Sitagliptin prevents inflammation and apoptotic cell death in the kidney of type 2 diabetic animals.

This study aimed to evaluate the efficacy of sitagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor, in preventing the deleterious effects of diabetes on the kidney in an animal model of type 2 diabetes mellitus; the Zucker diabetic fatty (ZDF) rat: 20-week-old rats were treated with sitagliptin (10 mg/kg bw/day) during 6 weeks. Glycaemia and blood HbA1c levels were monitored, as well as kidney function and lesions. Kidney mRNA and/or protein content/distribution of DPP-IV, GLP-1, GLP-1R, TNF-α, IL-1ß, BAX, Bcl-2, and Bid were evaluated by RT-PCR and/or western blotting/immunohistochemistry. Sitagliptin treatment improved glycaemic control, as reflected by the significantly reduced levels of glycaemia and HbA1c (by about 22.5% and 1.2%, resp.) and ameliorated tubulointerstitial and glomerular lesions. Sitagliptin prevented the diabetes-induced increase in DPP-IV levels and the decrease in GLP-1 levels in kidney. Sitagliptin increased colocalization of GLP-1 and GLP-1R in the diabetic kidney. Sitagliptin also decreased IL-1ß and TNF-α levels, as well as, prevented the increase of BAX/Bcl-2 ratio, Bid protein levels, and TUNEL-positive cells which indicates protective effects against inflammation and proapoptotic state in the kidney of diabetic rats, respectively. In conclusion, sitagliptin might have a major role in preventing diabetic nephropathy evolution due to anti-inflammatory and antiapoptotic properties.

A Questionnaire-Based Survey on the Long-Term Management of Canine Leishmaniosis by Veterinary Practitioners.

Canine Leishmaniosis (CanL) is a chronic and potentially fatal disease. In economically disadvantaged regions, costs associated with long-term patient monitoring may determine that some owners decline veterinary follow-up of their dogs. This online, questionnaire-based survey aimed to assess how Portuguese veterinary practitioners perform long-term patient monitoring and recognize relapses. More than 50% of respondents reported that 50-100% of dog owners declared financial restraints. Hence, in these circumstances, most veterinary practitioners only performed clinical examination and serology. However, when owners did not declare financial restriction, other tests were additionally performed, such as renal and hepatic profiles, hemogram, serum protein electrophoresis and urine protein creatinine ratio. The mean number of exams performed when owners presented financial restraints was significantly lower than the number of exams performed without economic limitations. Most veterinary practitioners prescribed allopurinol ad aeternum or until disease remission and domperidone. CanL relapses were recognized by more than half of respondents "Always", through the reappearance or worsening of clinical signs, whereas about a quarter detected an increase in anti-Leishmania antibody levels and identified abnormalities in the serum protein electrophoresis profile. The relapse rate was higher in the Lisbon Metropolitan Area and north, the most economically favored regions of Portugal. This study confirms that owner financial restraints negatively influence veterinary follow-up and relapse recognition, ultimately compromising clinical decision making and favoring the maintenance of Leishmania infantum infection endemicity.

Prevalence of Toxoplasma gondii Antibodies and Risk Factor Investigation in Portuguese Veterinarians: A Matched Case-Control Study.

(1) Background: Toxoplasma gondii is a widespread zoonotic agent that greatly impacts Public Health, being responsible for one of the most important parasitic zoonosis worldwide. T. gondii has a heteroxenous life cycle, with cats being the definitive hosts and all warm-blooded animals, including humans, being intermediate hosts. Veterinary practitioners (VP) may be at a higher risk than the general population for T. gondii infection, as they have direct and daily contact with many animal species. The aim of the present study was to ascertain if VP were more likely to be anti-T. gondii IgG seropositive than the general population, as well as to understand if age, accidents with blood-contaminated sharps (cross-blood contamination), gender, working years, and geographic regions play a role as risk factors for T. gondii infection. For this purpose, a case−control study using archived samples was performed. (2) Methods: A total of 350 veterinary practitioners were tested using a commercial semiquantitative enzyme immunoassay for anti-T. gondii IgG. From the general population, 175 anonymous volunteers (matched with cases by region, age, and gender) were studied for anti-T. gondii IgG. (3) Results: There was no statistical difference found between the presence of anti-T. gondii IgG in practitioners (26%; CI = 21.40−30.60%) and the general population (33.14%; CI = 26.17−40.12%) (p = 0.108). Univariate and multivariate analysis showed that only age (older groups) was found to be associated with a higher prevalence of anti-T. gondii IgG, with significant p values (p < 0.05) for both univariate and multivariate analysis. (4) Conclusions: To the best of our knowledge, this is the first case−control study fully focused on the prevalence of anti-T. gondii IgG in VP in Portugal, showing that there was no significant risk for T. gondii infection in veterinarians exposed daily and repeatedly to different species of animals.

Effects of sitagliptin treatment on dysmetabolism, inflammation, and oxidative stress in an animal model of type 2 diabetes (ZDF rat).

The purpose of this paper is to evaluate the chronic effect of sitagliptin on metabolic profile, inflammation, and redox status in the Zucker Diabetic Fatty (ZDF) rat, an animal model of obese type 2 diabetes. Diabetic and obese ZDF (fa/fa) rats and their controls (ZDF +/+) were treated during 6 weeks with vehicle (control) and sitagliptin (10 mg/kg/bw). Glucose, HbA1c, insulin, Total-c, TGs, IL-1beta, TNF-alpha, CRPhs, and adiponectin were assessed in serum and MDA and TAS in serum, pancreas, and heart. Pancreatic histology was also evaluated. Sitagliptin in diabetic rats promoted a decrease in glucose, HbA1c, Total-c, and TGs accompanied by a partial prevention of insulinopenia, together, with a decrease in CRPhs and IL-1beta. Sitagliptin also showed a positive impact on lipid peroxidation and hypertension prevention. In conclusion, chronic sitagliptin treatment corrected the glycaemic dysmetabolism, hypertriglyceridaemia, inflammation, and hypertension, reduced the severity of the histopathological lesions of pancreatic endocrine and exocrine tissues, together with a favourable redox status, which might be a further advantage in the management of diabetes and its proatherogenic comorbidities.

Occupationally Acquired Q Fever in Shepherds and Sheep Milk Cheesemakers.

Q fever is a zoonosis caused by Coxiella burnetii, and transmission to humans is often associated with contact with ovine and caprine livestock. Those exposed to sheep are particularly at high risk of infection. Recent studies show that Q fever is increasing in sheep farms in Portugal raising alerts on spillover to humans. We detected anti-C. burnetii IgG in shepherds and sheep milk cheesemakers (27 [28.1%] in a total of 96; 95% confidence interval [CI] 19.4-38.2%) and in controls (21 [8.1%] in a total of 260; 95% CI 5.1-12.1%), pointing to an increased risk of C. burnetii infection (P = 0.0001), with an odds ratio for anti-C. burnetii of 4.45 (95% CI 2.4-8.4%; P = 0.0001), in individuals with occupational contact with sheep in Portugal.

A Nationwide Seroepidemiologic Study on Q Fever Antibodies in Sheep of Portugal.

INTRODUCTION: Q fever is an almost global zoonotic disease caused by Coxiella burnetii. Human infections can produce acute and chronic disease that can lead to abortions and stillbirths in pregnant women, usually infected by the inhalation of C. burnetii-contaminated aerosols or through consumption of contaminated products. Sheep are one of the primary animal reservoirs with disease being associated with vast shedding of bacteria in placentas, feces, milk, and birth fluids. Although almost neglected in the past, recent outbreaks of sheep origin have alerted the public and the scientific community. MATERIALS AND METHODS: An epidemiologic survey to estimate the seroprevalence of Q fever antibodies was performed in a representative number of sheep of all regions of continental Portugal (n = 1068), using a commercial ELISA (ID Screen Q Fever Indirect Multi-species Kit; IDvet™, Montpellier, France). RESULTS AND DISCUSSION: An anti-C. burnetii seroprevalence of 11.4% (95% confidence interval 9.6-13.5) was found, with a clear distinction between the Center region with highest seroprevalence, and the rest of the territory. Sheep traditional farming is widely present in Portugal and is part of the cultural and gastronomical background of the country. This close proximity to small ruminants may contribute to the zoonotic transfer to humans.

Outbreaks of abortions by Coxiella burnetii in small ruminant flocks and a longitudinal serological approach on archived bulk tank milk suggest Q fever emergence in Central Portugal.

Q fever is a worldwide zoonotic infectious disease caused by Coxiella burnetii and sheep and goats are known to be the main reservoir for human infection. This study describes the epidemiological and laboratory findings of C. burnetii outbreaks affecting sheep and goat flocks and also provides the results of a prospective serosurvey in bulk tank milk samples to assess C. burnetii circulation in a population of sheep living in close contact to the human population in Central Portugal. In the epizooties, C. burnetii was identified in tissues of the resulting abortions by qPCR. As for the serological survey, 10.2% (95%CI: 4.5-19.2) of the 78 bulk tank milk samples collected in 2015 presented IgG antibodies against C. burnetii. The same farms were visited and sampled in 2016 and 25.6% (95%CI: 16.4-36.8) were positive. This steep increase in the number of anti-C. burnetii farms between the 2015 and 2016 collections showed to be statistically significant (p = 0.020) and is strongly suggestive of Q fever emergence in Central Portugal. Measures on animal health and on disease spread control to the human population should be considered.

Renoprotective Effects of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin: A Review in Type 2 Diabetes.

Diabetic nephropathy (DN) is now the single commonest cause of end-stage renal disease (ESRD) worldwide and one of the main causes of death in diabetic patients. It is also acknowledged as an independent risk factor for cardiovascular disease (CVD). Since sitagliptin was approved, many studies have been carried out revealing its ability to not only improve metabolic control but also ameliorate dysfunction in various diabetes-targeted organs, especially the kidney, due to putative underlying cytoprotective properties, namely, its antiapoptotic, antioxidant, anti-inflammatory, and antifibrotic properties. Despite overall recommendations, many patients spend a long time well outside the recommended glycaemic range and, therefore, have an increased risk for developing micro- and macrovascular complications. Currently, it is becoming clearer that type 2 diabetes mellitus (T2DM) management must envision not only the improvement in glycaemic control but also, and particularly, the prevention of pancreatic deterioration and the evolution of complications, such as DN. This review aims to provide an overview of the current knowledge in the field of renoprotective actions of sitagliptin, namely, improvement in diabetic dysmetabolism, hemodynamic factors, renal function, diabetic kidney lesions, and cytoprotective properties.

The Place of Dipeptidyl Peptidase-4 Inhibitors in Type 2 Diabetes Therapeutics: A "Me Too" or "the Special One" Antidiabetic Class?

Incretin-based therapies, the most recent therapeutic options for type 2 diabetes mellitus (T2DM) management, can modify various elements of the disease, including hypersecretion of glucagon, abnormal gastric emptying, postprandial hyperglycaemia, and, possibly, pancreatic ß cell dysfunction. Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) increase glucagon-like peptide-1 (GLP-1) availability and correct the "incretin defect" seen in T2DM patients. Clinical studies have shown good glycaemic control with minimal risk of hypoglycaemia or any other adverse effects, despite the reports of pancreatitis, whose association remains to be proved. Recent studies have been focusing on the putative ability of DPP-4 inhibitors to preserve pancreas function, in particular due to the inhibition of apoptotic pathways and stimulation of ß cell proliferation. In addition, other cytoprotective effects on other organs/tissues that are involved in serious T2DM complications, including the heart, kidney, and retina, have been increasingly reported. This review outlines the therapeutic potential of DPP-4 inhibitors for the treatment of T2DM, focusing on their main features, clinical applications, and risks, and discusses the major challenges for the future, in particular the possibility of becoming the preferred therapy for T2DM due to their ability to modify the natural history of the disease and ameliorate nephropathy, retinopathy, and cardiovascular complications.

Sitagliptin prevents aggravation of endocrine and exocrine pancreatic damage in the Zucker Diabetic Fatty rat - focus on amelioration of metabolic profile and tissue cytoprotective properties.

BACKGROUND: The purpose of this study was to investigate some of the possible mechanisms underlying the protective effects of a dipeptidyl peptidase IV (DPP-IV) inhibitor, sitagliptin, on pancreatic tissue in an animal model of type 2 diabetes mellitus (T2DM), the Zucker Diabetic Fatty (ZDF) rat, focusing on glycaemic, insulinic and lipidic profiles, as well as, on apoptosis, inflammation, angiogenesis and proliferation mediators. METHODS: Male obese diabetic ZDF (fa/fa) rats, aged 20 weeks, were treated with sitagliptin (10 mg/kg bw/day) during 6 weeks and compared to untreated diabetic and lean control littermates. Metabolic data was evaluated at the beginning and at the end of the treatment, including glycaemia, HbA1c, insulinaemia, HOMA-beta and TGs. Endocrine and exocrine pancreas lesions were assessed semiquantitatively by histopathological methods. Pancreas gene (mRNA) and protein expression of mediators of apoptotic machinery, inflammation and angiogenesis/proliferation (Bax, Bcl2, IL-1ß, VEGF, PCNA and TRIB3) were analyzed by RT-qPCR and/or by immunohistochemistry. RESULTS: Sitagliptin treatment for 6 weeks (between 20 and 26 week-old) was able to significantly (p < 0.001) ameliorate all the metabolic parameters, by preventing the increase in blood glucose and in serum TGs contents (16.54% and 37.63%, respectively, vs untreated), as well as, by preventing the decrease in serum insulin levels and in the functional beta cells capacity accessed via HOMA-beta index (156.28% and 191.74%, respectively, vs untreated). Sitagliptin-treated diabetic rats presented a reduced pancreas Bax/Bcl2 ratio, suggestive of an antiapoptotic effect; in addition, sitagliptin was able to completely reduce (p < 0.001) the pancreas overexpression of IL-1ß and TRIB3 found in the untreated diabetic animals; and promoted a significant (p < 0.001) overexpression of VEGF and PCNA. CONCLUSION: In this animal model of obese T2DM (the ZDF rat), sitagliptin prevented ß-cell dysfunction and evolution of pancreatic damage. The protective effects afforded by this DPP-IV inhibitor may derive from improvement of the metabolic profile (viewed by the amelioration of glucose and TGs levels and of insulin resistance) and from cytoprotective properties, such as antiapoptotic, anti-inflammatory, pro-angiogenic and pro-proliferative.

Diabetic nephropathy amelioration by a low-dose sitagliptin in an animal model of type 2 diabetes (Zucker diabetic fatty rat).

This study was performed to assess the effect of chronic low-dose sitagliptin, a dipeptidyl peptidase 4 inhibitor, on metabolic profile and on renal lesions aggravation in a rat model of type-2 diabetic nephropathy, the Zucker diabetic fatty (ZDF) rat. Diabetic and obese ZDF (fa/fa) rats and their controls ZDF (+/+) were treated for 6 weeks with vehicle (control) or sitagliptin (10 mg/kg/bw). Blood/serum glucose, HbA1c, insulin, Total-c, TGs, urea, and creatinine were assessed, as well as kidney glomerular and tubulointerstitial lesions (interstitial fibrosis/tubular atrophy), using a semiquantitative rating from 0 (absent/normal) to 3 (severe and extensive damage). Vascular lesions were scored from 0-2. Sitagliptin in the diabetic rats promoted an amelioration of glycemia, HbA1c, Total-c, and TGs, accompanied by a partial prevention of insulinopenia. Furthermore, together with urea increment prevention, renal lesions were ameliorated in the diabetic rats, including glomerular, tubulointerstitial, and vascular lesions, accompanied by reduced lipid peroxidation. In conclusion, chronic low-dose sitagliptin treatment was able to ameliorate diabetic nephropathy, which might represent a key step forward in the management of T2DM and this serious complication.