sitagliptin-phosphate and Inflammation

Inflammation is implicated in the development and severity of the coronavirus disease 2019 (COVID-19), as well as in the pathophysiology of diabetes. Diabetes, especially when uncontrolled, is also recognized as an important risk factor for COVID-19 morbidity and mortality. Furthermore, certain inflammatory markers [i.e. C-reactive protein (CRP), interleukin-6 (IL-6) and ferritin] were reported as strong predictors of worse outcomes in COVID-19 positive patients. The same biomarkers have been associated with poor glycemic control. Therefore, achieving euglycemia in patients with diabetes is even more important in the era of the COVID-19 pandemic. Based on the above, it is clinically interesting to elucidate whether antidiabetic drugs may reduce inflammation, thus possibly minimizing the risk for COVID-19 development and severity. The present narrative review discusses the potential anti-inflammatory properties of certain antidiabetic drugs (i.e. metformin, pioglitazone, sitagliptin, linagliptin, vildagliptin, alogliptin, saxagliptin, liraglutide, dulaglutide, exenatide, lixisenatide, semaglutide, empagliflozin, dapagliflozin, canagliflozin), with a focus on CRP, IL-6 and ferritin.

Topics: Anti-Inflammatory Agents; Comorbidity; COVID-19; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Inflammation; Metformin; Pioglitazone; Risk Factors; SARS-CoV-2; Sitagliptin Phosphate; Sodium-Glucose Transporter 2 Inhibitors

Sitagliptin is a member of a class of drugs that inhibit dipeptidyl peptidase (DPP-4). It increases the levels of the active form of incretins such as GLP-1 (glucagon-like peptide-1) or GIP (gastric inhibitory polypeptide) and by their means positively affects glucose metabolism. It is successfully applied in the treatment of diabetes mellitus type 2. The most recent scientific reports suggest beneficial effect of sitagliptin on diseases in which neuron damage occurs. Result of experimental studies may indicate a reducing influence of sitagliptin on inflammatory response within encephalon area. Sitagliptin decreased the levels of proinflammatory factors: TNF-

Topics: Alzheimer Disease; Animals; Blood Glucose; Cytokines; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Hypoglycemic Agents; Incretins; Inflammation; Mice; Sitagliptin Phosphate

To test the hypothesis that glucagon-like peptide-1 receptor (GLP-1R) agonists have beneficial effects on vascular endothelial function, fibrinolysis and inflammation through weight loss-independent mechanisms.. Individuals with obesity and prediabetes were randomized to 14 weeks of the GLP-1R agonist liraglutide, hypocaloric diet or the dipeptidyl peptidase-4 inhibitor sitagliptin in a 2:1:1 ratio. Treatment with drug was double blind and placebo-controlled. Measurements were made at baseline, after 2 weeks prior to significant weight loss and after 14 weeks. The primary outcomes were measures of endothelial function: flow-mediated vasodilation (FMD), plasminogen activator inhibitor-1 (PAI-1) and urine albumin-to-creatinine ratio (UACR).. Eighty-eight individuals were studied (liraglutide N = 44, diet N = 22, sitagliptin N = 22). Liraglutide and diet reduced weight, insulin resistance and PAI-1, while sitagliptin did not. There was no significant effect of any treatment on endothelial vasodilator function measured by FMD. Post hoc subgroup analyses in individuals with baseline FMD below the median, indicative of greater endothelial dysfunction, showed an improvement in FMD by all three treatments. GLP-1R antagonism with exendin (9-39) increased fasting blood glucose but did not change FMD or PAI-1. There was no effect of treatment on UACR. Finally, liraglutide, but not sitagliptin or diet, reduced the chemokine monocyte chemoattractant protein-1 (MCP-1).. Liraglutide and diet reduce weight, insulin resistance and PAI-1. Liraglutide, sitagliptin and diet do not change FMD in obese individuals with prediabetes with normal endothelial function. Liraglutide alone lowers the pro-inflammatory and pro-atherosclerotic chemokine MCP-1, indicating that this beneficial effect is independent of weight loss.

Topics: Diet, Reducing; Fibrinolysis; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Inflammation; Insulin Resistance; Liraglutide; Obesity; Plasminogen Activator Inhibitor 1; Prediabetic State; Sitagliptin Phosphate; Weight Loss

Dipeptidyl peptidase-4 (DPP4) modulates inflammation by enzymatic cleavage of immunoregulatory peptides and through its soluble form (sDPP4) that directly engages immune cells. Here we examine whether reduction of DPP4 activity alters inflammation. Prolonged DPP4 inhibition increases plasma levels of sDPP4, and induces sDPP4 expression in lymphocyte-enriched organs in mice. Bone marrow transplantation experiments identify hematopoietic cells as the predominant source of plasma sDPP4 following catalytic DPP4 inhibition. Surprisingly, systemic DPP4 inhibition increases plasma levels of inflammatory markers in regular chow-fed but not in high fat-fed mice. Plasma levels of sDPP4 and biomarkers of inflammation are lower in metformin-treated subjects with type 2 diabetes (T2D) and cardiovascular disease, yet exhibit considerable inter-individual variation. Sitagliptin therapy for 12 months reduces DPP4 activity yet does not increase markers of inflammation or levels of sDPP4. Collectively our findings dissociate levels of DPP4 enzyme activity, sDPP4 and biomarkers of inflammation in mice and humans.

Topics: Aged; Animals; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diet, Atherogenic; Diet, High-Fat; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Female; Glucagon-Like Peptide-1 Receptor; Humans; Inflammation; Inflammation Mediators; Male; Metformin; Mice; Mice, Knockout; Middle Aged; Protein Isoforms; Sitagliptin Phosphate

HIV infection is associated with a greater risk for fasting hyperinsulinemia, impaired glucose tolerance, and higher incidence rates for vascular disease, myocardial infarction, or stroke despite effective combination antiretroviral therapy (cART). The underlying mechanism(s) may involve chronic low-grade systemic inflammation and immune cell activation. Dipeptidyl peptidase-4 inhibitors (sitagliptin) improve glucose tolerance and may possess immunomodulatory effects because leukocyte CD26 cell surface receptors express dipeptidyl peptidase-4 activity.. Sitagliptin will reduce inflammatory and immune cell activation markers known to be elevated in cART-treated HIV-infected (HIV+) adults with impaired glucose tolerance.. This was designed as a prospective, randomized, placebo-controlled, double-blind trial of sitagliptin in HIV+ adults.. The setting was an academic medical center.. Patients were cART-treated HIV+ men and women (n = 36) with stable HIV disease and impaired glucose tolerance.. Interventions included sitagliptin 100 mg/d or placebo for 8 weeks.. At baseline and week 8, plasma high-sensitivity C-reactive protein and C-X-C motif chemokine 10 concentrations (ELISA), oral glucose tolerance, and abdominal sc adipose mRNA expression for M1 macrophage markers (monocyte chemotactic protein-1, EGF-like module-containing, mucin-like hormone receptor 1).. Sitagliptin reduced glucose area under the curve (P = .002) and improved oral glucose insulin sensitivity index (P = .04) more than placebo. Sitagliptin reduced plasma high-sensitivity C-reactive protein and C-X-C motif chemokine 10 levels more than placebo (P < .009). Adipose tissue monocyte chemotactic protein-1 mRNA abundance declined significantly more (P = .01), and adipose EGF-like module-containing, mucin-like hormone receptor 1 mRNA expression tended to decline more (P = .19) in sitagliptin than placebo.. Sitagliptin had beneficial systemic and adipose anti-inflammatory effects in cART-treated HIV+ adults with impaired glucose tolerance. Large-scale, long-term studies should determine whether sitagliptin reduces cardiovascular risk and events in HIV+ adults.

Topics: Adipokines; Adult; Chemokines; Endothelial Progenitor Cells; Female; Glucose Intolerance; HIV Infections; HIV-1; Humans; Hypoglycemic Agents; Inflammation; Lymphocyte Activation; Male; Middle Aged; Pyrazines; Sitagliptin Phosphate; Triazoles

Glucagon-like peptide-1 (GLP-1) exerts beneficial effects on the cardiovascular system. Here, we examined the effect of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, on systemic inflammation and pro-inflammatory (M1)/anti-inflammatory (M2)-like phenotypes of peripheral blood monocytes in diabetic patients.. Forty-eight type 2 diabetic patients were divided into the following two groups: sitagliptin-treatment (50mg daily for 3months) (n=24) and untreated control (n=24) groups. Measurements were undertaken to assess changes in glucose-lipid metabolism, serum levels of inflammatory cytokines such as serum amyloid A-LDL (SAA-LDL), C-reactive protein (CRP), interleukin-6 (IL-6), IL-10 and tumor necrosis factor-α (TNF-α). Furthermore, the effects of sitagliptin treatment on M1/M2-like phenotypes in peripheral blood monocytes were examined.. Treatment with sitagliptin significantly decreased fasting plasma glucose, hemoglobin A1c (HbA1c), serum levels of inflammatory markers, such as SAA-LDL, CRP, and TNF-α. In contrast, sitagliptin increased serum IL-10, an anti-inflammatory cytokine, as well as plasma GLP-1. In addition, sitagliptin increased monocyte IL-10 expression and decreased monocyte TNF-α expression. Multivariate regression analysis revealed that the sitagliptin treatment was the only factor independently associated with an increase in monocyte IL-10 (β=0.499; R(2)=0.293, P<0.05). However, other factors including the improvement of glucose metabolism were not associated with the increase.. This study is the first to show that a DPP-4 inhibitor, sitagliptin, reduces inflammatory cytokines and improves the unfavorable M1/M2-like phenotypes of peripheral blood monocytes in Japanese type 2 diabetic patients.

Topics: Blood Glucose; C-Reactive Protein; Cholesterol; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide 1; Humans; Inflammation; Interleukin-10; Interleukin-6; Leukocytes, Mononuclear; Male; Middle Aged; Multivariate Analysis; Prospective Studies; Pyrazines; Regression Analysis; Serum Amyloid A Protein; Sitagliptin Phosphate; Triazoles; Tumor Necrosis Factor-alpha

Blood glucose fluctuations have been found to be relevant to the progression of atherosclerosis in patients with type 2 diabetes and to be more detrimental for the development of atherosclerosis than the sustained hyperglycemia. We aim at evaluating the effect of blunted daily acute glucose fluctuations by DPP-IV inhibitors on intima-media thickness (IMT), a surrogate marker for early atherosclerosis.. Data from a 12-week prospective, randomized, open-label parallel group trial with a blinded-endopoint study on 90 patients with DMT2, assessing the role of Dipeptidyl Peptidase-4 inhibition in lowering oxidative stress and inflammation by reducing daily acute glucose fluctuations (MAGE), were included in the present analysis.. Administration of both sitagliptin and vildagliptin treatment resulted in a significant decline in IMT. Indeed, vs baseline data Vildagliptin vs Sitagliptin resulted in a greater IMT reduction. After 3 months therapy changes in IMT significantly correlated with changes in MAGE but not with change in HbA1c in the whole population. Only change in MAGE and LDL plasma levels resulted to be independent predictors of the reduced carotid intima-media thickness after adjusting for conventional cardiovascular risk factors in patients with type 2 diabetes. Significant correlations between change in MAGE, change in IMT and change in fasting and interprandial inflammation score and nitrotyrosine plasma levels were found.. Reduction of glucose excursion due to DPP-IV inhibitors administration, may prevent atherosclerosis progression in patients with type 2 diabetes probably through the reduction of daily inflammation and oxidative stress.

Topics: Adamantane; Atherosclerosis; Blood Glucose; Carotid Arteries; Carotid Artery Diseases; Carotid Intima-Media Thickness; Cytokines; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glycated Hemoglobin; Humans; Inflammation; Nitriles; Oxidative Stress; Prospective Studies; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Tyrosine; Vildagliptin

Evaluate the effects of two dipeptidyl peptidase-IV (DPP-4) inhibitors, sitagliptin and vildagliptin, known to have different efficacy on mean amplitude of glycemic excursions (MAGE), on oxidative stress, and on systemic inflammatory markers in patients with type 2 diabetes.. A prospective, randomized, open-label PROBE design (parallel group with a blinded end point) study was performed in 90 patients with type 2 diabetes inadequately controlled by metformin. The study assigned 45 patients to receive sitagliptin (100 mg once daily; sitagliptin group) and 45 patients to receive vildagliptin (50 mg twice daily; vildagliptin group) for 12 weeks. MAGE, evaluated during 48 h of continuous subcutaneous glucose monitoring, allowed an assessment of daily glucose fluctuations at baseline and after 12 weeks in all patients. Assessment of oxidative stress (nitrotyrosine) and systemic levels of inflammatory markers interleukin (IL)-6 and IL-18 was performed at baseline and after 12 weeks in all patients.. HbA(1c), fasting and postprandial glucose, MAGE, and inflammatory and oxidative stress markers were similar between the groups at baseline. After 12 weeks, MAGE (P < 0.01) was lower in the vildagliptin group than in the sitagliptin group. After treatment, HbA(1c) and postprandial glucose evidenced similar changes between the groups (P = NS). Vildagliptin treatment was associated with a stronger decrease in nitrotyrosine (P < 0.01), IL-6 (P < 0.05), and IL-18 (P < 0.05) than sitagliptin treatment. Nitrotyrosine and IL-6 changes significantly correlated with changes in MAGE but not in fasting glucose and HbA(1c).. MAGE reduction is associated with reduction of oxidative stress and markers of systemic inflammation in type 2 diabetic patients. These effects were greater in the vildagliptin group than in the sitagliptin group.

Topics: Adamantane; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Humans; Inflammation; Interleukin-18; Interleukin-6; Male; Metformin; Middle Aged; Nitriles; Oxidative Stress; Postprandial Period; Prospective Studies; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Vildagliptin

The aim of the study was to compare the effects of the addition of sitagliptin or metformin to pioglitazone monotherapy in poorly controlled type 2 diabetes mellitus patients on body weight, glycemic control, beta-cell function, insulin resistance, and inflammatory state parameters. One hundred fifty-one patients with uncontrolled type 2 diabetes mellitus (glycated hemoglobin [HbA(1c)] >7.5%) in therapy with pioglitazone 30 mg/d were enrolled in this study. We randomized patients to take pioglitazone 30 mg plus sitagliptin 100 mg once a day, or pioglitazone 15 mg plus metformin 850 mg twice a day. We evaluated at baseline and after 3, 6, 9, and 12 months these parameters: body weight, body mass index, HbA(1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), homeostasis model assessment beta-cell function index, fasting plasma proinsulin (Pr), Pr/FPI ratio, adiponectin, resistin (R), tumor necrosis factor-alpha (TNF-alpha), and high-sensitivity C-reactive protein. A decrease of body weight and body mass index was observed with metformin, but not with sitagliptin, at the end of the study. We observed a comparable significant decrease of HbA(1c), FPG, and PPG and a significant increase of homeostasis model assessment beta-cell function index compared with baseline in both groups without any significant differences between the 2 groups. Fasting plasma insulin, fasting plasma Pr, Pr/FPI ratio, and HOMA-IR values were decreased in both groups even if the values obtained with metformin were significantly lower than the values obtained with sitagliptin. There were no significant variations of ADN, R, or TNF-alpha with sitagliptin, whereas a significant increase of ADN and a significant decrease of R and TNF-alpha values were recorded with metformin. A significant decrease of high-sensitivity C-reactive protein value was obtained in both groups without any significant differences between the 2 groups. There was a significant correlation between HOMA-IR decrease and ADN increase, and between HOMA-IR decrease and R and TNF-alpha decrease in pioglitazone plus metformin group after the treatment. The addition of both sitagliptin or metformin to pioglitazone gave an improvement of HbA(1c), FPG, and PPG; but metformin led also to a decrease of body weight and to a faster and better improvement of insulin resistance and inflammatory state parameters, even if si

Topics: Adiponectin; Blood Glucose; Body Weight; C-Reactive Protein; Diabetes Mellitus, Type 2; Diet; Double-Blind Method; Drug Therapy, Combination; Exercise; Female; Humans; Hypoglycemic Agents; Inflammation; Insulin Resistance; Insulin-Secreting Cells; Male; Metformin; Middle Aged; Pioglitazone; Pyrazines; Resistin; Sitagliptin Phosphate; Thiazolidinediones; Triazoles; Tumor Necrosis Factor-alpha

Chronic inflammation is a risk factor for diabetes, but it can also be a complication of diabetes, leading to severe diabetes and causing many other clinical manifestations. Inflammation is a major emerging complication in both type I and type II diabetes, which causes increasing interest in targeting inflammation to improve and control diabetes. Diabetes with insulin resistance and impaired glucose utilization in humans and their underlying mechanism is not fully understood. But a growing understanding of the intricacy of the insulin signaling cascade in diabetic inflammatory cells reveals potential target genes and their proteins responsible for severe insulin resistance. With this baseline concept, the current project explores the binding affinities of the hyaluronic acid anti-diabetic compounds conjugates to such target proteins in diabetic inflammatory cells and their molecular geometries. A range of 48 anti-diabetic compounds was screened against aldose reductase binding pocket 3 protein target through in silico molecular docking, and results revealed that three compounds viz, metformin (CID:4091), phenformin (CID:8249), sitagliptin (CID:4,369,359), possess significant binding affinity out of 48 chosen drugs. Further, these three anti-diabetic compounds were conjugated with hyaluronic acid (HA), and their binding affinity and their molecular geometrics towards aldose reductase enzyme were screened compared with the free form of the drug. The molecular geometries of three shortlisted drugs (metformin, phenformin, sitagliptin) and their HA conjugates were also explored through density functional theory studies, and it proves their good molecular geometry towards pocket 3 of aldose reductase target. Further, MD simulation trajectories affirm that HA conjugates possess good binding affinity and simulation trajectories with protein target aldose reductase than a free form of the drug. Our current study unravels the new mechanism of drug targeting for diabetes through HA conjugation for inflammatory diabetes. HA conjugates act as novel drug candidates for treating inflammatory diabetes; however, it needs further human clinical trials.. For ligand structure, PubChem, ACD chem sketch, and online structure file generator platform are utilized for ligand preparation. Target protein aldose reductase obtained from protein database (PDB). For molecular docking analysis, AutoDock Vina (Version 4) was utilized. pKCSM online server used to predict ADMET properties of the above three shortlisted drugs from the docking study. Using mol-inspiration software (version 2011.06), three shortlisted compounds' bioactivity scores were predicted. DFT analysis for three shortlisted anti-diabetic drugs and their hyaluronic acid conjugates were calculated using a functional B3LYP set of Gaussian 09 software. Molecular dynamics simulation calculations for six chosen protein-ligand complexes were done through YASARA dynamics software and AMBER14 force field.

Topics: Aldehyde Reductase; Diabetes Mellitus, Type 2; Humans; Hyaluronic Acid; Inflammation; Insulin Resistance; Ligands; Metformin; Molecular Docking Simulation; Molecular Dynamics Simulation; Phenformin; Sitagliptin Phosphate

Sitagliptin is a well-established anti-diabetic drug that also exerts protective effects on diabetic complications. Previous work reveals that sitagliptin has a protective effect on diabetic nephropathy (DN). Vascular impairment frequently occurs in diabetic renal complications. Here, we evaluated the protective function of sitagliptin in human renal glomerular endothelial cells (HrGECs) under high glucose (HG) conditions. Expressions of the pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-8 (IL-8) were assessed using real-time PCR and ELISA. Endothelial cells permeability was assayed using the fluorescein isothiocyanate dextran (FITC-dextran) and trans-endothelial electrical resistance (TEER) assay. The results show that sitagliptin mitigated HG-induced oxidative stress in HrGECs with decreased levels of mitochondrial reactive oxygen species (ROS), Malondialdehyde (MDA), and 8-hydroxydeoxyguanosine (8-OHdG). Sitagliptin inhibited HG-induced production of pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-8 (IL-8) in HrGECs. It also ameliorated HG-induced aggravation of HrGECs permeability and reduction of the tight junction component claudin-5. Moreover, kruppel Like Factor 6 (KLF6) mediated the protective effects of sitagliptin on endothelial monolayer permeability against HG. Collectively, sitagliptin reversed the HG-induced oxidative stress, inflammation, and increased permeability in HrGECs via regulating KLF6. This study suggests that sitagliptin might be implicated as an effective strategy for preventing diabetic renal injuries in the future.

Topics: Cell Line; Diabetic Nephropathies; Endothelial Cells; Glucose; Humans; Inflammation; Kidney Glomerulus; Oxidative Stress; Sitagliptin Phosphate

A diet-induced non-alcoholic fatty liver disease (NAFLD) model causing obesity in rodents was used to examine whether sitagliptin and gliclazide therapies have similar protective effects on pathological liver change.. Male mice were fed a high-fat diet (HFD) or standard chow (Chow) ad libitum for 25 weeks and randomly allocated to oral sitagliptin or gliclazide treatment for the final 10 weeks. Fasting blood glucose and circulating insulin were measured. Inflammatory and fibrotic liver markers were assessed by qPCR. The second messenger ERK and autophagy markers were examined by Western immunoblot. F4/80, collagens and CCN2 were assessed by immunohistochemistry (IHC).. At termination, HFD mice were obese, hyperinsulinemic and insulin-resistant but non-diabetic. The DPP4 inhibitor sitagliptin prevented intrahepatic induction of pro-fibrotic markers collagen-IV, collagen-VI, CCN2 and TGF-β1 and pro-inflammatory markers TNF-α and IL-1β more effectively than sulfonylurea gliclazide. By IHC, liver collagen-VI and CCN2 induction by HFD were inhibited only by sitagliptin. Sitagliptin had a greater ability than gliclazide to normalise ERK-protein liver dysregulation.. These data indicate that sitagliptin, compared with gliclazide, exhibits greater inhibition of pro-fibrotic and pro-inflammatory changes in an HFD-induced NAFLD model. Sitagliptin therapy, even in the absence of diabetes, may have specific benefits in diet-induced NAFLD.

Topics: Animals; Diet, High-Fat; Gliclazide; Hypoglycemic Agents; Inflammation; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Sitagliptin Phosphate

Nonalcoholic fatty liver disease (NAFLD) is a common cause of clinical liver dysfunction and an important prepathological change of liver cirrhosis. Central obesity, type 2 diabetes mellitus, dyslipidemia, and metabolic syndrome are the major risk factors for NAFLD. Sitagliptin (Sig) is a novel hypoglycemic agent that improves blood glucose levels by increasing the level of active incretin. Sig has been shown to prevent the development of fatty livers in mice on a fructose-rich diet. The purpose of this study was to observe the efficacy of Sig on NAFLD in type 2 diabetic mice.. The diet-induced obesity mouse model was established, and the diabetic mice were screened by an intraperitoneal glucose tolerance trial. The mice were randomly divided into four groups for 8 weeks of intervention: high-fat diet (HFD) group, Sig group, metformin (Met) group, and Sig+Met group. After the intervention, the liver function indexes as well as the blood glucose and blood lipid levels of the mice were measured. In addition, the wet weight of the liver was measured; the pathological sections of the liver tissues were stained to observe the hepatocyte fatty degeneration, inflammation, necrosis, and fibrosis; and the hepatic histological injury was recorded as the NAFLD activity score (NAS).. Compared with the normal control group, the body weight, liver weight, blood glucose level, insulin resistance (IR), blood lipid level, and transaminase level of the mice in the HFD group were significantly increased, showing typical metabolic syndrome. After treatment with Sig and/or Met, the mice gained less weight, had lower levels of blood glucose, triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and transaminase, and had improved IR compared with the HFD group. The liver pathological NASs in the Sig group (P=0.01), Met group (P=0.028), and Sig+Met group (P<0.001) were lower than those in the HFD group (P<0.05), suggesting that the use of the two drugs alone or in combination can improve the state of liver inflammation. In terms of fibrosis, there was no fibrosis in the control group but there was significant fibrosis in the HFD group (P<0.001). There was no significant difference between the drug intervention groups and the HFD group, indicating that the drug therapy (Sig and/or Met) did not significantly improve the pre-existing fibrosis.. Our experiment proved that Sig can improve NAFLD, including improvement of the serum transaminase level, hepatic pathological inflammation level, and hepatocyte adiposis, suggesting that Sig may play a role by improving glucose and lipid metabolism, reducing the body weight and liver weight, improving insulin sensitivity, and inhibiting fatty liver inflammation. Sig may be a new direction for the treatment of patients with a nonalcoholic fatty liver and diabetes, delaying the progression of NAFLD.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Humans; Inflammation; Insulin Resistance; Liver Cirrhosis; Metabolic Syndrome; Metformin; Mice; Non-alcoholic Fatty Liver Disease; Obesity; Sitagliptin Phosphate; Transaminases

Sitagliptin and other dipeptidyl peptidase (DPP)-4 inhibitors/gliptins are antidiabetic drugs known to improve lipid profile, and confer anti-inflammatory and anti-fibrotic effects, which are independent of their hypoglycemic effects. However, in our previous short-term (35 days) studies, we showed that sitagliptin accentuates the hepato-inflammatory effects of high dietary cholesterol (Cho) in male Sprague-Dawley rats. Since most type 2 diabetics also present with lipid abnormalities and use DPP-4 inhibitors for glucose management, the present study was conducted to assess the impact of sitagliptin during long-term (98 days) feeding of a high Cho diet. An additional component of the present investigation was the inclusion of other gliptins to determine if hepatic steatosis, necro-inflammation, and fibrosis were specific to sitagliptin or are class effects.. Adult male Sprague-Dawley rats were fed control or high Cho (2.0%) diets, and gavaged daily (from day 30 through 98) with vehicle or DPP-4 inhibitors (sitagliptin or alogliptin or saxagliptin). On day 99 after a 4 h fast, rats were euthanized. Blood and liver samples were collected to measure lipids and cytokines, and for histopathological evaluation, determination of hepatic lesions (steatosis, necrosis, inflammation, and fibrosis) using specific staining and immunohistochemical methods.. Compared to controls, the high Cho diet produced a robust increase in NASH like phenotype that included increased expression of hepatic (Tnfa, Il1b, and Mcp1) and circulatory (TNFα and IL-1β) markers of inflammation, steatosis, necrosis, fibrosis, and mononuclear cell infiltration. These mononuclear cells were identified as macrophages and T cells, and their recruitment in the liver was facilitated by marked increases in endothelium-expressed cell adhesion molecules. Importantly, treatment with DPP-4 inhibitors (3 tested) neither alleviated the pathologic responses induced by high Cho diet nor improved lipid profile.. The potential lipid lowering effects of DPP-4 inhibitors were diminished by high Cho (a significant risk factor for inducing liver damage). The robust inflammatory responses induced by high Cho feeding in long-term experiment were not exacerbated by DPP-4 inhibitors and a consistent hepatic inflammatory environment persisted, implying a prospective physiological adaptation.

Topics: Animals; Cholesterol, Dietary; Diabetes Mellitus, Type 2; Diet; Dipeptidyl-Peptidase IV Inhibitors; Fibrosis; Hypercholesterolemia; Hypoglycemic Agents; Inflammation; Male; Necrosis; Prospective Studies; Rats; Rats, Sprague-Dawley; Sitagliptin Phosphate

Obesity is accompanied by a chronic low-grade inflammation associated with endothelial dysfunction and vascular complications. Procalcitonin is a marker of inflammation, secreted by adipose tissue and elevated in obese subjects. We here investigated whether visceral or perivascular fat-derived procalcitonin is a target to improve obesity-induced endothelial dysfunction.. Procalcitonin expression was identified by Western blot. Murine endothelial cells were isolated using CD31-antibody-coated magnetic beads and reactive oxygen species and nitric oxide (NO) determined by H2DCF- or DAF-FM diacetate loading. Endothelium-dependent vasorelaxation was analyzed using pressure myography of murine arterioles. Calcitonin gene-related peptide (CGRP) was used to activate the calcitonin receptor-like receptor (CRLR)/RAMP1 complex and olcegepant or the dipeptidyl-peptidase 4 (DPP4) inhibitor sitagliptin to block procalcitonin signaling or activation.. In addition to visceral adipose tissue, procalcitonin was present in perivascular and epicardial tissue. In concentrations typical for obesity, procalcitonin doubled reactive oxygen species formation and decreased endothelial nitric oxide production in murine endothelial cells. Intravenous delivery of procalcitonin to mice in obesity-associated concentrations impaired endothelium-dependent vasorelaxation in a CRLR/RAMP1-dependent manner and antagonized CGRP-induced endothelial NO release in vitro. Use of CRLR/RAMP1-receptor antagonist olcegepant counteracted procalcitonin effects on vasodilation, nitric oxide production and reactive oxygen species formation. Similarly, blocking procalcitonin activation by the DPP4 inhibitor sitagliptin antagonized endothelial procalcitonin effects.. Procalcitonin, liberated either from visceral or perivascular adipose tissue, contributes to endothelial dysfunction by antagonizing CGRP signaling in obesity. Targeting hyperprocalcitonemia may be a means to preserve endothelial function and reduce comorbidity burden in obese subjects.

Topics: Animals; Calcitonin Gene-Related Peptide; Calcitonin Receptor-Like Protein; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Endothelial Cells; Endothelium, Vascular; Inflammation; Mice; Nitric Oxide; Obesity; Procalcitonin; Reactive Oxygen Species; Sitagliptin Phosphate; Vasodilation

Topics: Acute Disease; Acute Lung Injury; Aldehydes; Animals; Autophagy; Autophagy-Related Protein 5; Beclin-1; Down-Regulation; Inflammation; Kelch-Like ECH-Associated Protein 1; Lung; Mice, Inbred C57BL; Mice, Knockout; NF-E2-Related Factor 2; Oxidative Stress; Pancreatitis; Protective Agents; Reactive Oxygen Species; Sequestosome-1 Protein; Signal Transduction; Sitagliptin Phosphate

This study was carried out to investigate the potential effects of vitamin B12 and sitagliptin, and their possible synergistic effect with doxorubicin (DOX) on the Ehrlich solid tumor model. B12, sitagliptin, and their combination with DOX were administered to tumor-bearing mice for 21 days. Treatment with B12, sitagliptin, as well as their combinations with DOX caused a significant inhibition of tumor growth and increased the survival time. Malondialdehyde levels and the relative expression of tumor necrosis factor-α and nuclear factor kappa B were significantly decreased, whereas the total antioxidant capacity was significantly increased in all treated groups, except the DOX-treated one, when compared with the positive control group. Moreover, increased apoptosis was also observed by increased cleaved caspase-3 immunostaining and histopathological examination. In conclusion, the antitumor activity of B12 and sitagliptin could be attributed to their ability to induce apoptosis and suppress oxidative stress and inflammation.

Topics: Animals; Carcinoma, Ehrlich Tumor; Female; Inflammation; Mice; NF-kappa B; Oxidative Stress; Sitagliptin Phosphate; Tumor Necrosis Factor-alpha; Vitamin B 12

Chronic consumption of unhealthy diet and sedentary lifestyle induces fatty liver and metabolic complications. Adipocytes get overloaded with lipid succeeding low-grade inflammation and disrupting adipokine release. This research aims to investigate the effect of sitagliptin on white adipose tissue inflammation, adipokine level, metabolic syndrome, and fatty liver through 5' adenosine monophosphate-activated protein kinase (AMPK) pathway. In sixteen weeks of the experimental protocol, Swiss albino mice were kept in a standard environment and were fed 60% high-fat diet and 20% fructose water (HFFW) where they developed metabolic syndrome features, adipose tissue inflammation, and altered adipokine profile. Sitagliptin was administered for the last eight weeks. They were allocated to following six groups, control diet with regular water (1), HFFW only (2), HFFW and metformin 100 mg/kg (3), HFFW and sitagliptin 10 mg/kg (4), HFFW and sitagliptin 20 mg/kg (5), and HFFW and sitagliptin 30 mg/kg (6). Fasting serum insulin (FSI), glucagon-like peptide-1 (GLP-1), adipokines (adiponectin and leptin), serum lipid profile, hepatic lipid content, and white adipose tissue inflammation were assessed. Protein expression of P-AMPK, P-Acetyl co-a carboxylase (ACC), and mRNA expression of fatty acid metabolism genes were also evaluated in the liver. Sitagliptin significantly and effectively reversed metabolic syndrome complexity. FSI and GLP-1 levels were improved. A significant reduction in hepatic lipid content and oxidative stress was also observed. Also, sitagliptin significantly ameliorated adipose tissue inflammation and adiponectin levels at 20 mg/kg and 30 mg/kg. P-AMPK and P-ACC expression increased significantly. Moreover, expression of fatty acid synthesis genes was down-regulated, and fatty acid oxidation genes were up-regulated. Sitagliptin significantly ameliorated obesity-induced adipose tissue inflammation, metabolic syndrome, and fatty liver via regulation of adiponectin and AMPK levels in obese mice. Also, increased GLP-1 levels would have induced insulin-independent effects on adipose tissue and liver.

Topics: Adiponectin; Adipose Tissue, White; AMP-Activated Protein Kinases; Animals; Fatty Liver; Inflammation; Lipid Metabolism; Liver; Male; Metabolic Syndrome; Mice; Oxidative Stress; Sitagliptin Phosphate

No Abstract.

Topics: Angiotensin-Converting Enzyme 2; Betacoronavirus; Coronavirus Infections; COVID-19; Cytokines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Repositioning; Humans; Inflammation; Lung; Pandemics; Peptidyl-Dipeptidase A; Pneumonia, Viral; SARS-CoV-2; Sitagliptin Phosphate

Patients with SARS-CoV-2 infections experience lymphopenia and inflammatory cytokine storms in the severe stage of the disease, leading to multi-organ damage. The exact pattern of immune system changes and their condition during the disease process is unclear. The available knowledge has indicated that the NF-kappa-B pathway, which is induced by several mediators, has a significant role in cytokine storm through the various mechanisms. Therefore, identifying the state of the immune cells and the dominant mechanisms for the production of cytokines incorporated in the cytokine storm can be a critical step in the therapeutic approach. On the other hand, some studies identified a higher risk for diabetic patients. Diabetes mellitus exhibits a close association with inflammation and increases the chance of developing COVID-19. Patients with diabetes mellitus have shown to have more virus entry, impaired immunity response, less viral elimination, and dysregulated inflammatory cytokines. The parallel analysis of COVID-19 and diabetes mellitus pathogenesis has proposed that the control of the inflammation through the interfering with the critical points of major signaling pathways may provide the new therapeutic approaches. In recent years, the role of Dipeptidyl Peptidase 4 (DPP4) in chronic inflammation has been proved. Numerous immune cells express the DPP4 protein. DPP4 regulates antibody production, cytokine secretion, and immunoglobulin class switching. DPP4 inhibitors like sitagliptin reduce inflammation intensity in different states. Following the accumulating data, we hypothesize that sitagliptin might reduce COVID-19 severity. Sitagliptin, an available DPP4 inhibitor drug, showed multidimensional anti-inflammatory effects among diabetic patients. It reduces the inflammation mostly by affecting on NF-kappa-B signaling pathway. Under the fact that inflammatory mediators are active in individuals with COVID-19, blocking the predominant pathway could be helpful.

Topics: Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Cytokines; Diabetes Complications; Diabetes Mellitus; Dipeptidyl Peptidase 4; Humans; Inflammation; Insulin Resistance; Models, Theoretical; NF-kappa B p50 Subunit; Pandemics; Pneumonia, Viral; Signal Transduction; Sitagliptin Phosphate

Type 2 diabetes (T2D) is a condition characterized by hyperglycemia and chronic complications. Antidiabetic drugs and lifestyle interventions are the current gold standard therapy for T2D; current therapies, however, can only delay long-term diabetic complications and can additionally be associated with beta cell failure. While the mechanism of beta cell failure is well-studied, little is known about the immunological and inflammatory events associated with antidiabetic agents. Here we studied the effects of three antidiabetic drugs (Metformin, Sitagliptin, and Liraglutide) on immune-relevant pathways in a human beta cell line. Costimulatory molecule expression, cytokine secretion, and gene expression profiles were evaluated at different time points following challenge with the aforementioned antidiabetic agents. Our results showed that these three antidiabetic agents, particularly Sitagliptin, downregulate HLA Class I and II expression and upregulate the immune-regulatory molecules PD-L1 and CTLA4. Metformin and Liraglutide were shown to elicit significantly greater release of TNFa, IL-6, and GM-CSF, while Sitagliptin had a lesser effect on pro-inflammatory cytokine production. Gene expression analysis confirmed the aforementioned observations and also demonstrated upregulation of NOS2, SIRT1, SITR3, POLRMT, MRPL43 and NFkB with antidiabetic agents. We conclude that Sitagliptin most effectively modulates beneficial immune-relevant pathways in a human beta cell line.

Topics: Cell Line; Diabetes Mellitus, Type 2; Gene Expression; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunologic Factors; Inflammation; Insulin-Secreting Cells; Interleukin-6; Liraglutide; Metformin; Signal Transduction; Sitagliptin Phosphate; Tumor Necrosis Factor-alpha; Up-Regulation

Severe acute pancreatitis (SAP) is a challenging disease with high morbidity and mortality, often complicated by multiple organ dysfunction syndrome (MODS). The intestine, a major organ involved in MODS, correlates strongly with the evolution of the disease. In this study, we demonstrated that the DPP4 inhibitor, sitagliptin, protects SAP-associated intestinal injury both in vitro and in vivo. These beneficial effects were achieved by suppressing oxidative stress and inflammatory responses. Moreover, in sitagliptin-treated SAP mice, expression of Nrf2 was induced and that of NF-

Topics: Acute Disease; Animals; Cell Proliferation; Dipeptidyl-Peptidase IV Inhibitors; Inflammation; Interleukin-6; Intestines; Lipopolysaccharides; Malondialdehyde; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Pancreatitis; Reactive Oxygen Species; Signal Transduction; Sitagliptin Phosphate; Superoxide Dismutase

Topics: Adiponectin; Animals; Antioxidants; Biomarkers; Cytokines; Diet, High-Fat; Disease Models, Animal; Hypoglycemic Agents; Inflammation; Inflammation Mediators; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Sitagliptin Phosphate; Thiobarbituric Acid Reactive Substances; Vitamin E

Chronic stimulation of the β-adrenergic sympathetic system induces vascular dysfunction which is associated with increased inflammatory cytokines production. A recently proposed therapy to control vascular injury through inflammatory processes involves inhibition of the enzyme dipeptidyl peptidase-IV (DPP4). The present study investigates whether the inhibition of DPP4 prevents the increase in inflammatory markers induced by isoproterenol and restores endothelial function in vivo and in vitro. Male Wistar rats were divided into four groups: vehicle (VHC), an isoproterenol-treated group (ISO), a sitagliptin-treated group (SITA), and an isoproterenol and sitagliptin-treated group (ISO + SITA). The ISO group exhibited significantly increased contractile responses to phenylephrine associated with reduced endothelial participation, which was totally prevented by DPP4 inhibition. In vitro incubation with isoproterenol had no effect on vascular smooth muscle cells, however isoproterenol increased the activity of DPP4 and the expression of inflammatory cytokines in endothelial cells, while sitagliptin reduced the level of cytokines to basal level. In conclusion, we have shown that beta-adrenergic receptor activation can increase DPP4 activity, which was associated with vascular dysfunction and cytokine expression in endothelial cells. The important role of DPP4 was further supported by sitagliptin, which reversed vascular changes induced by isoproterenol in vivo and in vitro.

Topics: Adrenergic beta-Agonists; Animals; Cytokines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Human Umbilical Vein Endothelial Cells; Humans; Hypoglycemic Agents; Inflammation; Isoproterenol; Male; Phenylephrine; Rats; Rats, Wistar; Sitagliptin Phosphate

The probably effects of sitagliptin and vitamin D3 (VitD3) on proliferation capacity and cytokines production were investigated in type 2 diabetes mellitus (T2DM) in vitro.. Peripheral blood mononuclear cells (PBMCs) were isolated from 35 patients with T2DM and 26 healthy controls (HCs). CFSE-labeled PBMCs stimulated with phytohamagglutinin (PHA, 5 μg/mL) in the presence/absence of sitagliptin (200 mg/mL) with/without VitD3 (10. The proliferation of CD4. Sitagliptin plus VitD3 effectively reduces the proliferative T cells response and modulates pro-inflammatory/anti-inflammatory cytokines production.

Topics: Adult; Cell Proliferation; Cells, Cultured; Cholecalciferol; Cytokines; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Inflammation; Male; Middle Aged; Sitagliptin Phosphate; T-Lymphocytes; Vitamins

Obesity-induced metabolic disease involves functional integration among several organs via circulating factors, but little is known about crosstalk between liver and visceral adipose tissue (VAT). In obesity, VAT becomes populated with inflammatory adipose tissue macrophages (ATMs). In obese humans, there is a close correlation between adipose tissue inflammation and insulin resistance, and in obese mice, blocking systemic or ATM inflammation improves insulin sensitivity. However, processes that promote pathological adipose tissue inflammation in obesity are incompletely understood. Here we show that obesity in mice stimulates hepatocytes to synthesize and secrete dipeptidyl peptidase 4 (DPP4), which acts with plasma factor Xa to inflame ATMs. Silencing expression of DPP4 in hepatocytes suppresses inflammation of VAT and insulin resistance; however, a similar effect is not seen with the orally administered DPP4 inhibitor sitagliptin. Inflammation and insulin resistance are also suppressed by silencing expression of caveolin-1 or PAR2 in ATMs; these proteins mediate the actions of DPP4 and factor Xa, respectively. Thus, hepatocyte DPP4 promotes VAT inflammation and insulin resistance in obesity, and targeting this pathway may have metabolic benefits that are distinct from those observed with oral DPP4 inhibitors.

Topics: Administration, Oral; Animals; Caveolin 1; Dipeptidyl Peptidase 4; Factor Xa; Hepatocytes; Humans; Inflammation; Insulin Resistance; Intra-Abdominal Fat; Macrophages; Male; Mice; Mice, Obese; Obesity; Receptor, PAR-2; Sitagliptin Phosphate

Diabetic retinopathy is considered a low-grade chronic inflammatory disease and several inflammatory molecules, including tumor necrosis factor (TNF)-α, are known to play a major role in the degeneration of retinal capillaries. Previous studies have reported that sitagliptin, a DPP-4 inhibitor, prevents the increase in blood-retinal barrier (BRB) permeability and inhibits the tight junction disassembly induced by diabetes.. Our goal was to investigate whether sitagliptin is able to prevent retinal endothelial cells (EC) dysfunction triggered by the pro-inflammatory cytokine TNF-α.. The effects of TNF-α and/or sitagliptin on primary cultures of bovine retinal EC were tested. The EC monolayer permeability was analyzed by using 70 kDa rhodamine isothiocyanate (RITC) dextran. The cellular distribution profile of claudin-5 was examined by immunofluorescence staining, and DPP-4 activity was evaluated by using a fluorogenic substrate. Cell viability was assessed by MTT assay, and cell proliferation by the BrdU incorporation assay. Retinal EC migration and angiogenesis were evaluated by a scratch assay and a capillary tube formation in matrigel assay, respectively.. TNF-α increased the permeability of EC monolayer and induced the loss of claudin-5 immunostaining at the cell borders. This impairment was associated with decreased migration and capillary morphogenesis of retinal EC. Sitagliptin was unable to prevent the effect of TNF-α on EC permeability. However, it decreased DPP-4 activity in bovine retinal EC exposed to TNF-α, without affecting cell viability. Moreover, sitagliptin enhanced the migration and capillary morphogenesis in bovine retinal EC challenged with TNF-α.. These results suggest that sitagliptin is able to positively modulate vascular EC function under conditions of retinal inflammation.

Topics: Animals; Capillaries; Cattle; Cell Membrane Permeability; Cell Movement; Cell Survival; Dipeptidyl-Peptidase IV Inhibitors; Endothelial Cells; Inflammation; Morphogenesis; Neovascularization, Physiologic; Retina; Sitagliptin Phosphate; Tumor Necrosis Factor-alpha

Acute respiratory distress syndrome (ARDS) is a severe clinical condition marked by acute respiratory failure and dysregulated inflammation. Pulmonary vascular endothelial cells (PVECs) function as an important pro-inflammatory source in ARDS, suggesting that modulation of inflammatory events at the endothelial level may have a therapeutic benefit. Dipeptidyl peptidase-4 (DPP4) inhibitors, widely used for the treatment of diabetes mellitus, have been reported to have possible anti-inflammatory effects. However, the potential anti-inflammatory effects of DPP4 inhibition on PVEC function and ARDS pathophysiology are unknown. Therefore, we evaluated the effects of sitagliptin, a DPP4 inhibitor in wide clinical use, on LPS-induced lung injury in mice and in human lung ECs in vitro. In vivo, sitagliptin reduced serum DPP4 activity, bronchoalveolar lavage protein concentration, cell number, and proinflammatory cytokine levels after LPS and alleviated histological findings of lung injury. LPS decreased the expression levels of CD26/DPP4 on pulmonary epithelial cells and PVECs isolated from mouse lungs, and the effect was partially reversed by sitagliptin. In vitro, human lung microvascular ECs (HLMVECs) expressed higher levels of CD26/DPP4 than human pulmonary arterial ECs. LPS induced the release of TNFα, IL-6, and IL-8 by HLMVECs that were inhibited by sitagliptin. LPS promoted the proliferation of HLMVECs, and sitagliptin suppressed this response. However, sitagliptin failed to reverse LPS-induced permeability in cultured ECs or lung epithelial cells in vitro. In summary, sitagliptin attenuates LPS-induced lung injury in mice and exerts anti-inflammatory effects on HLMVECs. These novel observations indicate DPP4 inhibitors may have potential as therapeutic drugs for ARDS.

Topics: Animals; Bronchoalveolar Lavage; Cell Proliferation; Cytokines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Endothelial Cells; Epithelial Cells; Female; Humans; Inflammation; Lipopolysaccharides; Lung; Mice; Mice, Inbred C57BL; Respiratory Distress Syndrome; Sitagliptin Phosphate

This study investigated the effect of sitagliptin prophylactic treatment on intestinal I/R rat model and explored the possible underlying mechanism.. Forty-five male Sprague-Dawley rats were randomly assigned to 3 groups: Sham group (operation without clamping), I/R group (operation with clamping) and sitagliptin pretreated group (300 mg/kg/day; p.o.) for 2 weeks before I/R insult. Intestinal I/R was performed by clamping the superior mesenteric artery for 30 min, followed by 60 min reperfusion after removal of clamping. At the end of the experimental period, all rats were sacrificed for histopathological, biochemical, PCR and western blot assessment.. Pretreatment with sitagliptin remarkably alleviated the pathological changes induced by I/R in the jejunum, suppressed upregulated NF-κB, TNF-α, IL-1βand MPO caused by I/R. Moreover, sitagliptin decreased the Bax/Bcl-2 ratio and accordingly suppressed apoptotic tissue damage as reflected by a caspase-3 level reduction in rat intestine subjected to I/R injury. Interestingly, sitagliptin could obviously increase the active GLP-1 level and GLP-1 receptor mRNA expression in the jejunum of I/R rats. This was associated with the augmentation of the cAMP level and enhancement of PKA activity. Simultaneously, sitagliptin treatment was able to increase the protein expression levels of phosphorylated PI3K and Akt.. Sitagliptin has shown protective effects against intestinal I/R injury in rats through reduction of intestinal inflammation and apoptosis. The molecular mechanisms may be partially correlated with activation of cAMP/PKA and PI3K/Akt signaling pathway by the GLP-1/GLP-1 receptor.

Topics: Animals; Apoptosis; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Inflammation; Inflammation Mediators; Intestinal Diseases; Intestinal Mucosa; Intestines; Male; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sitagliptin Phosphate

Febrile seizures (FS) are the most common seizure disorders in children aged 6 months to 5 years. Children suffering from complex FS have a high risk of developing subsequent temporal lobe epilepsy (TLE). Neuroinflammation is involved in the pathogenesis of FS although the mechanism remains unknown. Our previous study using the Whole Rat Genome Oligo Microarray determined that Dipeptidyl peptidase IV (DPP4) is potentially a related gene in FS rats. In this study, we demonstrated that DPP4 expression was significantly increased at both the protein and mRNA levels after hyperthermia induction. Sitagliptin, a specific enzyme inhibitor of DPP4, remarkably attenuated the severity of seizures in FS rats, and hyperthermia-induced astrocytosis was suppressed after DPP4 inhibition. Furthermore, sitagliptin significantly decreased the levels of the inflammatory cytokines IL-1β, TNF-α, and IL-6 but not IL-10. In addition, sitagliptin prevented NF-κB activation by decreasing phosphorylation of the p65 subunit. Taken together, our findings demonstrate that DPP4 functions as a critical regulator of neuroinflammation in hyperthermia-induced seizures and the DPP4 inhibitor may be a viable option for FS therapeutics.

Topics: Animals; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Hyperthermia, Induced; Inflammation; NF-kappa B; Rats; Rats, Sprague-Dawley; Seizures, Febrile; Sitagliptin Phosphate; Up-Regulation

Dipeptidyl peptidase-4 (CD26), a cell surface glycoprotein, is expressed by a variety of cells. It has been shown that dipeptidyl peptidase-4 (CD26) is involved in T cell activation. Nonetheless, its role in inflammatory effects in islet β cells has not been well investigated. In this study, we used sitagliptin, a classic inhibitor of dipeptidyl peptidase-4 (CD26), to research the effect of dipeptidyl peptidase-4 (CD26) on the activation of NF-κB, the expression of inflammatory cytokines, and cell apoptosis in rat insulinoma cells. Results showed that dipeptidyl peptidase-4 (CD26) was expressed on the surface of rat insulinoma cells. Lipopolysaccharide-induced NF-κB activation and expression of inflammatory cytokines were suppressed by sitagliptin treatment in rat insulinoma cells. Furthermore, sitagliptin treatment reduced cell apoptosis stimulated by lipopolysaccharide. Taken together, this study showed for the first time that sitagliptin suppressed NF-κB activation and inflammatory cytokines expression in rat insulinoma cells, suggesting that the dipeptidyl peptidase-4 inhibitor may exert direct anti-inflammatory effects in islet β cells.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cytokines; Dipeptidyl-Peptidase IV Inhibitors; Inflammation; Insulin-Secreting Cells; Insulinoma; NF-kappa B; Pancreatic Neoplasms; Phosphorylation; Rats; Sitagliptin Phosphate

Circulating dipeptidyl peptidase IV (DPPIV) activity correlates with cardiac dysfunction in humans and experimental heart failure (HF) models. Similarly, inflammatory markers are associated with poorer outcomes in HF patients. However, the contributions of DPPIV to inflammation in HF remain elusive. Therefore, this study aimed to investigate whether the cardioprotective effects of DPPIV inhibition after myocardial injury are accompanied by reduced cardiac inflammation, whether circulating DPPIV activity correlates with the levels of systemic inflammatory markers in HF patients, and whether leukocytes and/or splenocytes may be one of the sources of circulating DPPIV in HF. Experimental HF was induced in male Wistar rats by left ventricular myocardial injury after radiofrequency catheter ablation. The rats were divided into three groups: sham, HF, and HF + DPPIV inhibitor (sitagliptin). Six weeks after surgery, cardiac function, perfusion and inflammatory status were evaluated. Sitagliptin treatment improved cardiac function and perfusion, reduced macrophage infiltration, and diminished the levels of inflammatory biomarkers including TNF-α, IL-1β, and CCL2. In HF patients, serum DPPIV activity correlated with CCL2, suggesting that leukocytes may be the source of circulating DPPIV in HF. Unexpectedly, DPPIV release was higher in splenocytes from HF rats and similar in HF circulating mononuclear cells compared with those from sham, suggesting an organ-specific modulation of DPPIV in HF. Collectively, our data provide new evidence that the cardioprotective effects of DPPIV inhibition in HF may be due to suppression of inflammatory cytokines. Moreover, they suggest that a vicious circle between DPPIV and inflammation may contribute to HF development and progression.

Topics: Animals; Biomarkers; Chemokine CCL2; Dipeptidyl-Peptidase IV Inhibitors; Heart; Heart Failure; Inflammation; Interleukin-1beta; Macrophages; Male; Rats; Rats, Wistar; Sitagliptin Phosphate; Tumor Necrosis Factor-alpha

Dipeptidyl peptidase 4 (DPP-4) cleaves a large number of chemokine and peptide hormones involved in the regulation of the immune system. Additionally, DPP-4 may also be involved in macrophage-mediated inflammation and insulin resistance. Thus, the current study investigated the effect of linagliptin, an inhibitor of DPP-4, on macrophage migration and polarization in white adipose tissue (WAT) and liver of high-fat diet-induced obese (DIO) mice. DPP-4(+) macrophages in lean and obese mice were quantified by fluorescence-activated cell sorting (FACS) analysis. DPP-4 was predominantly expressed in F4/80(+) macrophages in crown-like structures compared with adipocytes in WAT of DIO mice. FACS analysis also revealed that, compared with chow-fed mice, DIO mice exhibited a significant increase in DPP-4(+) expression in cells within adipose tissue macrophages (ATMs), particularly M1 ATMs. Linagliptin showed a greater DPP-4 inhibition and antioxidative capacity than sitagliptin and reduced M1-polarized macrophage migration while inducing an M2-dominant shift of macrophages within WAT and liver, thereby attenuating obesity-induced inflammation and insulin resistance. Loss of macrophage inflammatory protein-1α, a chemokine and DPP-4 substrate, in DIO mice abrogated M2 macrophage-polarizing and insulin-sensitizing effects of linagliptin. Therefore, the inhibition of DPP-4 by linagliptin reduced obesity-related insulin resistance and inflammation by regulating M1/M2 macrophage status.

Topics: Adipose Tissue; Animals; Cell Movement; Cells, Cultured; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Flow Cytometry; Inflammation; Insulin Resistance; Linagliptin; Macrophages; Male; Mice; Mice, Inbred C57BL; Obesity; Sitagliptin Phosphate

The present study evaluated the effects of sitagliptin-insulin against type 2 diabetes mellitus with neuropathy in rats and possible neuroprotective mechanisms.. Diabetes was induced in 32 adult male albino rats by 6-week high-fat high-sugar diet followed by streptozotocin 30 mg/kg intraperitoneal injection. For 4 weeks thereafter, diabetic rats were divided into 4 groups, each group receiving one of the following daily: vehicle (untreated diabetic), insulin 10 IU/kg SC, sitagliptin 30 mg/kg PO or sitagliptin-insulin. We assessed systolic blood pressure (SBP), blood glucose, serum insulin and advanced glycation end-products (AGEs), thermal hyperalgesia and sciatic nerve tumor necrosis factor-alpha (TNF-α), superoxide dismutase (SOD) and malondialdehyde (MDA) and sciatic histopathology.. Compared to untreated and insulin-treated groups, sitagliptin decreased SBP, serum AGEs and sciatic MDA and TNF-α, and increased serum insulin and sciatic SOD, but insulin decreased blood glucose more. Sitagliptin-insulin (greater than sitagliptin or insulin alone) superiorly decreased and increased the above respective parameters, and ameliorated hyperalgesia and sciatic histopathological changes, but was similar to insulin in decreasing blood glucose, and similar to sitagliptin in rising serum insulin.. Sitagliptin-insulin combination produced hypoglycemic and neuroprotective effect and ameliorated hyperalgesia, oxidative stress and inflammation more than either drug alone. This combination might have clinical efficacy in uncontrolled type 2 diabetes with neuropathy.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Drug Therapy, Combination; Hypoglycemic Agents; Inflammation; Insulin; Male; Neuroprotection; Oxidative Stress; Rats; Rats, Sprague-Dawley; Sitagliptin Phosphate

Dipeptidyl peptidase (DPP)-4 inhibitors are used to treat hyperglycemia by increasing the incretin glucagon-like peptide-1 (GLP-1). Previous studies showed anti-inflammatory and antiatherosclerotic effects of DPP-4 inhibitors. Here, we compared the effects of linagliptin versus sitagliptin and liraglutide on survival and vascular function in animal models of endotoxic shock by prophylactic therapy and treatment after lipopolysaccharide (LPS) injection. Gliptins were administered either orally or subcutaneously: linagliptin (5 mg/kg/day), sitagliptin (50 mg/kg/day) or liraglutide (200 µg/kg/day). Endotoxic shock was induced by LPS injection (mice 17.5-20 mg/kg i.p., rats 10 mg/kg/day). Linagliptin and liraglutide treatment or DPP-4 knockout improved the survival of endotoxemic mice, while sitagliptin was ineffective. Linagliptin, liraglutide and sitagliptin ameliorated LPS-induced hypotension and vascular dysfunction in endotoxemic rats, suppressed inflammatory parameters such as whole blood nitrosyl-iron hemoglobin (leukocyte-inducible nitric oxide synthase activity) or aortic mRNA expression of markers of inflammation as well as whole blood and aortic reactive oxygen species formation. Hemostasis (tail bleeding time, activated partial thromboplastin time) was impaired in endotoxemic rats and recovered under cotreatment with linagliptin and liraglutide. Finally, the beneficial effects of linagliptin on vascular function and inflammatory parameters in endotoxemic mice were impaired in AMP-activated kinase (alpha1) knockout mice. The improved survival of endotoxemic animals and other data shown here may warrant further clinical evaluation of these drugs in patients with septic shock beyond the potential improvement of inflammatory complications in diabetic individuals with special emphasis on the role of AMP-activated kinase (alpha1) in the DPP-4/GLP-1 cascade.

Topics: Animals; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Endotoxemia; Glucagon-Like Peptide 1; Inflammation; Linagliptin; Lipopolysaccharides; Liraglutide; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxidative Stress; Purines; Pyrazines; Quinazolines; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Sitagliptin Phosphate; Triazoles

Sitagliptin, a new antidiabetic drug that inhibits dipeptidyl peptidase (DPP)-4 enzyme activity, has been reported to possess neuroprotective property. We tested the protective effects of sitagliptin against chronic cerebral hypoperfusion (CHP) in mice after bilateral carotid artery stenosis (BCAS).. Thirty C57BL/6 mice were divided into three groups: sham control (n = 10), CHP (n = 10) and CHP-sitagliptin (orally 600 mg/kg/day) (n = 10). Working memory was assessed with novel-object recognition test. MRI was performed at day 0 and day 90 after BCAS procedure prior to sacrifice.. Immunohistochemical (IHC) staining showed significantly enhanced white matter lesions, microglia activation and astrocytosis of white matter in CHP group than in sham control, but the changes were significantly suppressed after sitagliptin treatment (all P < 0.01). The mRNA expressions of inflammatory [tumour necrosis factor-alpha (TNF-α), monocyte chemoattractant protein (MCP-1) and matrix metalloproteinase (MMP)-2] and apoptotic (Bax) biomarkers showed an identical pattern, whereas the anti-inflammatory (interleukin, IL-10) and antiapoptotic (Bcl-2) biomarkers showed an opposite pattern compared with that of IHC among all groups (all P < 0.01). The protein expressions of oxidative stress (NOX-I, NOX-II, nitrotyrosin, oxidized protein), inflammatory [nuclear factor-kappa B (NF-κB), TNF-α and MMP-2], apoptotic [mitochondrial Bax, cleaved poly(ADP-ribose) polymerase (PARP)] and DNA-damage (γ-H2AX) markers showed an identical pattern, while expression pattern of antiapoptotic marker (Bcl-2) was opposite to that of IHC (all P < 0.01). Glycogen-like peptide-1 receptor protein expression progressively increased from sham control to CHP-sitagliptin (P < 0.01). The short-term working-memory loss and MRI/diffusion tensor imaging (DTI) showed a pattern identical to that of IHC in all groups (all P < 0.01).. Sitagliptin protected against cognitive impairment and brain damage in a murine CHP model.

Topics: Animals; Apoptosis; Brain; Brain Ischemia; Cognition Disorders; Drug Evaluation, Preclinical; Glucagon-Like Peptide 1; Hypoglycemic Agents; Inflammation; Interleukin-10; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Random Allocation; Sitagliptin Phosphate; Tumor Necrosis Factor-alpha

In this study the role of sitagliptin, dipeptidyl peptidase inhibitor, DPP-4, and dexamethasone in ameliorating inflammation and remodeling of chronic asthma in a mouse model were investigated. Mice sensitized to ovalbumin were chronically challenged with aerosolized antigen for 3days a week continued for 8weeks. During this period animals were treated with sitagliptin or dexamethasone daily. Assessment of inflammatory cell, oxidative markers, total nitrate/nitrite (NOx), interleukin (IL)-13, transforming growth factor-beta1 (TGF-β1) in bronchoalveolar lavage (BAL) and/or lung tissue were done. Also histopathological and immuno-histochemical analysis for lung was carried out. Compared with vehicle alone, treatment with sitagliptin or dexamethasone significantly reduced accumulation of eosinophils and chronic inflammatory cells, subepithelial collagenization, and thickening of the airway epithelium. Also both drug reduced goblet cell hyperplasia, oxidative stress, TGF-β1, IL-13 and epithelial cytoplasmic immunoreactivity for nuclear factor κ-B (NFκ-B). These data indicate that sitagliptin like dexamethasone may play a beneficial role reducing airway inflammation and remodeling in chronic murine model of asthma.

Topics: Airway Remodeling; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Bronchoalveolar Lavage Fluid; Chronic Disease; Cytokines; Dexamethasone; Female; Goblet Cells; Inflammation; Mice; Mice, Inbred BALB C; Ovalbumin; Oxidative Stress; Respiratory Tract Diseases; Sitagliptin Phosphate

Non-alcoholic steatohepatitis is characterized by hepatic fat accumulation, inflammation and varying degrees of fibrosis. The dipeptidyl peptidase‑IV enzyme is important in glucose metabolism, as well as lipid accumulation, extracellular matrix metabolism and immune stimulation. Furthermore, the enzyme activity of dipeptidyl peptidase‑IV is known to be increased in non‑alcoholic steatohepatitis. Therefore, dipeptidyl peptidase‑IV inhibitors are potential therapeutic agents for non‑alcoholic steatohepatitis. The present study assessed the therapeutic effects of sitagliptin, a dipeptidyl peptidase‑IV inhibitor, on non‑alcoholic steatohepatitis using fatty liver Shionogi‑ob/ob male mice. Sitagliptin (2 mg/kg/day; n=10) or placebo (control; n=10) was orally administered to fatty liver Shionogi‑ob/ob mice for 12 weeks, and hepatic steatosis, fibrosis, inflammation and oxidative stress were assessed in comparison with the controls. Sitagliptin administration reduced body weight and blood glucose levels, and improved hepatic fibrosis. It also inhibited the gene expression levels of fatty acid synthase, transforming growth factor‑β1, tissue inhibitor of metalloproteinases‑1, procollagen‑type 1, tumor necrosis factor‑α, monocyte chemoattractant protein‑1 and enhanced peroxisome proliferator activated receptor‑α. Furthermore, a marked attenuation of hepatic stellate cell activation and Kupffer cells was observed in the sitagliptin group. A decrease in oxidative stress and apoptosis was also observed. Sitagliptin attenuated the progression of hepatic fibrosis by improving lipid metabolism, inflammation and oxidative stress in non-alcoholic steatohepatitis.

Topics: Animals; Apoptosis; Dipeptidyl-Peptidase IV Inhibitors; Fibrosis; Inflammation; Liver; Male; Mice; Mice, Obese; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Sitagliptin Phosphate

Diabetic retinopathy, a leading cause of vision loss in working-age population, is often associated with inflammation and apoptosis. We have previously reported that sitagliptin, a DPP-IV inhibitor, exerts beneficial effects in the retina of type 2 diabetic animals. The present study aimed to evaluate whether sitagliptin can exert protective effects in the retina of type 1 diabetic animals by a mechanism independent of insulin secretion and glycemia normalization. Streptozotocin-induced diabetic rats were treated orally with sitagliptin (5mg/kg/day) for the last two weeks of 4 weeks of diabetes. Sitagliptin treatment did not change the weight and glucose, HbA1c or insulin levels. However, it prevented the diabetes-induced increase in DPP-IV/CD26 activity and levels in serum and retina. Sitagliptin also prevented the increase in blood-retinal barrier (BRB) permeability and inhibited the changes in immunoreactivity and endothelial subcellular distribution of occludin, claudin-5 and ZO-1 proteins induced by diabetes. Furthermore, sitagliptin decreased the retinal inflammatory state and neuronal apoptosis. Sitagliptin inhibited the BRB breakdown in a type 1 diabetic animal model, by a mechanism independent of normalization of glycemia, by preventing changes in tight junctions (TJs) organization. Sitagliptin also exerted protective effects against inflammation and pro-apoptotic state in the retina of diabetic rats. Altogether, these results suggest that sitagliptin might be envisaged to be used to prevent or delay some of the alterations associated with the development of diabetic retinopathy.

Topics: Animals; Apoptosis; Biomarkers; Blood-Retinal Barrier; Blotting, Western; Cell Death; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Enzyme-Linked Immunosorbent Assay; Immunoenzyme Techniques; Inflammation; Male; Neurons; Pyrazines; Rats; Rats, Wistar; Retina; Sitagliptin Phosphate; Triazoles

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-1β, 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-1β 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.

Topics: Animals; Apoptosis; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Inflammation; Kidney; Pyrazines; Rats; Rats, Zucker; Sitagliptin Phosphate; Triazoles; Tumor Necrosis Factor-alpha

Accumulating evidence suggests that inhibitors of dipeptidyl peptidase-4 (DPP-4), such as sitagliptin, may play an important role in the prevention of non-alcoholic steatohepatitis (NASH). This study was conducted to elucidate whether sitagliptin could prevent steatohepatitis by inhibiting pathways involved in hepatic steatosis, inflammation, and fibrosis.. C57BL/6 mice were fed a methionine/choline-deficient (MCD) diet with or without supplement with sitagliptin for 5 weeks. Liver and adipose tissue from mice were examined histologically and immunohistochemically to estimate the effect of sitagliptin on the development of NASH.. Supplementation with sitagliptin resulted in significant improvement of MCD diet-induced fat accumulation in the liver. In addition, sitagliptin treatment lowered fatty acid uptake, expression of VLDL receptor and hepatic triglyceride content. Sitagliptin also effectively attenuated MCD diet-induced hepatic inflammation, endoplasmic reticulum (ER) stress, and liver injury, as evidenced by reduced proinflammatory cytokine levels, ER stress markers, and TUNEL staining. Expression of CYP2E1 and 4NHE were strongly increased by the MCD diet, but this effect was successfully prevented by sitagliptin treatment. Furthermore, sitagliptin significantly decreased levels of MCD diet-induced fibrosis-associated proteins such as fibronectin and α-SMA in the liver. Inflammatory and atrophic changes of adipose tissue by MCD diet were restored by sitagliptin treatment.. Sitagliptin attenuated MCD diet-induced hepatic steatosis, inflammation, and fibrosis in mice through amelioration of mechanisms responsible for the development of NASH, including CD36 expression, NF-κB activation, ER stress, CYP2E1 expression, and lipid peroxidation. Treatment with sitagliptin may represent an effective approach for the prevention and treatment of NASH.

Topics: Animals; Biomarkers; Blotting, Western; Choline Deficiency; Diet; Dipeptidyl-Peptidase IV Inhibitors; Endoplasmic Reticulum Stress; Fatty Liver; Immunoenzyme Techniques; Inflammation; Lipid Peroxidation; Liver Cirrhosis; Male; Methionine; Mice; Mice, Inbred C57BL; NF-kappa B; Pyrazines; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Sitagliptin Phosphate; Triazoles; Triglycerides

Type 2 diabetic patients have a high incidence of cerebrovascular disease, elevated inflammation, and high risk of developing cognitive dysfunction following carotid endarterectomy (CEA). To elucidate the relationship between inflammation and the risk of cognitive dysfunction in type 2 diabetic patients, we aim to determine whether elevated levels of systemic inflammatory markers are associated with cognitive dysfunction 1 day after CEA.. One hundred fifteen type 2 diabetic CEA patients and 156 reference surgical patients were recruited with written informed consent in this single-center cohort study. All patients were evaluated with an extensive battery of neuropsychometric tests. Preoperative monocyte counts, HbA1c, C-reactive protein (CRP), intercellular adhesion molecule 1, and matrix metalloproteinase 9 activity levels were obtained.. In a multivariate logistic regression model constructed to identify predictors of cognitive dysfunction in type 2 diabetic CEA patients, each unit of monocyte counts (odds ratio [OR] 1.76 [95% CI 1.17-2.93]; P=0.005) and CRP (OR 1.17 [1.10-1.29]; P<0.001) was significantly associated with higher odds of developing cognitive dysfunction 1 day after CEA in type 2 diabetic patients.. Type 2 diabetic patients with elevated levels of preoperative systemic inflammatory markers exhibit more cognitive dysfunction 1 day after CEA. These observations have implications for the preoperative medical management of this high-risk group of surgical patients undergoing carotid revascularization with CEA.

Topics: Aged; Cognition Disorders; Diabetes Mellitus, Type 2; Endarterectomy, Carotid; Glyburide; Humans; Hypoglycemic Agents; Inflammation; Logistic Models; Metformin; Middle Aged; Pyrazines; Sitagliptin Phosphate; Sulfonylurea Compounds; Triazoles

Hypertension induces cardiac dysfunction, calcium (Ca(2+)) dysregulation, and arrhythmogenesis. Dipeptidyl peptidase (DPP)-4 inhibitors, an antidiabetic agent with anti-inflammation and anti-hypertension potential, may regulate peroxisome proliferator-activated receptors (PPARs)-α, -γ, and -δ and Ca(2+) homeostasis.. The purpose of this study was to investigate whether DPP-4 inhibitor, sitagliptin, can modulate PPARs and Ca(2+) handling proteins in hypertensive hearts.. A Western blot analysis was used to evaluate protein expressions of myocardial PPAR isoforms, tumor necrosis factor (TNF)-α, interleukin (IL)-6, sarcoplasmic reticulum ATPase (SERCA2a), Na(+)-Ca(2+) exchanger (NCX), ryanodine receptor (RyR), voltage-dependent Ca(2+) (CaV1.2), slow-voltage potassium currents (Kvs), angiotensin II type 1 receptor (AT1R), and receptor of advanced glycated end-products (RAGE) from Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR), and SHR treated with sitagliptin (10mg/kg for 4weeks). Conventional microelectrodes were used to record action potentials (APs) in the ventricular myocytes from each group.. Compared to the control group, SHR had lower cardiac PPAR-α and PPAR-δ protein expressions, but had greater cardiac PPAR-γ levels, and TNF-α, IL-6, RAGE, and AT1R protein expressions, which were ameliorated in the sitagliptin-treated SHR. SHR had prolonged QT interval and AP duration with less SERCA2a and RyR, and greater CaV1.2 expressions, which were also attenuated in sitagliptin-treated SHR.. Sitagliptin significantly changed the cardiac electrophysiological characteristics and Ca(2+) regulation, which may have been caused by its effects on cardiac PPARs, proinflammatory cytokines, and AT1R.

Topics: Action Potentials; Animals; Blood Pressure; Calcium; Cardiotonic Agents; Dipeptidyl-Peptidase IV Inhibitors; Electrocardiography; Heart Ventricles; Hypertension; Inflammation; Interleukin-6; Peroxisome Proliferator-Activated Receptors; PPAR alpha; PPAR delta; PPAR gamma; Pyrazines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor for Advanced Glycation End Products; Receptor, Angiotensin, Type 1; Receptors, Immunologic; Sitagliptin Phosphate; Triazoles; Tumor Necrosis Factor-alpha

This study tested the hypothesis that exendin-4 and sitagliptin can effectively protect kidney from acute ischemia-reperfusion (IR) injury.. Adult SD-rats (n = 48) equally divided into group 1 (sham control), group 2 (IR injury), group 3 [IR + sitagliptin 600 mg/kg at post-IR 1, 24, 48 hr)], and group 4 [IR + exendin-4 10 μm/kg at 1 hr after procedure] were sacrificed after 24 and 72 hrs (n = 6 at each time from each group) following clamping of bilateral renal pedicles for 60 minutes (groups 2-4).. Serum creatinine level and urine protein to creatinine ratio were highest in group 2 and lowest in group 1 (all p < 0.001) without notable differences between groups 3 and 4. Kidney injury score, expressions of inflammatory biomarkers at mRNA (MMP-9, TNF-α, IL-1β, PAI-1), protein (TNF-α, NF-κB and VCAM-1), and cellular (CD68+) levels in injured kidneys at 24 and 72 hr showed an identical pattern compared to that of creatinine level in all groups (all p < 0.0001). Expressions of oxidized protein, reactive oxygen species (NOX-1, NOX-2), apoptosis (Bax, caspase-3 and PARP), and DNA damage marker (γH2AX+) of IR kidney at 24 and 72 hrs exhibited a pattern similar to that of inflammatory mediators among all groups (all p < 0.01). Renal expression of glucagon-like peptide-1 receptor, and anti-oxidant biomarkers at cellular (GPx, GR) and protein (NQO-1, HO-1, GPx) levels at 24 and 72 hr were lowest in group 1, significantly lower in group 2 than in groups 3 and 4 (all p < 0.01).. Exendin-4 and sitagliptin provided significant protection for the kidneys against acute IR injury.

Topics: Animals; Biomarkers; Creatinine; Exenatide; Inflammation; Kidney; Male; Oxidative Stress; Peptides; Proteinuria; Pyrazines; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Reperfusion Injury; Sitagliptin Phosphate; Triazoles; Venoms

Sitagliptin, a new oral glucose lowering medication, is used for treatment of type 2 diabetes mellitus. The anti-inflammatory property of sitagliptin is reported, yet no studies have been done on asthma. In the present study, the effect of sitagliptin on allergic asthma was investigated using ovalbumin (OVA)-induced asthma model in mice. Swiss male albino mice sensitized and challenged to ovalbumin were treated with sitagliptin (8 mg/kg administered orally twice a day). Drug treatment was done on each day from days 16 to 23, 1 h before the challenge on the days of challenge. Sitagliptin treatment markedly decreased inflammatory cell accumulation in bronchoalveolar lavage (BAL) fluid and in the lungs, as revealed by histopathological examination. Furthermore, the levels of interleukin (IL)-13 in BAL fluid, total and OVA specific immunoglobulins (Ig)-E in serum, were significantly reduced as compared to the OVA group. In addition, sitagliptin significantly increased superoxidase dismutase (SOD) and reduced glutathione (GSH) activities with significant decrease in malondialdehyde (MDA) content in the lung. Importantly, sitagliptin decreased mRNA expression of the inflammatory cytokines tumor necrosis factor-α (TNF-α) and transforming growth factor-β(1) (TGF-β(1)) in lung tissues as compared to the OVA group. Moreover, nitric oxide content as well as the mRNA expression of inducible nitric oxide synthase (iNOS) was remarkably decreased by sitagliptin treatment. Sitagliptin attenuates the allergic airway inflammation suggesting that sitagliptin may have applications in the treatment of bronchial asthma.

Topics: Animals; Anti-Allergic Agents; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Bronchoalveolar Lavage Fluid; Cytokines; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Inflammation; Lung; Male; Mice; Nitric Oxide Synthase Type II; Ovalbumin; Pyrazines; RNA, Messenger; Sitagliptin Phosphate; Triazoles

BACKGROUND. Liraglutide leading to improve not only glycaemic control but also liver inflammation in non-alcoholic fatty liver disease (NAFLD) patients. AIMS. The aim of this study is to elucidate the effectiveness of liraglutide in NAFLD patients with type 2 diabetes mellitus (T2DM) compared to sitagliptin and pioglitazone. METHODS. We retrospectively enrolled 82 Japanese NAFLD patients with T2DM and divided into three groups (liraglutide: N = 26, sitagliptin; N = 36, pioglitazone; N = 20). We compared the baseline characteristics, changes of laboratory data and body weight. RESULTS. At the end of follow-up, ALT, fast blood glucose, and HbA1c level significantly improved among the three groups. AST to platelet ratio significantly decreased in liraglutide group and pioglitazone group. The body weight significantly decreased in liraglutide group (81.8 kg to 78.0 kg, P < 0.01). On the other hands, the body weight significantly increased in pioglitazone group and did not change in sitagliptin group. Multivariate regression analysis indicated that administration of liraglutide as an independent factor of body weight reduction for more than 5% (OR 9.04; 95% CI 1.12-73.1, P = 0.04). CONCLUSIONS. Administration of liraglutide improved T2DM but also improvement of liver inflammation, alteration of liver fibrosis, and reduction of body weight.

Topics: Adult; Alanine Transaminase; Blood Glucose; Body Weight; Comorbidity; Diabetes Mellitus, Type 2; Drug Evaluation; Drug Therapy, Combination; Fatty Liver; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Inflammation; Liraglutide; Liver Cirrhosis; Logistic Models; Male; Middle Aged; Multivariate Analysis; Non-alcoholic Fatty Liver Disease; Odds Ratio; Pioglitazone; Platelet Count; Pyrazines; Retrospective Studies; Sitagliptin Phosphate; Thiazolidinediones; Treatment Outcome; Triazoles

Adipose tissue inflammation and reduced pancreatic β-cell function are key issues in the development of cardiovascular disease and progressive metabolic dysfunction in type 2 diabetes mellitus. The aim of this study was to determine the effect of the DPP IV inhibitor sitagliptin on adipose tissue and pancreatic islet inflammation in a diet-induced obesity model. C57Bl/6J mice were placed on a high-fat (60% kcal fat) diet for 12 wk, with or without sitagliptin (4 g/kg) as a food admix. Sitagliptin significantly reduced fasting blood glucose by 21% as well as insulin by ∼25%. Sitagliptin treatment reduced body weight without changes in overall body mass index or in the epididymal and retroperitoneal fat mass. However, sitagliptin treatment led to triple the number of small adipocytes despite reducing the number of the very large adipocytes. Sitagliptin significantly reduced inflammation in the adipose tissue and pancreatic islet. Macrophage infiltration in adipose tissue evaluated by immunostaining for Mac2 was reduced by sitagliptin (P < 0.01), as was the percentage of CD11b+/F4/80+ cells in the stromal vascular fraction (P < 0.02). Sitagliptin also reduced adipocyte mRNA expression of inflammatory genes, including IL-6, TNFα, IL-12(p35), and IL-12(p40), 2.5- to fivefold as well as 12-lipoxygenase protein expression. Pancreatic islets were isolated from animals after treatments. Sitagliptin significantly reduced mRNA expression of the following inflammatory cytokines: MCP-1 (3.3-fold), IL-6 (2-fold), IL-12(p40) (2.2-fold), IL-12(p35) (5-fold, P < 0.01), and IP-10 (2-fold). Collectively, the results indicate that sitagliptin has anti-inflammatory effects in adipose tissue and in pancreatic islets that accompany the insulinotropic effect.

Topics: Adipocytes; Adipose Tissue; Adiposity; Animals; Anti-Inflammatory Agents; Body Weight; Cytokines; Dipeptidyl-Peptidase IV Inhibitors; Flow Cytometry; Glucose; Glucose Intolerance; Glucose Tolerance Test; Immunohistochemistry; Inflammation; Insulin; Islets of Langerhans; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Neutrophil Infiltration; Pyrazines; Reverse Transcriptase Polymerase Chain Reaction; Sitagliptin Phosphate; Triazoles