Adverse cardiac events of hypercholesterolemia are enhanced by sitagliptin in sprague dawley rats.

BACKGROUND: Cardiovascular disease (CVD) affects millions worldwide and is the leading cause of death among non-communicable diseases. Western diets typically comprise of meat and dairy products, both of which are rich in cholesterol (Cho) and methionine (Met), two well-known compounds with atherogenic capabilities. Despite their individual effects, literature on a dietary combination of the two in the context of CVD are limited. Therefore, studies on the combined effects of Cho and Met were carried out using male Sprague Dawley rats. An additional interest was to investigate the cardioprotective potential of sitagliptin, an anti-type 2 diabetic drug. We hypothesized that feeding a dietary combination of Cho and Met would result in adverse cardiac effects and would be attenuated upon administration of sitagliptin. METHODS: Adult male Sprague-Dawley rats were fed either a control (Con), high Met (1.5%), high Cho (2.0%), or high Met (1.5%) + high Cho (2.0%) diet for 35 days. They were orally gavaged with an aqueous preparation of sitagliptin (100 mg/kg/d) or vehicle (water) from day 10 through 35. On day 36, rats were euthanized, and tissues were collected for analysis. RESULTS: Histopathological evaluation revealed a reduction in myocardial striations and increased collagen deposition in hypercholesterolemia (HChol), responses that became exacerbated upon sitagliptin administration. Cardiac pro-inflammatory and pro-fibrotic responses were adversely impacted in similar fashion. The addition of Met to Cho (MC) attenuated all adverse structural and biochemical responses, with or without sitagliptin. CONCLUSIONS: Adverse cardiac outcomes in HChol were enhanced by the administration of sitagliptin, and such effects were alleviated by Met. Our findings could be significant for understanding or revisiting the risk-benefit evaluation of sitagliptin in type 2 diabetics, and especially those who are known to consume atherogenic diets.

Adverse Cardiac Events of Hypercholesterolemia Are Enhanced by Sitagliptin Administration in Sprague Dawley Rats.

Background: Cardiovascular disease (CVD) affects millions worldwide and is the leading cause of death among non-communicable diseases. Western diets typically comprise of meat and dairy products, both of which are rich in cholesterol (Cho) and methionine (Met), two well-known compounds with atherogenic capabilities. Despite their individual effects, literature on a dietary combination of the two in the context of CVD are limited. An additional interest was to investigate the cardioprotective potential of sitagliptin, an anti-type 2 diabetic drug. Thus, we hypothesized that atherogenic feeding would result in adverse cardiac effects and would attenuate upon sitagliptin administration. Methods: Six-week-old adult male Sprague-Dawley rats were fed either a control (Con), high Met (1.5%), high Cho (2.0%), or high Met (1.5%) + high Cho (2.0%) diet for 35 days. They were orally gavaged with vehicle (water) or sitagliptin (100 mg/kg/d) from day 10 through 35. On day 36, rats were euthanized, and tissues were collected for analysis. Results: Histopathological evaluation revealed a reduction in myocardial striations and increased collagen deposition in hypercholesterolemia (HChol), responses that became exacerbated upon sitagliptin administration. Cardiac pro-inflammatory and pro-fibrotic responses were adversely impacted in similar fashion. The addition of Met to Cho (MC) attenuated all adverse structural and biochemical responses, with or without sitagliptin. Conclusion: Adverse cardiac outcomes in HChol were enhanced with sitagliptin administration and such effects were alleviated by Met. Our findings could be significant for understanding the risk-benefit of sitagliptin in type 2 diabetics who are known to consume atherogenic diets.

Prolonged effects of DPP-4 inhibitors on steato-hepatitic changes in Sprague-Dawley rats fed a high-cholesterol diet.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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-1ß) 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. CONCLUSIONS: 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.

High levels of dietary methionine improves sitagliptin-induced hepatotoxicity by attenuating oxidative stress in hypercholesterolemic rats.

BACKGROUND: Both cholesterol (Cho) and methionine (Met, a precursor for homocysteine) are risk factors for fatty liver disease. Since Western diets are rich in Cho and Met, we investigated the hepatic effects of feeding a diet enriched in Met and Cho. Further, based on the reported anti-oxidative and lipid lowering properties of sitagliptin (an antidiabetic drug), we tested whether it could counteract the negative effects of high Cho and Met. We therefore hypothesized that sitagliptin would ameliorate the development of liver pathology that is produced by feeding diets rich in either Cho, Met, or both. METHODS: Male Sprague Dawley rats were fed ad libitum a) control diet, or b) high Met or c) high Cho, or d) high Met + high Cho diets for 35 days. From day 10 to 35, 50% of rats in each dietary group were gavaged with either vehicle or an aqueous suspension of sitagliptin (100 mg/kg/day). Liver samples were harvested for histological, molecular, and biochemical analyses. RESULTS: The high Cho diet produced significant hepatic steatosis which was unaffected by sitagliptin. Contrary to expectation, sitagliptin exacerbated expression of hepatic markers of oxidative stress and fibrosis in rats fed high Cho. Corresponding increases in 4-hydroxynonenal adducts and collagen deposition were demonstrated by immunohistochemistry and sirius red staining. These hepatic changes were absent in rats on the high Met diet and they were comparable to controls. The inclusion of Met in the high Cho diet resulted in significant reduction of the hepatic steatosis, oxidative stress, and fibrosis produced by high Cho alone. CONCLUSION: Sitagliptin exacerbated the effects of high Cho on both oxidative stress and fibrosis, resulting in NASH like symptoms that were significantly reversed by the inclusion of Met.

The incretin enhancer, sitagliptin, exacerbates expression of hepatic inflammatory markers in rats fed a high-cholesterol diet.

OBJECTIVE: Hypercholesterolemia is associated with the development of a pro-inflammatory state and is a documented risk factor for progression to insulin resistance, nonalcoholic fatty liver and cardiovascular diseases. Sitagliptin is an incretin enhancer that improves glucose tolerance by inhibiting dipeptidyl peptidase-4, but it also has reported anti-inflammatory effects. The current study was thus undertaken to examine the interactions of dietary Cholesterol (Cho) and sitagliptin on markers of inflammation. METHODS: Male Sprague-Dawley rats were provided diets high in Cho and gavaged with vehicle or an aqueous suspension of sitagliptin (100 mg/kg/day) from day 10 through day 35. Molecular methods were used to analyze the lipid profile and inflammatory markers in liver and serum samples. H&E-stained liver sections were used for histopathological evaluation. Hepatic influx of mononuclear cells and necrosis were assessed by immunohistochemistry. RESULTS: Sitagliptin reduced triglyceride and Cho levels in serum of rats on the control diet but these effects were abrogated in rats on the high-Cho diet. Sitagliptin produced a significant increase in the expression of hepatic inflammatory markers (Tnfa, Il1b, and Mcp1) and a corresponding increase in serum TNFα and IL-1ß in rats on the high-Cho diet, but it had no effect on rats on the control diet. Additionally, sitagliptin had no effect on liver morphology in rats on the control diet, but it produced hepatic histopathological changes indicative of necrosis and mononuclear cell infiltration in rats on the high-Cho diet. These mononuclear cells were identified as macrophages and T cells. CONCLUSION: When provided in the context of a high-Cho diet, these findings reveal previously unrecognized hepato-inflammatory effects of sitagliptin that are accompanied by evidence of hepatic necrosis and mononuclear cell infiltration.

The metabolism and significance of homocysteine in nutrition and health.

An association between arteriosclerosis and homocysteine (Hcy) was first demonstrated in 1969. Hcy is a sulfur containing amino acid derived from the essential amino acid methionine (Met). Hyperhomocysteinemia (HHcy) was subsequently shown in several age-related pathologies such as osteoporosis, Alzheimer's disease, Parkinson's disease, stroke, and cardiovascular disease (CVD). Also, Hcy is associated with (but not limited to) cancer, aortic aneurysm, hypothyroidism and end renal stage disease to mention some. The circulating levels of Hcy can be increased by defects in enzymes of the metabolism of Met, deficiencies of vitamins B6, B12 and folate or by feeding Met enriched diets. Additionally, some of the pharmaceuticals currently in clinical practice such as lipid lowering, and anti-Parkinsonian drugs are known to elevate Hcy levels. Studies on supplementation with folate, vitamins B6 and B12 have shown reduction in Hcy levels but concomitant reduction in certain associated pathologies have not been definitive. The enormous importance of Hcy in health and disease is illustrated by its prevalence in the medical literature (e.g. > 22,000 publications). Although there are compelling data in favor of Hcy as a modifiable risk factor, the debate regarding the significance of Hcy mediated health effects is still ongoing. Despite associations between increased levels of Hcy with several pathologies being well documented, whether it is a causative factor, or an effect remains inconclusive. The present review though not exhaustive, is focused on several important aspects of Hcy metabolism and their relevance to health.