La dipeptidil peptidasa 4 y su función frente a la COVID-19 / Dipeptidyl peptidase 4 and its function against COVID-19

Ante la aparición de un nuevo virus en la ciudad de Wuhan-China, llamado SARS-CoV-2, causante del conocido síndrome agudo respiratorio severo (COVID-19), muchos de científicos tratan de hallar una solución contra el virus que ha ocasionado una pandemia. En esta búsqueda, se encontró a una glicoproteína de transmembrana llamada dipeptidil peptidasa 4 o DPP-4 presente en la superficie de diferentes tipos de células y diana en la infección por el MERS-Co-V que abre una esperanza al sospechar que la DPP-4 puede ser un blanco en diferentes coronavirus al servir como estrategia terapéutica. A ello se suman resultados que encuentran la DPP-4 elevada en pacientes con complicaciones graves ante COVID-19, lo que puede ser un posible marcador de gravedad. Sin embargo, aún existe poco énfasis en la identificación y asociación de esta glicoproteína a la COVID-19. Para ello, se realizó una revisión bibliográfica sobre los aspectos más significativos de la Dipeptidil Peptidasa 4 y su función frente a la COVID-19(AU)

Given the appearance of a new virus in the of Wuhan city, China, called SARS-CoV-2, which causes the well-known severe acute respiratory syndrome (COVID-19), many scientists are trying to find a solution against the virus that has caused a pandemic. In this search, a transmembrane glycoprotein called dipeptidyl peptidase 4 or DPP-4 was found present on the surface of different types of cells and a target in MERS-Co-V infection, which opens hope by suspecting that DPP- 4 can be a target in different coronaviruses by serving as a therapeutic strategy. Added to this, there are results that find elevated DPP-4 in patients with severe complications from COVID-19, which may be a possible marker of severity. However, there is still little emphasis on the identification and association of this glycoprotein with COVID-19. To this effect, a bibliographic review was carried out on the most significant aspects of Dipeptidyl Peptidase 4 and its function against COVID-19(AU)

Non-alcoholic fatty liver disease: Epidemiology, pathophysiology and an update on the therapeutic approaches

Non-alcoholic fatty liver disease (NAFLD) denotes a spectrum of fatty liver disease in individuals without significant alcohol consumption. NAFLD is set to be the most common etiology of serious liver diseases in numerous nations when accompanied by obesity and type 2 diabetes. It is further histologically categorized into the non-alcoholic fatty liver (NAFL; steatosis without hepatocellular injury) and non-alcoholic steatohepatitis (NASH) which is characterized by the coexistence of hepatic steatosis and inflammation and is accompanied by hepatocyte injury (ballooning), either with or without fibrosis. NAFL is considered the benign and reversible stage arising from the excessive accumulation of triglycerides in hepatocytes. However, NASH is a more progressive stage of NAFLD, due to the increased risks of evolving more serious diseases such as cirrhosis, hepatocellular carcinoma. This concept, however, has been lately challenged by a hypothesis of multiple parallel hits of NAFLD, in which steatosis and NASH are separate entities rather than two points of the NAFLD spectrum, not only from a set of histological patterns but also from a pathophysiological perspective. The current review highlights the epidemiology and pathophysiology of NAFLD, and its progression towards steatohepatitis, with special focus on the novel imminent therapeutic approaches targeting the molecular aspects and the pathogenic pathways involved in the development, and progression of NAFLD.

Effects of Incretin - based Therapy on High - sensitivity C - reactive Protein in Patients with Type 2 Diabetes: A Systematic Review and Meta - Analysis

ABSTRACT Background: Recently, studies had shown that incretin-based therapies could reduce the levels of pro-inflammatory markers. The data on the effects of incretin-based therapies on serum high-sensitivity C-reactive protein (hs-CRP) in type 2 diabetes (T2DM) were inconsistent. Objective: The objective of the study was to assess the effects of incretin-based therapies on hs-CRP in patients with T2DM by meta-analysis. Methods: We searched PubMed, EMBASE, the Cochrane Collaboration Library, and Web of Science to identify the eligible randomized clinical trials until August 2019. The pooled standard mean differences (SMD) were calculated by random-effects model using STATA 11.0. Results: Twenty-five studies with 28 randomized controlled trials were finally included into the meta-analysis. Meta-analysis revealed a significant reduction in hs-CRP following treatment with incretin-based regimens compared to controls (SMD = −0.452, p < 0.001). Subgroup analysis of different class of incretin-based drugs showed that therapy with both dipeptidyl peptidase 4 inhibitors (DPP-4Is, SMD = −0.338, p = 0.026) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs, SMD = −0.544, p = 0.003) caused significant reductions in hs-CRP. Besides, there was a significant reduction in hs-CRP with an intervention duration more than 24 weeks (SMD = −0.465, p = 0.001), while no significant difference with <24 weeks. Meta-regression analyses showed that better glycemic control and more body mass index (BMI) decline were associated with hs-CRP reduction after incretin-based therapies. Conclusions: This meta-analysis suggests that incretin-based therapies, both GLP-1 RAs and DPP-4Is, can cause a significant reduction in hs-CRP in patients with T2DM, which is related to long intervention duration, better glycemic control, and more BMI decline.

Effects of treatment with sitagliptin on hepatotoxicity induced by acetaminophen in mice

Up to date, the management of hepatotoxicity induced by a suicidal or unintentional overdose of acetaminophen (APAP) remains a therapeutic challenge. The present study aimed to elucidate the potential effect of sitagliptin, a DPP-4 inhibitor, to ameliorate the acute injurious effects of acetaminophen on the liver. APAP toxicity was induced in mice by an intraperitoneal injection of APAP (400 mg/kg). The effect of treatment with sitagliptin, initiated 5 days prior to APAP injection, was evaluated. Serum indices of hepatotoxicity, oxidative stress markers in liver tissues, serum IL-1ß, and TNF-α in addition to hepatic- NF-E2-related factor-2 (Nrf2) were determined. Our results showed that APAP induced marked hepatic injury as evidenced by an increase in serum levels of ALT and AST, in addition to the deterioration of histological grading. Oxidative stress markers, serum TNF-α, and IL-1ß were also elevated. Sitagliptin successfully ameliorated the histological changes induced by APAP, improving liver function tests and liver oxidant status accompanied with a marked increase in Nrf2 level in hepatic tissues. Thus, the hepatoprotective effects of sitagliptin in this animal model seem to involve Nrf2 modulation, coincidental with its anti-inflammatory and antioxidant effects

Are dipeptidyl peptidase-4 inhibitors effective and safe in long term when added to ongoing therapies of diabetics? a real-life study in tertiary referral center

Background: The aim of this study was to determine how HbA1c, lipid, renal functions and such parameters were affected in the long term by adding dipeptidyl peptidase-4 inhibitors to the ongoing treatment regimens of patients with Type 2 diabetes mellitus.Methods: The study was conducted in diabetes mellitus outpatient clinic of Kayseri Training and Research Hospital between February 2012 and May 2017, with patients who did not achieve the sufficient success in diabetes their controls at the time of admission. From these patients, those who added (dipeptidyl peptidase-4 inhibitors) to their treatments were selected. Patients were followed up as long as they continued to these new treatments and the parameters at the baseline were compared with final values.Results: A total of 80 diabetic patients were followed in the study. The median age of the patients was 56.08±9.71 years. During this follow-up, an average decrease of 1.03% was noted when patients were compared with 9.53±1.87% of the initial hemoglobin A1c, and 8.50±1.48% of the Hemoglobin A1c values at the end of follow-up. This decrease was statistically significant (p <0.001). However, differences in the initial and final values of the lipid parameters of the patients were not statistically significant.Conclusions: Addition of dipeptidyl peptidase-4 inhibitors to patients' treatments causes significant decreases in Hemoglobin A1c mean values. This decline is long lasting. However, there are no positive or negative effects on biochemical parameters such as lipids, kidney and liver functions.

Renoprotection Provided by Dipeptidyl Peptidase-4 Inhibitors in Combination with Angiotensin Receptor Blockers in Patients with Type 2 Diabetic Nephropathy / 中华医学杂志(英文版)

Background@#Treatment with the dipeptidyl peptidase-4 inhibitors (DPP4i) and angiotensin receptor blockers (ARBs) in patients with type 2 diabetic nephropathy (DN) has not been well characterized. This study aimed to assess the renoprotection of this combined treatment in DN patients.@*Methods@#A total of 159 type 2 DN patients from 2013 to 2015 were enrolled retrospectively from a prospective DN cohort at the National Clinical Research Center of Kidney Diseases, Jinling Hospital (China). Fifty-seven patients received DPP4i and ARB treatment, and 102 patients were treated with ARBs alone. All patients were followed up for at least 12 months. Statistical analyses were performed using Stata version 12.0.@*Results@#There were no significant differences at baseline for age, sex, body mass index, duration of diabetes, fasting blood glucose (FBG), hemoglobin A1c (HbA1c), and estimated glomerular filtration rate (eGFR) between the two groups. Antihypertensive and antidiabetic medication use was similar in each group except calcium channel antagonists (P = 0.032). No significant changes in FBG and HbA1c were observed in the two groups after treatment. The eGFR decreased slower in the DPP4i + ARB group than in the ARB group at 12 months (Δ12 months: -2.48 ± 13.86 vs. -6.81 ± 12.52 ml·min·1.73m, P = 0.044). In addition, proteinuria was decreased further in the DPP4i + ARB group than in the ARB group after 24 months of treatment (Δ24 months: -0.18 [-1.00, 0.17] vs. 0.32 [-0.35, 0.88], P = 0.031). There were 36 patients with an eGFR decrease of more than 30% over 24 months. After adjusting for FBG, HbA1c, and other risk factors, DPP4i + ARB treatment was still associated with a reduced incidence of an eGFR decrease of 20% or 30%.@*Conclusions@#The combined treatment of DPP4i and ARBs is superior to ARBs alone, as evidenced by the greater proteinuria reduction and lower eGFR decline. In addition, the renoprotection of DPP4i combined with ARBs was independent of glycemic control.

Application and mechanism of dipeptidyl peptidase-4 inhibitor in East Asia type 2 diabetic patients / 中华内分泌代谢杂志

Dipeptidyl peptidase 4 (DPP-4) inhibitors are novel oral hypoglycemic agents, which have been used to inhibit degradation of endogenously released glucagon-like peptide-1 ( GLP-1 ) via inhibiting DPP-4 activity, consequently increasing level of GLP-1 in circulation, enhancing the effect of incretin hormone, and finally leading to improve glucose control. Meta-analysis showed that DPP-4 inhibitors exhibit better glucose-lowering effect in Asians compared with that in Caucasian. The racial differences of hypoglycemic effect could be mainly ascribed to the differences in the frequency of pancreatic-related gene mutations, the severity ofβ-cell dysfunction, the level of GLP-1, and the intake of carbohydrates in patients with diabetes mellitus.

The Role of Common Pharmaceutical Agents on the Prevention and Treatment of Pancreatic Cancer

Survival from pancreatic cancer remains poor. Conventional treatment has resulted in only marginal improvements in survival compared with survival in the previous several decades. Thus, considerable interest has emerged regarding the potential use of common pharmaceutical agents as chemopreventative and chemotherapeutic options. Aspirin, metformin, statins, β-blockers, and bisphosphonates have biologically plausible mechanisms to inhibit pancreatic neoplasia, whereas dipeptidyl-peptidase 4 inhibitors may promote it. Regardless, real-world epidemiological data remain inconclusive. This review examines the hypotheses, evidence, and current state of the literature for each of these medications and their potential roles in the prevention and treatment of pancreatic cancer.

Economic Impact of Combining Metformin with Dipeptidyl Peptidase-4 Inhibitors in Diabetic Patients with Renal Impairment in Spanish Patients

BACKGROUND: To evaluate resource use and health costs due to the combination of metformin and dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with diabetes and renal impairment in routine clinical practice. METHODS: An observational, retrospective study was performed. Patients aged > or =30 years treated with metformin who initiated a second oral antidiabetic treatment in 2009 to 2010 were included. Two groups of patients were analysed: metformin+DPP-4 inhibitors and other oral antidiabetics. The main measures were: compliance, persistence, metabolic control (glycosylated hemoglobin< 7%) and complications (hypoglycemia, cardiovascular events) and total costs. Patients were followed up for 2 years. RESULTS: We included 395 patients, mean age 70.2 years, 56.5% male: 135 patients received metformin+DPP-4 inhibitors and 260 patients received metformin+other oral antidiabetics. Patients receiving DPP-4 inhibitors showed better compliance (66.0% vs. 60.1%), persistence (57.6% vs. 50.0%), and metabolic control (63.9% vs. 57.3%), respectively, compared with those receiving other oral antidiabetics (P<0.05), and also had a lower rate of hypoglycemia (20.0% vs. 47.7%) and lower total costs (euro 2,486 vs. euro 3,002), P=0.001. CONCLUSION: Despite the limitations of the study, patients with renal impairment treated with DPP-4 inhibitors had better metabolic control, lower rates (association) of hypoglycaemia, and lower health costs for the Spanish national health system.

Effects of 6-Month Sitagliptin Treatment on Insulin and Glucagon Responses in Korean Patients with Type 2 Diabetes Mellitus

BACKGROUND: This study aimed to evaluate the effect of sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, on insulin secretion and glucagon suppression in Korean subjects with type 2 diabetes mellitus. METHODS: Twenty-four subjects underwent a 75-g oral glucose tolerance test (OGTT) before and after 6 months of sitagliptin treatment. Sitagliptin, insulin, and sulfonylurea were withdrawn for 3 days before OGTT to eliminate any acute effects on beta-cell insulin or alpha-cell glucagon secretion. Venous samples were drawn five times during each OGTT to measure plasma glucose, insulin, and glucagon. Indices on insulin secretion and resistance were calculated. RESULTS: Early phase insulin secretion, measured by the insulinogenic index significantly increased after 6 months of sitagliptin treatment, especially in the higher baseline body mass index group and higher baseline glycosylated hemoglobin (HbA1c) group. There were no significant differences in the insulin resistance indices before and after sitagliptin treatment. Although no significant differences were observed in the absolute levels of glucagon and the glucagon-to-insulin ratio, there was a significant reduction in the percentile change of glucagon-to-insulin ratio at 30- and 120-minute during the OGTT. CONCLUSION: Although the HbA1c level did not decrease significantly after 6 months of sitagliptin treatment, an increase in insulin secretion and reduction in early phase postprandial plasma glucagon-to-insulin ratio excursion was confirmed in Korean subjects with type 2 diabetes.

Effect of dipeptidyl peptidase-4 inhibitors linagliptin on the expression of serum pigment epithelium-derived factor in type 2 diabetes patients / 中华内分泌代谢杂志

[Summary] To investigate the difference in serum pigment epithelium-derived factor ( PEDF) among type 2 diabetic patients before and after use of dipeptidyl peptidase-4 inhibitors linagliptin for treatment, and to explore the correlation of serum PEDF with lipids, body mass index, and HbA1C . 39 patients with recently diagnosed type 2 diabetes and 30 healthy individuals were enrolled. Baseline weight, waist circumference, body mass index, fasting plasma glucose, HbA1C , serum glutamic-pyruvic transaminase, glutamic oxaloacetic transaminase, total cholesterol, triglyceride, high density lipoprotein-cholesterol, low density lipoprotein-cholesterol ( LDL-C) , and PEDF measured by enzyme linked immunosorbant assay were determined both in the diabetic and control subject. The treatment group was treated with oral linagliptin 5 mg/d for six month, serum PEDF and clinical parameters were determined in the diabetic group during 6 months of treatment. ( 1 ) PEDF levels were found to be comparable with the controls ( P=0. 584);LDL-C and waist circumference showed positive correlation with PEDF(P<0. 05 or P<0. 01). (2) PEDF level was significantly increased in patients with type 2 diabetes after linagliptin treatment [(3. 21 ± 1. 91 vs 2. 45 ± 1.53)μg/ml,P<0.01]. SerumPEDFlevelinpatientswithtype2diabeteswassimilartothatofhealthycontrolswith associated LDL-C and waist circumference. After linagliptin treatment, serum PEDF level was raised, suggesting that it may have certain protective effect for diabetic vascular complications.

Research progress of alogliptin in treatment of type 2 diabetes mellitus / 中华内分泌代谢杂志

Alogliptin is a novel dipeptide peptidase-4 inhibitor approved for the treatment of type 2 diabetic mellitus.Numerous clinical studies showed that alogliptin alone or in combination with other oral antidiabetic drugs or insulin can substantially control the level of plasma glucose and glycated hemoglobin (HbA1c) in type 2 diabetic patients.12.5 to 25 mg alogliptin alone once daily reduced HbA1c by 0.56％ to 0.59％ ; while combination with other antidiabetic agents resulted additional HbA1c lowering of 0.4％ to 0.8％.Alogliptin was well tolerated,with low incidence of hypoglycemia and no weight gain.Furthermore,alogliptin displayed no extra cardiovascular risk in patients with cardiovascular diseases.

Islet dysfunction in type 2 diabetes mellitus and incretin-based therapy / 中华内分泌代谢杂志

Several studies have demonstrated that the development of pancreatic islet α- and β-cell dysfunction is pivotal to the onset and progression of hyperglycemia in type 2 diabetes mellitus ( T2DM ).Mealstimulated insulin secretion from β-cell is reduced and fails to meet the demands of the insulin-resistant state.In addition,glucagon production by α-cell,which normally maintains hepatic glucose production during fasting periods,is not suppressed.We all know that islet dysfunction is a critical target for T2DM treatment.lncretin-based therapies,including glucagon-like peptide-1 ( GLP-1 ) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors,have been shown to be able to restore glucose sensitivity of islet cells and thus improve glycemic control.Nevertheless,their potential impact on islet function in humans remains uncertain and needs further more investigation.

The mechanism of the action of dipeptidyl peptidase-4 inhibitors and its use in type 2 diabetes / 中华内分泌代谢杂志

The critical role of α- and β-cell dysfunction in the development of type 2 diabetes has been established.Dipeptidyl peptidase-4 (DPP-4) inhibitors are new class of oral anti-hyperglycemia agents that acts to increase active levels of the incretin hormone glucagon-like peptide-1 ( GLP-1 ) and glucose-dependent insulinotropic polypeptide ( GIP),which improved α- and β-cell function.This action is shown as improved α- and β-cell sensitivity to glucose,increased glucose-dependent insulin secretion and decreased glucagon secretion.DPP-4 inhibitors treatment has also been associated with beneficial extrapancreatic effects,including improved peripheral insulin sensitivity and lipid metabolism.Additionally,DPP-4 inhibitors have shown a minimal risk of hypoglycemia and bodyweight neutrality without effects on gastric emptying.Numerous clinical trials have verified the favorable efficacy,safety,and tolerability of DPP-4 inhibitors treatment in monotherapy or combination with other anti-diabetic agents for patients with type 2 diabetes.

DPP-4 inhibitors in the treatment of type 2 diabetes / 中华内分泌代谢杂志

Glucagon-like peptide-1 (GLP-1) can maintain glucose homeostasis, improve islet function,delay and even reverse deterioration of type 2 diabetes by several pathways.But shortly after secreting and releasing into the blood, endogenous intact GLP-1 is cleavaged by dipeptidyl peptidase-4 (DPP-4) into inactive forms.DPP4 inhibitors prevent the inactivation and enhance the physiological effects of GLP-1 through selectively suppressing the enzymic activity of DPP-4, resulting in reduction of HbA1C, fasting and postprandial plasma glucose in type 2diabetes mellitus.The favorable efficacy, safety, and tolerability of DPP-4 inhibitors, which have been well verified in numerous clinical trials and clinical practice for type 2 diabetes mellitus, render them a novel type of oral antidiabetic drugs.