules. We hypothesized that the sodium-glucose cotransporter 1 (SGLT1) participates in salivary dysfunctions, through the sympatheticand protein kinase A(PKA) induced regulation of SGLT1. The analysis were performed in Wistar Kyoto rats (WKY), diabetic WKY (WKY-D), spontaneously hypertensive rats (SHR), diabetic SHR (SHR-D). Rats were rendered diabetic (WKY-D or SHR-D) by a single intravenous injection of alloxan (40 mg/Kg body weight). The parotid and submandibular glands were harvested for SLC5A1 and SLC2A1 gene expression (RT-PCR) and SGLT1, GLUT1 and PKA protein content (Western blotting and/or immunohistochemistry) analysis. Moreover, sympathetic nerve activity to the salivary glands was measured in post-ganglionic fibers. Diabetes decreased the nerve activity in WKY and SHR (~50%, P<0.05), pointing out that it was 250% higher in SHR, as compared to WKY (P<0.001). The regulation of catalytic subunit of PKA was parallel to the sympathetic nerve activity. Plasma membrane SGLT1 protein content increased in SHR (~130%, p<0.001) and decreased in WKY-D (~50%, P<0.05), as compared with WKY. Moreover, in diabetic and/or hypertensive rats, imunohistochemical analysis showed increased SGLT1 protein in luminal membrane of ductal cells, where it may promote water uptake, reducing the salivary flow. Confirming that, nonstimulated salivary secretion was reduced (~50%, p<0.001) in WKY-D, SHR and SHR-D rats. No differences were observed in GLUT1 mRNA and protein in plasma membrane. The results show a highly coordinated regulation of sympathetic activity, catalytic subunit of PKA and SGLT1 protein in plasma membrane of acinar cells of salivary glands in diabetic, hypertensive or not, rats. Importantly, in luminal membrane of ductal cells SGLT1 protein increased inversely proportional to the nonstimulated salivary flux in diabetic and hypertensive rats. This indicates the water transporter role of SGLT1, and, by increasing salivary water reabsorption, may explain the hyposalivation complained by diabetic and hypertensive subjects.

The coronavirus disease 2019 (COVID-19) pandemic is caused by a novel betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), similar to SARS-CoV and Middle East respiratory syndrome (MERS-CoV), which cause acute respiratory distress syndrome and case fatalities. COVID-19 disease severity is worse in older obese patients with comorbidities such as diabetes, hypertension, cardiovascular disease, and chronic lung disease. Cell binding and entry of betacoronaviruses is via their surface spike glycoprotein; SARS-CoV binds to the metalloprotease angiotensin-converting enzyme 2 (ACE2), MERS-CoV utilizes dipeptidyl peptidase 4 (DPP4), and recent modeling of the structure of SARS-CoV-2 spike glycoprotein predicts that it can interact with human DPP4 in addition to ACE2. DPP4 is a ubiquitous membrane-bound aminopeptidase that circulates in plasma; it is multifunctional with roles in nutrition, metabolism, and immune and endocrine systems. DPP4 activity differentially regulates glucose homeostasis and inflammation via its enzymatic activity and nonenzymatic immunomodulatory effects. The importance of DPP4 for the medical community has been highlighted by the approval of DPP4 inhibitors, or gliptins, for the treatment of type 2 diabetes mellitus. This review discusses the dysregulation of DPP4 in COVID-19 comorbid conditions; DPP4 activity is higher in older individuals and increased plasma DPP4 is a predictor of the onset of metabolic syndrome. DPP4 upregulation may be a determinant of COVID-19 disease severity, which creates interest regarding the use of gliptins in management of COVID-19. Also, knowledge of the chemistry and biology of DPP4 could be utilized to develop novel therapies to block viral entry of some betacoronaviruses, potentially including SARS-CoV-2.

In 1964, studies in just 2 subjects offered a simple, salient, and fundamental observation reported in 612 words: Glucose induces a greater insulin response when introduced through the gastrointestinal tract than when injected intravenously (the Figure, A).2 This finding built on studies dating to 1928 that injecting extracts of small intestine into animals lowered their glucose levels. Subsequently, this incretin effect was found to be mediated by glucagon-like peptide-1 (GLP1) and its action on pancreatic GLP1 receptors, in addition to contributions from glucose-dependent insulinotropic polypeptide.3,4 Moreover, the incretin response was found to be impaired in those with type 2 diabetes mellitus (T2D). We now know that the incretin axis also includes the enzyme dipeptidyl peptidase-IV (DPPIV), a serine protease that rapidly degrades GLP1 and other proteins.5 Ultimately, this arc of discovery led to new approved antidiabetic therapies: GLP1 analogs (exenatide, liraglutide) and DPPIV inhibitors (saxagliptin, sitagliptin, and, outside the United States, vildagliptin).4 For both classes of drugs, early preclinical experiments and smaller human studies suggest that targeting the incretin axis might address the elusive goal of an antidiabetic agent that improves cardiovascular disease.6,7 In the current issue of Circulation , Shah et al8 add this evolving story with their report that alogliptin, a DPPIV inhibitor in development, limits atherosclerosis and inflammation in 2 different mouse models. Given the increasing clinical use of approved incretin modulators, current large cardiovascular outcome trials with GLP1 agents and DPPIV inhibitors, and ongoing development of novel agents that target incretin signaling, further consideration of how the incretin axis might intersect the cardiovascular system is well warranted. Figure. A , The incretin effect. The well-documented phenomenon of oral glucose eliciting a higher insulin response than intravenous glucose at identical plasma levels of glucose is known as …

Proteases catalyse irreversible posttranslational modifications that often alter a biological function of the substrate. The protease dipeptidyl peptidase 4 (DPP4) is a pharmacological target in type 2 diabetes therapy primarily because it inactivates glucagon-like protein-1. DPP4 also has roles in steatosis, insulin resistance, cancers and inflammatory and fibrotic diseases. In addition, DPP4 binds to the spike protein of the MERS virus, causing it to be the human cell surface receptor for that virus. DPP4 has been identified as a potential binding target of SARS-CoV-2 spike protein, so this question requires experimental investigation. Understanding protein structure and function requires reliable protocols for production and purification. We developed such strategies for baculovirus generated soluble recombinant human DPP4 (residues 29–766) produced in insect cells. Purification used differential ammonium sulphate precipitation, hydrophobic interaction chromatography, dye affinity chromatography in series with immobilised metal affinity chromatography, and ion-exchange chromatography. The binding affinities of DPP4 to the SARS-CoV-2 full-length spike protein and its receptor-binding domain (RBD) were measured using surface plasmon resonance and ELISA. This optimised DPP4 purification procedure yielded 1 to 1.8 mg of pure fully active soluble DPP4 protein per litre of insect cell culture with specific activity >30 U/mg, indicative of high purity. No specific binding between DPP4 and CoV-2 spike protein was detected by surface plasmon resonance or ELISA. In summary, a procedure for high purity high yield soluble human DPP4 was achieved and used to show that, unlike MERS, SARS-CoV-2 does not bind human DPP4.

CD26 or dipeptidyl-peptidase IV (DPPIV) is engaged in immune functions by co-stimulatory effects on activation and proliferation of T lymphocytes, binding to adenosine deaminase, and regulation of various chemokines and cytokines. DPPIV peptidase activity is inhibited by both Tat protein from human immunodeficiency virus (HIV)-1 and its N-terminal nonapeptide Tat-(1-9) with amino acid sequence MDPVDPNIE, suggesting that DPPIV mediates immunosuppressive effects of Tat protein. The 2.0- and 3.15-A resolution crystal structures of the binary complex between human DPPIV and nonapeptide Tat-(1-9) and the ternary complex between the variant MWPVDPNIE, called Trp(2)-Tat-(1-9), and DPPIV bound to adenosine deaminase show that Tat-(1-9) and Trp(2)-Tat-(1-9) are located in the active site of DPPIV. The interaction pattern of DPPIV with Trp(2)-Tat-(1-9) is tighter than that with Tat-(1-9), in agreement with inhibition constants (K(i)) of 2 x 10(-6) and 250 x 10(-6) m, respectively. Both peptides cannot be cleaved by DPPIV because the binding pockets of the N-terminal 2 residues are interchanged compared with natural substrates: the N-terminal methionine occupies the hydrophobic S1 pocket of DPPIV that normally accounts for substrate specificity by binding the penultimate residue. Because the N-terminal sequence of the thromboxane A2 receptor resembles the Trp(2)-Tat-(1-9) peptide, a possible interaction with DPPIV is postulated.

Objective. To review the efficacy, safety, and tolerability of combination treatment regimens including a dipeptidyl peptidase-4 (DPP-4) inhibitor and/or sodium-glucose cotransporter 2 (SGLT2) inhibitor for type 2 diabetes mellitus (T2DM). Methods. Clinical trials of combination therapies including a DPP-4 and/or SGLT2 inhibitor were identified through a PubMed database search. To be included, studies had to have a primary end point of change from baseline to ≥24 weeks in glycated hemoglobin, include ≥1 other oral antidiabetic drug (OAD), and have randomized more than 200 patients. Results were limited to medications approved by the US Food and Drug Administration at the time of the search (March 2015). Results. A total of 1534 articles for the DPP-4 inhibitor class and 434 articles for the SGLT2 inhibitor class were retrieved from PubMed. Of these, 33 articles from the DPP-4 inhibitor class and 24 articles from the SGLT2 inhibitor class were included for review. In each study, the addition of a DPP-4 or SGLT2 inhibitor as a second or third agent resulted in improved glycemic control versus comparator arms. Reductions in weight or lack of weight gain were consistently observed, as were low rates of hypoglycemic events, particularly when the combination regimen also included metformin. Overall, the pattern of adverse events observed in combination treatment groups was consistent with the known effects of the individual agents. Conclusion. Combination treatment with a DPP-4 and/or SGLT2 inhibitor is an efficacious option for patients with T2DM starting pharmacological therapy, or for patients who have received treatment but require additional glycemic control. Study findings indicate that the underlying mechanisms of action of DPP-4 inhibitors and SGLT2 inhibitors complement a variety of OADs.

IL-33 prevents the enhancement of AP-N, DPP4, and ACE2 expression induced by rhinovirus HRV16 in the human lung endothelium-potential implications for coronaviral airway infections.

INTRODUCTIONGlucagon‐like peptide‐1 (GLP‐1) receptor agonists, sodium‐glucose cotransporter‐2 (SGLT‐2) inhibitors, and dipeptidyl peptidase‐4 (DPP‐4) inhibitors have potential beneficial effects in Alzheimer's disease (AD).METHODSWe conducted pharmacoepidemiologic studies using two large‐scale real‐world databases. We fitted covariate‐adjusted Cox models to compare the risks of AD among initiators of GLP‐1 receptor agonists, SGLT‐2 inhibitors, and DPP‐4 inhibitors.RESULTSWe identified GLP‐1 receptor agonist initiation compared to DPP‐4 inhibitors initiation was associated with a reduced risk of AD (hazard ratio [HR] ≤ 0.69 and P value < 0.001) and SGLT‐2 inhibitor initiation compared to DPP‐4 inhibitor initiation was associated with a reduced risk of AD (HR ≤ 0.67 and P value < 0.001).DISCUSSIONGLP‐1 receptor agonist initiation and SGLT‐2 inhibitor initiation are associated with a reduced risk of AD. Randomized clinical trials are warranted to validate the causal beneficial effects of GLP‐1 receptor agonists and SGLT‐2 inhibitors in AD.HighlightsGlucagon‐like peptide‐1 (GLP‐1) receptor agonists are significantly associated with a reduced risk of Alzheimer's disease (AD) compared to dipeptidyl peptidase‐4 (DPP‐4) inhibitors.Sodium‐glucose cotransporter‐2 (SGLT‐2) inhibitors are significantly associated with a reduced risk of AD compared to dipeptidyl peptidase‐4 (DPP‐4) inhibitors.Two GLP‐1 receptor agonists (liraglutide and semaglutide) and three SGLT‐2 inhibitors (dapagliflozin, canagliflozin, and empagliflozin) are associated with a reduced risk of AD in drug‐specific sensitivity analyses.

BackgroundRecent studies reported that sodium glucose cotransporter 2 (SGLT2) inhibitors reduced the cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus (T2DM) compared to placebo in contrast to no reduction with dipeptidyl peptidase 4 (DPP4) inhibitors. However, there are no comparative studies on the effects of SGLT2 inhibitors and DPP4 inhibitors on HbA1c, body weight and hypoglycemia as risk factors of cardiovascular diseases. The aim of the present ongoing study is to compare the effects of dapagliflozin, a SGLT2 inhibitor, with those of sitagliptin, a DPP4 inhibitor, on cardiovascular risk factors in T2DM patients with inadequate glycemic control.MethodsThe study of dapagliflozin versus sitagliptin treatment efficacy on prevention of cardiovascular risk factors in T2DM patients (DIVERSITY-CVR study) is a prospective, randomized, open-label, blinded-endpoint, parallel-group, comparative study. A total of 340 T2DM patients treated with metformin alone or with no glucose-lowering agents (hemoglobin A1c ≥ 7.0 and < 10.0%) will be randomized into the dapagliflozin group (5–10 mg/day, n = 170) and the sitagliptin group (50–100 mg/day, n = 170), and treated for 24 weeks. The primary endpoint is the rate of achieving a composite endpoint of the following three items at 24th week; (1) HbA1c < 7.0%; (2) body weight loss of ≥ 3.0% from baseline; (3) avoidance of hypoglycemia. Hypoglycemia will be monitored using the flash glucose monitoring system. The secondary outcomes include each component of the primary endpoint, plus indices of lipid metabolism, and evaluations related to safety.ConclusionsThere is lack of solid information on differences in the therapeutic effects of SGLT2 inhibitors and DPP4 inhibitors on multiple risk factors for cardiovascular diseases. It is anticipated that the results of the DIVERSITY-CVR study provides useful clinical data on the management of patients with T2DM, including reducing the risk of CVD. The results of this study will become available in 2019.Trial registration University Hospital Medical Information Network Clinical Trial Registry (UMIN000028014). Registered 30 June 2017

Background: The relentless orchestration and uncompromising regulation of Type 2 Diabetes Mellitus (T2DM) frequently demand an intensified combinatorial pharmacotherapeutic strategy to enforce stringent glycemic homeostasis. Sodium-glucose Co-Transporter 2 (SGLT2) Inhibitors and Dipeptidyl Peptidase-4 (DPP4) Inhibitors emerge as indispensable reinforcements for patients exhibiting persistent glycemic dysregulation despite exhaustive Metformin monotherapy. Objective: This exhaustive analytical review meticulously scrutinizes the comparative therapeutic efficacy and multidimensional safety profile of Sodium-Glucose Co-Transporter 2 (SGLT2) inhibitors versus Dipeptidyl Peptidase-4 (DPP4) inhibitors when deployed as adjunctive pharmacotherapeutic interventions in the intricate management paradigm of Type 2 Diabetes Mellitus (T2DM). Methods: A rigorous and methodologically structured literature exploration was undertaken, encompassing randomized controlled trials (RCTs) and high-quality observational studies that delineate the comparative efficacy and safety profiles of Sodium-Glucose Co-Transporter 2 (SGLT2) inhibitors and Dipeptidyl Peptidase-4 (DPP4) inhibitors within this therapeutic framework. Efficacy Outcomes: The assessment of therapeutic efficacy was predominantly quantified through variations in glycated hemoglobin (HbA1c) levels, fasting plasma glucose (FPG), and body weight. Evidence consistently demonstrates that Sodium-Glucose Co-Transporter 2 (SGLT2) inhibitors elicit superior reductions in HbA1c and body weight relative to Dipeptidyl Peptidase-4 (DPP4) inhibitors. Furthermore, SGLT2 inhibitors confer additional cardiometabolic advantages, including significant reductions in blood pressure and amelioration of key cardiovascular risk parameters. Safety Outcomes: The pharmacovigilance assessment encompassed an extensive evaluation of adverse event profiles, including hypoglycemic episodes, urinary tract infections (UTIs), genital infections, and cardiovascular ramifications. Sodium-Glucose Co-Transporter 2 (SGLT2) inhibitors demonstrated a disproportionately elevated predisposition to UTIs and genital infections, attributed to their glucosuric mechanism, whereas Dipeptidyl Peptidase-4 (DPP4) inhibitors exhibited a comparatively superior safety paradigm, marked by a diminished incidence of UTIs and an absence of statistically significant augmentation in hypoglycemic episodes. Conclusion: SGLT2 inhibitors manifest an advanced glycemic regulatory capacity, coupled with auxiliary metabolic enhancements, particularly in weight reduction and cardiovascular risk attenuation. However, their therapeutic utility is counterbalanced by an escalated vulnerability to genitourinary infections. In contrast, DPP4 inhibitors emerge as a pharmacologically safer alternative, albeit demonstrating a comparatively attenuated efficacy profile. The dichotomous selection between these pharmacotherapeutic agents necessitates a meticulously stratified, patient-centric approach, rigorously integrating individualized clinical parameters such as intrinsic cardiovascular risk burden, infection susceptibility, and drug tolerability thresholds.

Objectives Primary objective of this study was to compare the overall health expenditures of patients with type 2 diabetes on sodium–glucose cotransporter-2 (SGLT2) inhibitors versus dipeptidyl peptidase-4 (DPP4) inhibitors. Methods Two cohorts of type 2 diabetes patients receiving either SGLT2 inhibitor with metformin or DPP4 inhibitor with metformin were identified from 2015 to 2016 Medical Expenditure Panel Survey (MEPS) data. Propensity score matching was used to balance cohorts based on socio-economic status, insulin utilization status, and the Charlson comorbidity score. Patients in SGLT2 inhibitor cohort were matched with patients in DPP4 inhibitor cohort using 1 : 2 ratio on the logit of propensity score using caliper width of 0.1 of the standard deviation of the logit of the propensity score. Expenditure variables were analysed using a generalized linear model with log link function and gamma distribution and adjusted for socio-economic variables. Unadjusted means were obtained using bootstrap. Results After propensity score matching, 240 patients were left in the sample with 80 patients in SGLT2 inhibitor cohort and 160 patients in DPP4 inhibitor cohort. Unadjusted average annual total health expenditure was significantly higher in the SGLT2 inhibitor cohort versus DPP4 inhibitor cohort ($17,325 versus $15,702; P value &amp;lt;0.0001). After adjusting for socio-economic factors, overall health expenditure (β = −0.3516; P = 0.0038) was significantly lower in DPP4 inhibitor cohort compared to SGLT2 inhibitor. Conclusion SGLT2 inhibitors were associated with significantly higher overall and prescription expenditures compared to DPP4 inhibitors during the study period evaluated. Future studies need to utilize administrative claims data to assess current comparativeness effectiveness trends.

ObjectivesDue to the increase of type 2 diabetes (T2D), the number of patients in treatment with multiple anti-diabetic agents is increased. According to the recent recommendation of treatment guidelines, sodium-glucose cotransporter 2 (SGLT2) inhibitors would be used as additional treatment to the currently administered anti-diabetic drugs for poorly controlled T2D patients. Here, we assessed the efficacy of SGLT2 inhibitors added to the current treatment with metformin, dipeptidyl peptidase-4 (DPP4) inhibitors, or both in Japanese T2D patients.ResultsJapanese T2D subjects with poor glucose control, who were treated with metformin (n = 10), DPP4 inhibitors (n = 11), or both (n = 28) and who were in need of additional treatment, were recruited. HbA1c levels before and 6 months after addition of SGLT2 inhibitor treatment were used to compare the effectiveness. The HbA1c levels after addition of SGLT2 inhibitors significantly decreased in all groups. The change in HbA1c levels (delta HbA1c) showed no significant difference between the three groups. The present data indicated that addition of SGLT2 inhibitors to metformin and/or DPP4 inhibitors is equally effective in the treatment of Japanese T2D patients.

Purpose Hyperglycemia is an overlooked triggering factor for cancer, despite being critical to the survival and growth of cancer cells through a unique process known as the “Warburg effect.” Therefore, blocking glycolysis by using antidiabetic agents is an attractive approach for impeding cancer growth and enhancing their responsiveness to cancer treatments, while leaving healthy cells unaffected. This review aims to explore the potential of antidiabetics as cytotoxic agents for cancer treatment through their role as glucose deprivation candidates and the clinical considerations of using antidiabetics with their risk as carcinogenic in cancer therapy. Methods PubMed, Cochrane Library, and Google Scholar were explored by applying the main topic-relevant keywords to consider articles that had been published up to February 2024 and which met our selection criteria. Results The potential of antidiabetic agents to modify the risk of cancer is an exciting area of research in cancer therapy. Some classes of antidiabetics, such as biguanide, sulfonylureas, dipeptidyl peptidase 4 (DPP4) inhibitors, and sodium–glucose co-transporter 2 (SGLT2) inhibitors, have a direct cytotoxic effect on cancer cells, while others, such as glucagon-like peptide 1 (GLP-1) agonists and thiazolidinediones, have an indirect cytotoxic effect on cancer cells. Conclusion Antidiabetic agents differ in their cytotoxic effectiveness toward cancer cells through several mechanisms. Apart from their potential effects on carcinogenicity, these medications hold promise for future cancer treatment. However, not all antidiabetic agents were good candidates for repurposing because of the well-documented carcinogenicity risk.