sitagliptin-phosphate and Non-alcoholic-Fatty-Liver-Disease

Non-alcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease. However, the treatment is limited. The aim of this meta-analysis was to evaluate the effects and safety of sitagliptin, a selective inhibitor of dipeptidyl peptidase-4 (DPP-4I), in treating NAFLD. Studies were sourced from electronic databases including PubMed, CENTRAL (Cochrane Controlled Trials Register), Embase, Medline, Web of Science, Clinical Trials, and CNKI to identify all randomized controlled clinical trials (RCTs) and non-RCTs in adult patients with NAFLD. Key outcomes were changes in serum levels of liver enzymes and improvement in hepatic histology and fat content measured by imaging or liver biopsy. Stata14.0 and RevMan5.3 were used for the meta-analysis. Seven studies with 269 NAFLD patients were included. Compared to the control group, sitagliptin treatment improved serum gamma-glutamyl transpeptidase (GGT) levels in the RCT subgroup (SMD = 0.79, 95% CI: 0.01-1.58). However, there was no significant improvement in serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels following sitagliptin treatment. Four of the included studies performed liver imaging, but sitagliptin treatment did not result in a significant reduction in liver fat content. Only five participants developed sitagliptin-related gastrointestinal discomfort. Our study suggests that sitagliptin effects individuals with NAFLD by improving serum GGT. Although sitagliptin is safe and well tolerated in NAFLD patients, it exerts no beneficial effects on liver transaminase and liver fat content in these patients.

Topics: Aged; Clinical Trials as Topic; Female; Humans; Hypoglycemic Agents; Liver; Liver Function Tests; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Sitagliptin Phosphate; Treatment Outcome

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum that ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) and to cirrhosis. The recommended treatment for this disease includes measures that target obesity and insulin resistance. The present review summarizes the role of newer anti-diabetic agents in treatment of NAFLD.. PubMed, MEDLINE and Ovid databases were searched to identify human studies between January 1990 and January 2013 using specified key words. Original studies that enrolled patients with a diagnosis of NAFLD or NASH and involved use of newer classes of anti-diabetic agents for a duration of at least 3 months were included.. Out of the screened articles, four met eligibility criteria and were included in our review. The classes of newer anti-diabetic medications described were dipeptidyl peptidase IV inhibitors and glucagon-like peptide-1 analogues.. Liraglutide and Exenatide showed improvement in transaminases as well as histology in patients with NASH. Sitagliptin showed improvement in transaminases but limited studies are there to access its effect on histology. Further studies are needed to support use of newer anti-diabetic medications in patients with NAFLD.

Topics: Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Fatty Liver; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Liver; Non-alcoholic Fatty Liver Disease; Peptides; Pyrazines; Sitagliptin Phosphate; Transaminases; Treatment Outcome; Triazoles; Venoms

To compare the effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors and dipeptidyl peptidase-4 inhibitors on ectopic fat accumulation and tissue-specific insulin sensitivity.. This randomized controlled trial enrolled 44 patients with type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). They were randomly assigned to receive either empagliflozin 10 mg/day or sitagliptin 100 mg/day for 12 weeks. The primary endpoint was the change in intrahepatic lipid content (IHL) measured using proton magnetic resonance spectroscopy (. At baseline, the mean duration of diabetes, HbA1c level and IHL were 3.7 years, 7.2% and 20.9%, respectively. The median NAFLD activity score was 3.0. IHL was significantly more decreased in the empagliflozin group than that in the sitagliptin group (between-group difference was -5.2% ± 1.1% and -1.9% ± 1.2%, respectively, (95% confidence interval); -3.3 (-6.5, -0.1), P = .044). However, there were no significant between-group differences in the change of insulin sensitivity in the liver, muscle or adipose tissues. Interestingly, hepatic insulin sensitivity was significantly increased only in the empagliflozin group and was significantly negatively associated with the change in IHL.. Empagliflozin significantly improves hepatic steatosis compared with sitagliptin, and this may protect against subsequent hepatic insulin resistance. Early administration of SGLT2 inhibitors is preferable for T2D patients with NAFLD.

Topics: Diabetes Mellitus, Type 2; Glucose; Humans; Insulin Resistance; Lipids; Non-alcoholic Fatty Liver Disease; Prospective Studies; Sitagliptin Phosphate; Sodium-Glucose Transporter 2 Inhibitors

Dipeptidyl peptidase-4 inhibitors (DPP-4I), key regulators of the actions of incretin hormones, exert anti-hyperglycemic effects in type 2 diabetes mellitus (T2DM) patients. A major unanswered question concerns the potential ability of DPP-4I to improve intrahepatic lipid (IHL) content in nonalcoholic fatty liver disease (NAFLD) patients. The aim of this study was to evaluate the effects of sitagliptin on IHL in NAFLD patients.. A prospective, 24-week, single-center, open-label, comparative study enrolled 68 Chinese NAFLD patients with T2DM. Subjects were randomly divided into 4 groups: control group who did not take medicine (14 patients); sitagliptin group who received sitagliptin treatment (100mg per day) (17 patients); metformin group who received metformin (500mg three times per day) (17 patients); and sitagliptin plus metformin group who received sitagliptin (100mg per day) and metformin (500 mg three times per day) (20 patients). IHL, physical examination (waist circumstances, WC; body mass index, BMI), glucose-lipid metabolism (fasting plasma glucose, FPG; hemoglobin A1c, Hb1A1c; triglycerides; cholesterol; alanine aminotransferase, ALT; aspartate aminotransferase, AST) were measured at baseline and at 24 weeks.. Sitagliptin improves abnormalities in glucose metabolism, but not reduces the IHL in T2DM with NAFLD, indicating that sitagliptin might be a therapeutic option for treatment of NAFLD indirectly while not directly on IHL. Clinical Trial Registration: https://clinicaltrials.gov/, identifier CTR# NCT05480007.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Metformin; Non-alcoholic Fatty Liver Disease; Prospective Studies; Sitagliptin Phosphate; Triglycerides

To investigate the effect of antidiabetic agents on nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM), 75 patients with T2DM and NAFLD under inadequate glycemic control by metformin were randomized (1:1:1) to receive add-on liraglutide, sitagliptin, or insulin glargine in this 26-week trial. The primary endpoint was the change in intrahepatic lipid (IHL) from baseline to week 26 as quantified by magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF). Secondary endpoints included changes in abdominal adiposity (subcutaneous adipose tissue [SAT] and visceral adipose tissue [VAT]), glycated hemoglobin, and body weight from baseline to week 26. We analysed data from intent-to-treat population. MRI-PDFF, VAT, and weight decreased significantly with liraglutide (15.4% ± 5.6% to 12.5% ± 6.4%, P < 0.001; 171.4 ± 27.8 to 150.5 ± 30.8, P = 0.003; 86.6 ± 12.9 kg to 82.9 ± 11.1 kg, P = 0.005, respectively) and sitagliptin (15.5% ± 5.6% to 11.7% ± 5.0%, P = 0.001; 153.4 ± 31.5 to 139.8 ± 27.3, P = 0.027; 88.2 ± 13.6 kg to 86.5 ± 13.2 kg, P = 0.005, respectively). No significant change in MRI-PDFF, VAT, or body weight was observed with insulin glargine. SAT decreased significantly in the liraglutide group (239.9 ± 69.0 to 211.3 ± 76.1; P = 0.020) but not in the sitagliptin and insulin glargine groups. Changes from baseline in MRI-PDFF, VAT, and body weight were significantly greater with liraglutide than insulin glargine but did not differ significantly between liraglutide and sitagliptin. Conclusion: Combined with metformin, both liraglutide and sitagliptin, but not insulin glargine, reduced body weight, IHL, and VAT in addition to improving glycemic control in patients with T2DM and NAFLD.

Topics: Adult; Aged; Blood Glucose; Body Weight; Comorbidity; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Hypoglycemic Agents; Insulin Glargine; Linear Models; Lipid Metabolism; Liraglutide; Male; Metformin; Middle Aged; Multivariate Analysis; Non-alcoholic Fatty Liver Disease; Prognosis; Prospective Studies; Sitagliptin Phosphate; Treatment Outcome

Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases in recent years. The aim of this study was to evaluate the effects of sitagliptin with and without a synbiotic supplement in the treatment of patients with NAFLD.. In total, 138 NAFLD patients aged 18-60 years were enrolled in the study. Patients were randomized to one of the following treatments for 16 weeks: Group I (n=68), sitagliptin 50 mg daily plus placebo (one capsule per day) or group II (n=70) sitagliptin 50 mg daily plus synbiotic (one capsule per day). Changes in fasting blood glucose (FBS), liver enzymes, lipid profile, and body mass index were compared between the groups.. The mean change in FBS with sitagliptin-placebo from baseline was -10.47±5.77 mg/dL, and that with sitagliptin-synbiotic was -13.52±4.16 mg/dL. There was a significant difference between the groups (P<0.001). The mean change in cholesterol (Chol) was -8.34±28.83 mg/dL with sitagliptin-placebo and -21.25±15.50 mg/dL with sitagliptinsynbiotic. There was a significant difference between the two groups (P=0.029). The administration of sitagliptin-placebo induced an increase of 6.13±27.04 mg/dL in low density lipoprotein (LDL), whereas sitagliptin-synbiotic induced a decrease of 14.92±15.85 mg/dL in LDL. A significant difference was observed between the two groups (P<0.001). On the other hand, in the sitagliptin-synbiotic group, there was significant improvement in aspartate aminotransferase (AST) level compared to the sitagliptin-placebo group (P=0.018).. Sitagliptin-synbiotic produced greater improvement in FBS, AST, Chol, and LDL compared to sitagliptin alone in patients with NAFLD.

Topics: Adolescent; Adult; Aspartate Aminotransferases; Blood Glucose; Body Mass Index; Cholesterol; Female; Humans; Hypoglycemic Agents; Lipoproteins, LDL; Logistic Models; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Placebo Effect; Sitagliptin Phosphate; Synbiotics; Triglycerides; Young Adult

This study aimed to evaluate the efficacy and safety of sitagliptin for treating Chinese patients with type 2 diabetes mellitus (T2DM) with nonalcoholic fatty liver disease (NAFLD).. In total, 72 Chinese T2DM patients with NAFLD were divided randomly into two groups of 36 patients each group. All 72 patients were assigned to receive either sitagliptin or diet and exercise for 52 weeks between January 2013 and December 2015. The outcomes' measurements included serum levels of hemoglobin A1c, fasting plasma glucose, aspartate aminotransferase, and alanine aminotransferase.. Seventy patients completed the study. Sitagliptin showed greater efficacy than the diet and exercise in decreasing the hemoglobin A1c and fasting plasma glucose levels at weeks 13, 26, 39, and 52. In addition, no significant changes in the average aspartate aminotransferase and alanine aminotransferase levels were found during the 52-week follow-up in both the sitagliptin and the control groups.. The results of this study indicate that sitagliptin is an effective and safe treatment for patients with T2DM and NAFLD.

Topics: Aged; Biomarkers; Blood Glucose; China; Diabetes Mellitus, Type 2; Diet, Reducing; Dipeptidyl-Peptidase IV Inhibitors; Energy Intake; Exercise; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Risk Reduction Behavior; Sitagliptin Phosphate; Time Factors; Treatment Outcome

Oral antidiabetic drugs (OADs) such as pioglitazone and metformin have beneficial effects in patients with nonalcoholic steatohepatitis. We prospectively assessed the effects of OADs on nonalcoholic fatty liver disease (NAFLD) in 886 men with type 2 diabetes mellitus and in a murine model of NAFLD.. Patients were randomized to receive pioglitazone, metformin, sitagliptin, or a non-OAD (control) for 6 months. All the patients received dietary and exercise guidance once a month during this study. Changes in the liver-to-spleen ratio on computed tomography (CT) and NAFLD-related parameters were measured from baseline to the end of treatment.. The liver/spleen ratio improved significantly in the pioglitazone and metformin groups compared with the control group (both P < 0.01), but not in the sitagliptin group (P = 0.73). The mean changes from baseline were -3.464 ± 10.156%, 19.236 ± 9.896%, 4.783 ± 1.467%, and 1.328 ± 0.802% in the control, pioglitazone, metformin, and sitagliptin groups, respectively. Multivariable analysis showed that the liver/spleen ratio was strongly correlated with high-sensitivity C-reactive protein concentration in the pioglitazone group (F = 9.973; P < 0.01) and abdominal visceral fat volume in the metformin group (F = 6.049; P < 0.05).. Pioglitazone elicited the greatest improvements in features of NAFLD in type 2 diabetes mellitus. (Trial Registration: www.isrctn.org/, ISRCTN33414972, http://www.isrctn.org/).

Topics: Adult; Aged; Biomarkers; C-Reactive Protein; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Non-alcoholic Fatty Liver Disease; Pioglitazone; Sitagliptin Phosphate; Spleen; Thiazolidinediones; Tomography, X-Ray Computed

Uncontrolled studies show sitagliptin, an oral DPP-4 inhibitor, may improve alanine aminotransferase and liver histology in non-alcoholic fatty liver disease (NAFLD) patients. We aimed to compare sitagliptin vs. the efficacy of a placebo in reducing liver fat measured by MRI-derived proton density-fat fraction (MRI-PDFF).. This randomized, double-blind, allocation-concealed, placebo-controlled trial included 50 NAFLD patients with prediabetes or early diabetes randomized to sitagliptin orally 100mg/day or placebo for 24weeks. Primary outcome was liver fat change measured by MRI-PDFF in colocalized regions of interest within each of nine liver segments. Additional advanced assessments included MR spectroscopy (MRS) for internal validation of MRI-PDFF's accuracy, and magnetic resonance elastography (MRE) and FIBROSpect® II to assess liver fibrosis.. Sitagliptin was not significantly better than placebo in reducing liver fat measured by MRI-PDFF (mean difference between sitagliptin and placebo arms: -1.3%, p=0.4). Compared to baseline, there were no significant differences in end-of-treatment MRI-PDFF for sitagliptin (18.1% to 16.9%, p=0.27) or placebo (16.6% to 14.0%, p=0.07). The groups had no significant differences for changes in alanine aminotransferase, aspartate aminotransferase, low-density lipoprotein, homeostatic model assessment insulin resistance, and MRE-derived liver stiffness. In both groups at baseline and post-treatment, MRI-PDFF and MRS showed robust correlation coefficients ranging from r(2)=0.96 to r(2)=0.99 (p<0.0001), demonstrating the strong internal validity of the findings. FIBROSpect® II showed no changes in the sitagliptin group but was significantly increased in the placebo group (p=0.03).. Sitagliptin was safe but not better than placebo in reducing liver fat in prediabetic or diabetic patients with NAFLD.. In a randomized, double-blind, placebo-controlled study, the anti-diabetic drug sitagliptin was no more effective than placebo for improving liver fat and liver fibrosis in patients with non-alcoholic fatty liver disease. This study demonstrates that non-invasive magnetic resonance imaging techniques, including magnetic resonance imaging-proton density-fat fraction and magnetic resonance elastography, can be used to assess treatment response in non-alcoholic fatty liver disease clinical trials.

Topics: Double-Blind Method; Elasticity Imaging Techniques; Humans; Liver; Magnetic Resonance Imaging; Non-alcoholic Fatty Liver Disease; 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

Diabetes is the fifth leading cause of death in the People's Republic of China. The aim of the article is to compare the effects of nursing care on the laboratory findings and ultrasound results of diabetic patients with chronic liver diseases (CLD) who were treated with antiglycemic drugs.. Diabetic were patients treated with metformin hydrochloride in combination with gliclazide, pioglitazone hydrochloride, sitagliptin, exenatide or liraglutide. Non-alcoholic fatty liver disease (NAFLD) was evaluated by abdominal ultrasound, and fibrosis stages were evaluated at baseline and 8 months. All the patients were equally divided into two groups depending on the therapeutic approach.. The first group of patients additionally received nursing care, and the second group adhered to the prescribed therapy on their own. In total 90 patients, or 55.6%, had NAFLD at baseline, and its course was dependent upon changes in the weight (P = 0.009) and waist circumference (P = 0.012). The proportions of patients who demonstrated an ultrasonographic improvement in the control group were: 24 (56.8%) with gliclazide, 15 (41.3%) with pioglitazone hydrochloride, 28 (66.1%) with sitagliptin, 16 (79%) with exenatide and 15 (66.7%) with liraglutide (P = 0.2). For the group that received nursing care an ultrasonographic improvement was in: 29 (68.16%) with gliclazide, 18 (49.56%) with pioglitazone hydrochloride, 33 (79.32%) with sitagliptin, 19 (94.8%) with exenatide and 21 80.04% with liraglutide (P = 0.2).. Outcomes from the type 2 diabetes treatment paralleling of CLD were presented. Treatment of type 2 diabetes with pioglitazone hydrochloride, gliclazide, sitagliptin, liraglutide and exenatide was proven effective.

Topics: Diabetes Mellitus, Type 2; Exenatide; Gliclazide; Humans; Hypoglycemic Agents; Liraglutide; Metformin; Non-alcoholic Fatty Liver Disease; Pioglitazone; Sitagliptin Phosphate

Non-alcoholic fat liver disease (NAFLD) is the most common chronic liver disease in the world. NAFLD is a spectrum of diseases ranging from simple steatosis to hepatic carcinoma. The complexity of pathomechanisms makes treatment difficult. The oral antidiabetic agents, dipeptidyl peptidase four inhibitors (DPP-4i) have been proposed as possible therapeutic agents. This study was performed using a well-established NAFLD model in rats to elucidate whether sitagliptin could prevent steatohepatitis. Rats were fed a methionine/choline-deficient (MCD) diet with or without sitagliptin treatment for six weeks. Liver tissue was examined to estimate sitagliptin's effect on the development of NASH. The MCD diet decreased the SAM/SAH ratio, and increased plasma levels of homocysteine, free fatty acids, and long-chain acylcarnitines in the MCD rats. MMP2 and Col1A2 expression also increased under the MCD diet. Sitagliptin treatment did not reverse these effects and increased steatosis and long-chain acylcarnitines. In conclusion, sitagliptin was ineffective to prevent from NAFLD in the MCD rat model. This result challenges previous data reporting beneficial effects and is consistent with the clinical trials' negative results.

Topics: Animals; Choline Deficiency; Diet; Liver; Male; Methionine; Non-alcoholic Fatty Liver Disease; Rats; Rats, Wistar; Sitagliptin Phosphate

Several studies have shown that expression of hepatic fibroblast growth factor 21 (FGF21) can be stimulated by glucagon-like peptide 1 (GLP-1)-based diabetes drugs. As GLP-1 receptor (GLP-1R) is unlikely to be expressed in hepatocytes, we aimed to compare such stimulation in mice and in mouse hepatocytes, determine the involvement of GLP-1R, and clarify whether FGF21 mediates certain functions of the GLP-1R agonist liraglutide.. Liver FGF21 expression was assessed in mice receiving a daily liraglutide injection for 3 days or in mouse primary hepatocytes (MPHs) undergoing direct liraglutide treatment. The effects of liraglutide on metabolic improvement and FGF21 expression were then assessed in high-fat diet (HFD)-fed mice and compared with the effects of the dipeptidyl-peptidase 4 inhibitor sitagliptin. Animal studies were also performed in Glp1r. We suggest that liraglutide-stimulated hepatic Fgf21 expression may require GLP-1R to be expressed in extrahepatic organs. Importantly, we revealed that hepatic FGF21 is required for liraglutide to lower body weight and improve hepatic lipid homeostasis. These observations advanced our mechanistic understanding of the function of GLP-1-based drugs in NAFLD.

Topics: Animals; Cells, Cultured; Diet, High-Fat; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Fibroblast Growth Factors; Glucagon-Like Peptide-1 Receptor; Hepatocytes; Hypoglycemic Agents; Lipid Metabolism; Liraglutide; Mice; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Sitagliptin Phosphate

Topics: Body Weight; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin Glargine; Lipids; Liraglutide; Metformin; Non-alcoholic Fatty Liver Disease; Sitagliptin Phosphate

Topics: Body Weight; Diabetes Mellitus, Type 2; Humans; Insulin Glargine; Lipids; Liraglutide; Metformin; Non-alcoholic Fatty Liver Disease; Sitagliptin Phosphate

Menopause increases the risk of non-alcoholic fatty liver disease (NAFLD). We investigated the effect of incretin and/ or exercise on the hepatic fat accumulation in ovariectomized rats. Rats were divided into five groups: Group 1: Control rats, Group 2: Ovariectomized rats, Group 3: Ovariectomized rats + Dipeptidyl peptidase-4 inhibitor (DPPi) (30 mg/kg/day, orally), Group 4: Ovariectomized rats + swimming, and Group 5: Ovariectomized rats + swimming + DPPi. After 6 weeks, Alanine aminotransferase (ALT), glucose, insulin, HOMA IR (Homeostatic Model Assessment for Insulin Resistance), FFA (free fatty acids), Tumor necrosis factor alpha (TNF α), IL6, IL1B levels were measured in blood. The livers were collected for Hematoxylin and eosin (H&E) examination and evaluation of hepatic gene expression of SREBP (sterol regulatory element-binding protein1c), PPAR α (peroxisome proliferator-activated receptor alpha), ACC 1 (acetyl-CoA carboxylase), LC3 (microtubule-associated protein 1 light chain 3), SIRT (sirtuin), hepatic triglycerides, IL6, IL10, caspase 3 and AMPK (adenosine monophosphate-activated protein kinase). A significant increase in ALT level and area of liver tissue defects with a significant increase in glucose HOMA IR, serum FFA, IL6, IL1B, TNF α, liver TGs (triglycerides), inflammation, apoptosis, SREBP1c, ACC1 were found in ovariectomized rats as compared to control group with a significant decrease in PPAR α, LC3, AMPK and SIRT1. DPPi treated rats with and without exercise showed a significant improvement in ALT and area of liver tissue defects, inflammation and apoptosis and serum IL6, IL1B, TNF α, FFA, liver LC3, SIRT1, AMPK, TGs, PPAR α, ACC1 and SREBP1c as compared to the ovariectomized group. Findings from the study confirm the derangement of fat metabolism in the ovariectomized rats and showed that incretin-based therapy and exercise synergistically improved liver fat metabolism, achieved significant beneficial metabolic effects and offer full protection against NAFLD.

Topics: Acetyl-CoA Carboxylase; AMP-Activated Protein Kinase Kinases; Animals; Apoptosis; Dipeptidyl-Peptidase IV Inhibitors; Fatty Acids; Female; Interleukin-1beta; Interleukin-6; Liver; Microtubule-Associated Proteins; Non-alcoholic Fatty Liver Disease; Ovariectomy; Physical Conditioning, Animal; PPAR alpha; Protein Kinases; Rats; Sirtuin 1; Sitagliptin Phosphate; Sterol Regulatory Element Binding Protein 1; Triglycerides; Tumor Necrosis Factor-alpha

CD26, a multifunctional transmembrane glycoprotein, is expressed in various cancers and functions as dipeptidyl peptidase 4 (DPP4). We investigated whether CD26 expression is associated with hepatocellular carcinoma (HCC) progression and whether DPP4 inhibitors exert antitumor effects against HCC.. CD26 expression was examined in 41 surgically resected HCC specimens. The effects of DPP4 inhibitors on HCC were examined by using HCC cell lines (Huh-7 and Li-7), xenograft tumors in nude mice, and a nonalcoholic steatohepatitis-related HCC mouse model.. CD26 expression in HCC specimens was associated with increased serum DPP4 activity, as well as a more advanced stage, less tumor immunity, and poorer prognosis in HCC patients. The HCC cell lines and xenograft tumors exhibited CD26 expression and DPP4 activity. The DPP4 inhibitors did not exhibit antitumor effects in vitro, but natural killer (NK) and/or T-cell tumor accumulation suppressed growth of xenograft tumor and HCC in vivo. The antitumor effects of DPP4 inhibitors were abolished by the depletion of NK cells or the neutralization of CXCR3, a chemokine receptor on NK cells. EZ-TAXIScan, an optical horizontal chemotaxis apparatus, identified enhanced NK and T-cell chemotaxis by DPP4 inhibitors ex vivo in the presence of Huh-7 cells and the chemokine CXCL10, which binds to CXCR3. The DPP4 inhibitors prevented the biologically active form of CXCL10 from being truncated by Huh-7 cell DPP4 activity. DPP4 inhibitors also suppressed tumor angiogenesis.. These results provide a rationale for verifying whether DPP4 inhibitors clinically inhibit the progression of HCC or augment the antitumor effects of molecular-targeting drugs or immunotherapies against HCC.

Topics: Aged; Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Cycle; Cell Line, Tumor; Chemokine CXCL10; Chemotaxis; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Killer Cells, Natural; Liver Neoplasms; Lymphocytes, Tumor-Infiltrating; Male; Mice; Mice, Nude; Middle Aged; Models, Biological; Neovascularization, Pathologic; Non-alcoholic Fatty Liver Disease; Pyrimidines; Sitagliptin Phosphate; T-Lymphocytes; Vildagliptin; Xenograft Model Antitumor Assays

We sincerely thank Dr. Sikarin Upala for his interest in our article and for sharing his experience in the treatment of nonalcoholic fatty liver disease (NAFLD). NAFLD is prevalent in patients with type 2 diabetes mellitus (T2DM), yet only preliminary evidence are available on the effect of anti-diabetic agents to NAFLD in T2DM patients. According to clinical practice guidelines for NAFLD management

Topics: Body Weight; Diabetes Mellitus, Type 2; Humans; Insulin Glargine; Lipids; Liraglutide; Metformin; Non-alcoholic Fatty Liver Disease; Sitagliptin Phosphate

We read with interest a recent article written by Yan et al.

Topics: Body Weight; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin Glargine; Lipids; Liraglutide; Metformin; Non-alcoholic Fatty Liver Disease; Sitagliptin Phosphate

Topics: Body Weight; Diabetes Mellitus, Type 2; Humans; Incretins; Insulin Glargine; Lipids; Liraglutide; Metformin; Non-alcoholic Fatty Liver Disease; Sitagliptin Phosphate

Topics: Blood Glucose; Humans; Non-alcoholic Fatty Liver Disease; Sitagliptin Phosphate; Synbiotics

BACKGROUND In clinics, patients with type 2 diabetes complicated with non-alcoholic fatty liver disease (NAFLD) have been shown to receive significant improvements in blood glucose levels, lipid levels, and liver function after sitagliptin treatment, although the mechanism of drug action remains poorly understood. This study investigated the possible mechanism of sitagliptin on lipid metabolism of NAFLD mice. MATERIAL AND METHODS Male C57/BL6 mice were induced for NAFLD via 16 weeks of a high-fat diet, and were treated with 15 mg/kg/day sitagliptin for 16 consecutive weeks. Blood lipid levels were measured and samples were stained with hematoxylin and eosin (H&E) and oil red staining for liver pathology and lipid deposition. Serum levels of fibroblast growth factor (FGF)-9 and FGF-21 were quantified by enzyme-linked immunosorbent assay (ELISA). Peroxisome proliferator-activated receptor (PPAR)-α, and cAMP reactive element binding homolog (CREBH) were measured by Western blotting, while fatty acid synthase and carnitine palmitoyltransferase 1 (CPT1) mRNA levels were assayed by RT-PCR. RESULTS Compared to the control group, the NAFLD model mice had liver fatty disease, lower serum FGF-21 and FGF-19 levels, elevated serum lipid levels, depressed PPAR-α, CREBH, and CPT1 expression, and enhanced FAS expression (p<0.05). Sitagliptin treatment depressed blood lipid levels, increased serum FGF-21 and FGF-19 levels, PPAR-α, CREBH, and CPT1 expression, and suppressed FAS expression (p<0.05). CONCLUSIONS Sitagliptin can protect liver tissue and modulate lipid metabolism in NAFLD mice via elevating FGF-21 and FGF-19, upregulating liver PPAR-a and CREBH levels, and mediating expression levels of key enzymes for lipid metabolism.

Topics: Animals; Carnitine O-Palmitoyltransferase; Cyclic AMP Response Element-Binding Protein; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Fatty Liver; Fibroblast Growth Factors; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; PPAR alpha; Sitagliptin Phosphate

Depression and non-alcoholic steatohepatitis (NASH) are highly co-morbid, and hepatic JNK pathway may be involved in their relation.. To evaluate the impact of depression on NASH through the involvement of JNK1 and to assess the effect of sitagliptin and metformin on hepatic JNK1 expression in both NASH and NASH associated with depression.. Eight groups of male Wistar rats were used: naïve rats, non-stressed NASH, non-stressed NASH sitagliptin treated, non-stressed NASH metformin treated, stressed, stressed NASH untreated, stressed NASH sitagliptin treated and stressed NASH metformin treated. Behavioral, biochemical, molecular and histopathological studies were performed.. Non-stressed NASH group showed depressive like symptoms, disturbed glucose homeostasis, impairment of liver functions, decrease adiponectin and increase malondialdehyde, which were aggreviated by stress. Sitagliptin produced significant improvement compared to metformin regarding biochemical and histopathological parameters. Furthermore, sitagliptin significantly decreased expression of hepatic JNK1 in both stressed and non-stressed rats. All these changes were accompanied by significant improvement of behavioral changes.. The link between NASH and depression raised the role of JNK activation through increase expression of JNK1. Since sitagliptin was associated with preferable effects than metformin, therefore, it is potentially preferred in the management of either NASH or NASH associated with depression.

Topics: Animals; Behavior, Animal; Biomarkers; Chronic Disease; Depression; Diet, High-Fat; Disease Models, Animal; Down-Regulation; Gene Expression Regulation, Enzymologic; Insulin Resistance; Liver; Male; Metformin; Mitogen-Activated Protein Kinase 8; Non-alcoholic Fatty Liver Disease; Rats, Wistar; Signal Transduction; Sitagliptin Phosphate; Stress, Psychological; Time Factors

Topics: Diabetes Mellitus, Type 2; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Liraglutide; Non-alcoholic Fatty Liver Disease; Sitagliptin Phosphate

The present study aimed to evaluate the effect of trigonelline (TRG) on the hepatic complications associated with high-fat high-fructose (HFHF) diet-induced insulin resistance (IR) in rats. IR was induced by giving a saturated fat diet and 10% fructose in drinking water to rats for 8 weeks. Insulin-resistant rats were orally treated with TRG (50 and 100 mg/kg), sitagliptin (SIT; 5 mg/kg), or a combination of TRG (50 mg/kg) and SIT (5 mg/kg) for 14 days. Liver homogenates were used for assessment of hepatic lipids, oxidative stress biomarkers, and inflammatory cytokines. Histopathological and DNA cytometry examinations were carried out for hepatic and pancreatic tissues. Hepatic tissues were examined using Fourier-transform infrared spectroscopy for assessment of any molecular changes. Results of the present study revealed that oral treatment of insulin-resistant rats with TRG or TRG in combination with SIT significantly decreased homeostatic model assessment of IR, hepatic lipids, oxidative stress biomarkers, and the inflammatory cytokines. TRG or TRG in combination with SIT ameliorated the histopathological, DNA cytometry, and molecular alterations induced by a HFHF diet. Finally, it can be concluded that TRG has beneficial effects on the hepatic complications associated with IR due to its hypoglycemic effect and antioxidant potential.

Topics: Alkaloids; Animals; Antioxidants; Biomarkers; Blood Glucose; Cytokines; Diet, Carbohydrate Loading; Diet, High-Fat; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Lipids; Liver; Male; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Rats; Rats, Wistar; Sitagliptin Phosphate

To compare the effect of different hypoglycemic drugs on laboratory and ultrasonographic markers of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes not controlled on metformin alone.. Prospective study of diabetic patients treated with metformin in combination with gliclazide, pioglitazone, sitagliptin, exenatide, or liraglutide. NAFLD was assessed by abdominal ultrasound and NAFLD fibrosis score was calculated at baseline and 6 months.. Fifty-eight patients completed 6 months of follow-up: 15 received gliclazide, 13 pioglitazone, 15 sitagliptin, 7 exenatide, and 8 liraglutide. NAFLD affected 57.8% of patients at baseline, and its ultrasonographic course varied depending on changes in weight (P=.009) and waist circumference (P=.012). The proportions of patients who experienced ultrasonographic improvement in the different treatment groups were: 33.3% with gliclazide, 37.5% with pioglitazone, 45.5% with sitagliptin, 80% with exenatide, and 33% with liraglutide (P=.28).. Qualitative ultrasonographic NAFLD improvement in diabetic patients treated with metformin in combination with other hypoglycemic drugs is associated to change over time in weight and waist circumference. Long-term clinical trials are needed to assess whether incretin therapies result in better liver outcomes than other hypoglycemic therapies.

Topics: Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Female; Gliclazide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Lipids; Liraglutide; Liver Function Tests; Male; Metabolic Syndrome; Metformin; Middle Aged; Non-alcoholic Fatty Liver Disease; Peptides; Pilot Projects; Pioglitazone; Prospective Studies; Sitagliptin Phosphate; Thiazolidinediones; Venoms; Waist Circumference

Previous studies indicated that miR-200s participated in IL-6-induced hepatic insulin resistance. However, the role of miR-200s in hepatic lipid accumulation has not been elucidated. Here we found that miR-200b and miR-200c were reduced in the steatotic livers of mice fed a high-fat diet (HFD) and patients with nonalcoholic fatty liver disease. This down-regulation was accompanied by an increase in the expression of lipogenic proteins such as sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FAS). The suppression of miR-200b and miR-200c in Hep1-6 and NCTC1469 hepatocytes enhanced intracellular triglyceride levels, which were associated with increased SREBP-1 and FAS protein levels. In contrast, the over-expression of miR-200b and miR-200c suppressed lipid accumulation and reduced the expression of SREBP1 and FAS in Hep1-6 and NCTC1469 cells transfected with miR-200b or miR-200c mimics. Importantly, the up-regulation of miR-200b and miR-200c could reverse oleic acid/palmitic acid-induced lipid accumulation in hepatocytes. A luciferase reporter assay identified that miR-200b and miR-200c could directly bind the 3'UTR of jun. JUN activated the transcription of srebp1 to increase lipid accumulation. The data also demonstrated that increased miR-200b and miR-200c expression might be associated with sitagliptin-reduced hepatic lipid accumulation in mice fed a HFD. These findings suggest, for the first time, that reduced miR-200b and miR-200c expression contributes to abnormal hepatic lipid accumulation by stimulating JUN expression and activating the transcription of srebp1.

Topics: 3' Untranslated Regions; Adult; Animals; Cell Line; Cell Line, Tumor; Diet, High-Fat; Female; Gene Expression Regulation; Humans; Hypoglycemic Agents; Lipids; Liver; Male; Mice, Inbred C57BL; MicroRNAs; Middle Aged; Non-alcoholic Fatty Liver Disease; Proto-Oncogene Proteins c-jun; Sitagliptin Phosphate; Sterol Regulatory Element Binding Protein 1

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

Studies investigating the effects of dipeptidyl peptidase-4 inhibitors on hepatic steatosis are lacking. We aimed to determine the effects of sitagliptin on nonalcoholic fatty liver disease (NAFLD) in rats with diet-induced obesity.. A total of 24 adult female Sprague-Dawley rats, which were 24 weeks old and weighed 199-240 grams, were used. The rats were randomly separated into two groups. The control group (n=6) was fed with standard rat diet; the remaining rats (n=18) were fed with a high-fat diet (HFD) to induce NAFLD. After 12 weeks, rats that were fed with a HFD were randomly separated into two groups: (1) HFD-only group (n=8) was fed with a HFD for an additional 4 weeks, (2) HFD-sitagliptin group (n=10) received sitagliptin (3 mg/kg) for 4 weeks in addition to HFD. At the end of the study (16(th) week), blood samples were drawn from all rats to determine serum glucose, triglyceride, cholesterol, alanine aminotransferase (ALT), and plasma insulin levels. Insulin resistance was determined using the homeostasis model assessment of insulin resistance (HOMA-IR) index. Histopathologic evaluation of liver samples was undertaken.. The HFD-sitagliptin group had significantly lower serum glucose (140.8±18.8 vs. 224.7±20.6 mg/dL, P<0.001), plasma insulin (15.8±4.4 vs. 28.0±5.9 μIU/L, P<0.001), HOMA-IR index (4.9±1.8 vs. 15.9±2.3, P<0.001), serum triglycerides (199.0±108.7 vs. 468.0±370.7 mg/dL, P<0.001), and cholesterol (82.0±26.7 vs. 90.5±7.0, P<0.001) values compared to the HFD-only group. Hepatic steatosis was significantly less (mean score, 1 vs. 2; P<0.001) in the HFD-sitagliptin group compared to the HFD-only group, whereas there was no difference in hepatic inflammation (P=0.057), liver weight (P=0.068), and ALT levels (P=0.232).. Sitagliptin may improve hepatic steatosis by increasing insulin sensitivity and improving lipid profiles in rats.

Topics: Alanine Transaminase; Animals; Blood Glucose; Cholesterol; Diet, High-Fat; Dipeptidyl-Peptidase IV Inhibitors; Fatty Liver; Female; Insulin; Insulin Resistance; Liver; Non-alcoholic Fatty Liver Disease; Obesity; Pyrazines; Rats; Rats, Sprague-Dawley; Sitagliptin Phosphate; Triazoles; Triglycerides

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