gamma-sitosterol and Diabetes-Mellitus--Type-2

Anagliptin, a dipeptidyl peptidase-4 inhibitor, is reported to reduce the level of low-density lipoprotein cholesterol (LDL-C). The underlying mechanism of this effect and effect on lipid metabolism however remains uncertain.. We therefore evaluate the effects of anagliptin on lipid metabolism-related markers compared with those of sitagliptin. The study was a secondary analysis using data obtained from the Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. This trial in patients with type 2 diabetes at a high risk of cardiovascular events and on statin therapy showed that anagliptin reduced LDL-C levels to a greater extent than sitagliptin. Cholesterol absorption (campesterol and sitosterol) and synthesis (lathosterol) markers were measured at baseline and 52 weeks in the study cohort (n = 353).. There was no significant difference in the changes of campesterol or sitosterol between the two treatment groups (p = 0.85 and 0.55, respectively). Lathosterol concentration was increased significantly at 52 weeks with sitagliptin treatment (baseline, 1.2 ± 0.7 μg/mL vs. 52 weeks, 1.4 ± 1.0 μg/mL, p = 0.02), whereas it did not change in the anagliptin group (baseline, 1.3 ± 0.8 μg/mL vs. 52 weeks, 1.3 ± 0.7 μg/mL, p = 0.99). The difference in absolute change between the two groups showed a borderline significance (p = 0.06).. These findings suggest that anagliptin reduces LDL-C level by suppressing excess cholesterol synthesis, even in combination with statin therapy. Trial registration ClinicalTrials.gov number NCT02330406. https://clinicaltrials.gov/ct2/show/NCT02330406; registered January 5, 2015.

Topics: Aged; Biomarkers; Cholesterol; Cholesterol, LDL; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dyslipidemias; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Japan; Male; Middle Aged; Phytosterols; Pyrimidines; Sitagliptin Phosphate; Sitosterols; Time Factors; Treatment Outcome

The mechanism responsible for the lipid-lowering effect of dipeptidyl peptidase-4 (DPP-4) inhibitors remains unknown in humans. We evaluated the effect of anagliptin on serum lipid profiles, including cholesterol synthesis and absorption markers, in Japanese patients with type 2 diabetes.. Thirty patients with type 2 diabetes (20 - 70 years old, low-density lipoprotein cholesterol (LDL-C) level over 120 mg/dl, and no history of treatment with antidiabetic or antihyperlipidemic drugs) were enrolled. One hundred milligrams of anagliptin were administered twice a day for a month.. After treatment of anagliptin, the LDL-C and total cholesterol (TC) levels did not decrease overall, but the TC level decreased significantly in 28 patients whose HbA1c levels decreased. Lathosterol decreased significantly, whereas no changes in campesterol, sitosterol or cholestanol were observed.. These results of our study show no significant change in LDL-C, a tendency of decrease in TC and non-high-density lipoprotein cholesterol (non-HDL-C) after treatment of anagliptin for 1 month. Anagliptin therapy decreased the cholesterol synthesis marker lathosterol without changing cholesterol absorption markers.

Topics: Adult; Aged; Biomarkers; Cholestanol; Cholesterol; Cholesterol, LDL; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Lipids; Lipoproteins, HDL; Male; Middle Aged; Phytosterols; Pilot Projects; Pyrimidines; Sitosterols; Young Adult

To date, there are very few clinical reports that have compared the effects of ezetimibe on lipid parameters between hypercholesterolemic patients with and without type 2 diabetes mellitus (T2DM). In this study, we recruited patients for hypercholesterolemic groups with T2DM (n = 42; men/women = 24/18; HbA1c = 6.7 ± 5.4%) and without T2DM (n = 21; men/women = 7/14; HbA1c = 5.3 ± 0.4%). Patients were prescribed ezetimibe at a dose of 10 mg/daily for the course of the 12-week study. At baseline and after 12 weeks of treatment, several lipid parameters, including serum low-density-lipoprotein cholesterol (LDL-C), non-high-density-lipoprotein cholesterol (non-HDL-C), high-sensitivity C-reactive protein (hs-CRP), and cholesterol synthesis/absorption-related markers, were measured. Compared with those at the baseline, the levels of LDL-C, non-HDL-C, campesterol, and sitosterol were significantly reduced after 12 weeks of ezetimibe treatment in both groups. After adjusting for confounding factors, such as age, gender, smoking, and BMI, the levels of LDL-C and non-HDL-C displayed significantly greater reductions in the patients with T2DM (-25.1 ± 13.6% in LDL-C, -20.5 ± 11.2% in non-HDL-C) than those without T2DM (-20.5 ± 7.8% in LDL-C, P < 0.05; -17.4 ± 7.6% in non-HDL-C, P < 0.05). The reduction of the level of cholestanol was significantly and positively correlated with those of LDL-C and non-HDL-C in the patients with T2DM. Taken together, these findings indicate that ezetimibe could reduce the levels of atherogenic lipoproteins to a greater extent in hypercholesterolemic patients with T2DM than in those without T2DM.

Topics: Aged; Azetidines; Biomarkers; Body Mass Index; C-Reactive Protein; Cardiovascular Diseases; Cholestanol; Cholesterol; Cholesterol, LDL; Diabetes Mellitus, Type 2; Ezetimibe; Female; Humans; Hypercholesterolemia; Hypolipidemic Agents; Lipids; Male; Middle Aged; Phytosterols; Sitosterols

Previous studies in our laboratory in ex vivo assays have demonstrated H. hemerocallidea extract as potential antidiabetic agent through increased insulin release from pancreatic beta cells. Thus, for this study the early stage type II spontaneous diabetic mutant mice model was used to evaluate and determine the degree of the antidiabetic efficacy of H. hemerocallidea.. Eight-weeks-old type II spontaneous pre-diabetic mutant BKS-Leprdb mice were fed with feed supplemented with either H. hemerocallidea extract, isolated compound (β-sitosterol) or chlorpropamide (positive control) for 4 weeks. The haematological parameters, clinical chemistry, glucose tolerance, feed intake, faecal output and body weights were measured.. The blood glucose concentrations of all the animals treated with plant extract, β-sitosterol compound and non-treated pre-diabetic animals did not return to baseline levels. Only the β-sitosterol treatment and positive control groups resulted in a respective small decrease of 5.8 and 5.2% in the mouse weights over the study period, with no significant changes (p > 0.05) in food intake. However, there was a general trend for decrease in faecal output for all the groups. Albumin, triglycerides, and total cholesterol levels in β-sitosterol and chlorpropamide-treated animals were lower, relative to untreated-animals. Animals fed with plant extract showed large amounts of internal fat. There were no significant changes (p > 0.05) in total serum protein, globulin, alanine aminotransferase, alkaline phosphatase, urea nitrogen and creatinine attributed to administration of treatments. In all groups, some animals showed lesions associated with cardiac puncture. Few animals except animals treated with plant extract, showed presence of a left-ventricular hypertrophic cardiomyopathy. The liver and kidneys for all groups appeared macroscopically normal and the thymuses were small (±2 mg). There were pathological signs in some of the animals particularly in myocardial fibres, renal tubular, glomerular, hepatocyte granularity and pancreas islets. However, there was no significance trend between the groups.. Based on the results, none of the treatments could be considered highly effective for the management of type II pre-diabetes as sole therapeutic intervention.

Topics: Animals; Chlorpropamide; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Hypoxis; Mice; Plant Extracts; Prediabetic State; Sitosterols

β-sitosterol (SIT), the most abundant bioactive component of vegetable oil and other plants, is a highly potent antidiabetic drug. Our previous studies show that SIT controls hyperglycemia and insulin resistance by activating insulin receptor and glucose transporter 4 (GLUT-4) in the adipocytes of obesity induced type 2 diabetic rats. The current research was undertaken to investigate if SIT could also exert its antidiabetic effects by circumventing adipocyte induced inflammation, a key driving factor for insulin resistance in obese individuals. Effective dose of SIT (20 mg/kg b.wt) was administered orally for 30 days to high fat diet and sucrose induced type-2 diabetic rats. Metformin, the conventionally used antidiabetic drug was used as a positive control. Interestingly, SIT treatment restores the elevated serum levels of proinflammatory cytokines including leptin, resistin, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) to normalcy and increases anti-inflammatory adipocytokines including adiponectin in type 2 diabetic rats. Furthermore, SIT decreases sterol regulatory element binding protein-1c (SREBP-1c) and enhances Peroxisome Proliferator-activated receptor-γ (PPAR-γ) gene expression in adipocytes of diabetic rats. The gene and protein expression of c-Jun-N-terminal kinase-1 (JNK1), inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ) and nuclear factor kappa B (NF-κB) were also significantly attenuated in SIT treated groups. More importantly, SIT acts very effectively as metformin to circumvent inflammation and insulin resistance in diabetic rats. Our results clearly show that SIT inhibits obesity induced insulin resistance by ameliorating the inflammatory events in the adipose tissue through the downregulation of IKKβ/NF-κB and c-Jun-N-terminal kinase (JNK) signaling pathway.

Topics: Adipocytes; Adipokines; Adipose Tissue; Animals; Body Weight; Cytokines; Diabetes Mellitus, Type 2; Diet, High-Fat; Down-Regulation; Feeding Behavior; I-kappa B Kinase; Inflammation; Inflammation Mediators; Insulin Resistance; Male; MAP Kinase Signaling System; Molecular Docking Simulation; NF-kappa B; Obesity; PPAR gamma; Rats; RNA, Messenger; Sitosterols; Sterol Regulatory Element Binding Protein 1; Sucrose; Up-Regulation

In our previous study, we have shown that β-sitosterol (SIT) enhances glycemic control by increasing the activation of insulin receptor (IR) and glucose transporter 4 (GLUT4) proteins in adipose tissue. However, the possible role of SIT on the regulation of post-receptor insulin signal transduction is not known. Hence, the study was aimed to assess the effects of SIT on IRS-1/Akt mediated insulin signaling molecules in high-fat diet and sucrose induced type-2 diabetic rats. An oral effective dose of SIT (20 mg/kg b.wt) was given for 30 days to high fat-fed type-2 diabetic rats to find out whether SIT regulates IRS-1/Akt pathway of insulin signaling. The results showed that SIT attenuated the insulin receptor substrate-1 serine phosphorylation (p-IRS-1

Topics: Adipose Tissue; Animals; beta-Arrestin 2; Computer Simulation; Diabetes Mellitus, Type 2; Diet, High-Fat; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Male; Models, Molecular; Molecular Dynamics Simulation; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Signal Transduction; Sitosterols; src-Family Kinases; Sucrose

Changes in cholesterol absorption and cholesterol synthesis may promote dyslipidemia and cardiovascular disease in individuals with type 2 diabetes mellitus (T2DM).. To assess cholesterol synthesis and absorption in lean individuals, obese individuals, and individuals with T2DM.. We measured lathosterol and lanosterol (markers of cholesterol synthesis) as well as campesterol and β-sitosterol (markers of cholesterol absorption) in the serum of 15 to 26 years old individuals with T2DM (n = 95), as well as their lean (n = 98) and obese (n = 92) controls.. Individuals with T2DM showed a 51% increase in lathosterol and a 65% increase in lanosterol compared to lean controls. Similarly, obese individuals showed a 31% increase in lathosterol compared to lean controls. Lathosterol and lanosterol were positively correlated with body mass index, fasting insulin and glucose, serum triglycerides, and C-reactive protein, and negatively correlated with HDL-cholesterol. In contrast, campesterol and β-sitosterol were not altered in individuals with T2DM. Moreover, campesterol and β-sitosterol were negatively correlated with body mass index, fasting insulin, and C-reactive protein and were positively correlated with HDL-cholesterol.. Adolescents and young adults with T2DM show evidence of increased cholesterol synthesis compared to non-diabetic lean controls. These findings suggest that T2DM may promote cardiovascular disease by increasing cholesterol synthesis, and provide additional rationale for the use of cholesterol synthesis inhibitors in this group.

Topics: Adolescent; Adult; Biomarkers; Body Mass Index; Case-Control Studies; Cholesterol; Diabetes Mellitus, Type 2; Humans; Obesity; Phytosterols; Sitosterols; Young Adult

Adipose tissue is the primary site of storage for excess energy as triglyceride and it helps in synthesizing a number of biologically active compounds that regulate metabolic homeostasis. Consumption of high dietary fat increases stored fat mass and is considered as a main risk factor for metabolic diseases. Beta-sitosterol (β-sitosterol) is a plant sterol. It has the similar chemical structure like cholesterol. Clinical and experimental studies have shown that β-sitosterol has anti-diabetic, hypolipidemic, anti-cancer, anti-arthritic, and hepatoprotective role. However, effect of β-sitosterol on insulin signaling molecules and glucose oxidation has not been explored. Hence in the present study we aimed to discover the protective role of β-sitosterol on the expression of insulin signaling molecules in the adipose tissue of high-fat diet and sucrose-induced type-2 diabetic experimental rats. Effect dose of β-sitosterol (20 mg/kg b.wt, orally for 30 days) was given to high fat diet and sucrose-induced type-2 diabetic rats to study its anti-diabetic activity. Results of the study showed that the treatment with β-sitosterol to diabetes-induced rats normalized the altered levels of blood glucose, serum insulin and testosterone, lipid profile, oxidative stress markers, antioxidant enzymes, insulin receptor (IR), and glucose transporter 4 (GLUT4) proteins. Our present findings indicate that β-sitosterol improves glycemic control through activation of IR and GLUT4 in the adipose tissue of high fat and sucrose-induced type-2 diabetic rats. Insilico analysis also coincides with invivo results. Hence it is very clear that β-sitosterol can act as potent antidiabetic agent.

Topics: Adipose Tissue; Animals; Blood Glucose; Computer Simulation; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Glucose Transporter Type 4; Hypoglycemic Agents; Insulin; Lipid Metabolism; Male; Molecular Docking Simulation; Rats, Wistar; Receptor, Insulin; Signal Transduction; Sitosterols

Pterospermum acerifolium (L.) Willd (Sterculiaceae) has been traditionally used in the treatment of diabetes mellitus but no scientific data has been published supporting the claimed ethnomedical use.. The present study was designed to estimate the in silico, in vitro α-amylase inhibition potential and anti-diabetic activity of Pterospermum acerifolium bark.. In silico studies were performed between human pancreatic α-amylase (HPA) and β-sitosterol by using autodock 4.2 software. In vitro α-amylase inhibition study was carried out with 50% ethanol extract of the bark (PABEE) and its various fractions. The active ethyl acetate fraction (PABEF) was sub-fractionated into three fractions (PABE1, PABE2 and PABE3). Two doses (15 and 30 mg/kg) based on acute toxicity studies, of the above fractions were subjected to antidiabetic screening in vivo by STZ-nicotinamide induced type II diabetic rats.. In silico studies showed the potent inhibition of β-sitosterol on human pancreatic amylase (HPA) with an estimated inhibition constant (Ki) of 269.35 nmol and two hydrogen bond interactions. PABEF showed marked α-amylase inhibition (69.94%) compared to other fractions. Diabetic rats treated with PABE3 (30 mg/kg) reduced the levels of fasting blood glucose, HbA1c, ALT, AST, ALP, triglycerides, total cholesterol, TBARS significantly (p < 0.01) and increased the levels of HDL-C, catalase, GSH, SOD significantly (p < 0.01) as compared to that of diabetic control animals. Histological studies on PABE3 treated group showed remarkable positive changes in β-cells.. The present study confirmed the antihyperglycemic activity along with its status on hepatic biomarkers, antihyperlipidemic and antioxidant properties of Pterospermum acerifolium bark.

Topics: Animals; Computer Simulation; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Humans; Hydrogen Bonding; Hypoglycemic Agents; Male; Malvaceae; Niacinamide; Pancreatic alpha-Amylases; Plant Bark; Plant Extracts; Rats; Rats, Wistar; Sitosterols; Software; Streptozocin; Toxicity Tests, Acute

The use of medicinal plants has turned out to be an alternative method for the treatment of diseases, such as diabetes mellitus. The recommendation of the World Health Organization Committee on Diabetes encouraging research on hypoglycemic agents of plant origin used in traditional medicine has greatly motivated research in this area. The hypoglycemic activity of Ipomoea digitata tuber extract was investigated in streptozotocin-induced diabetic rats.. An oral administration of the hydroalcoholic extract of I. digitata tuber (100 and 200 mg/kg) and glibenclamide was given for 28 days. Blood glucose levels were measured at 0, 2, 4, 6, and 24 h in the acute study and at 0, 7, 14, 21, and 28 days in the chronic study. The weight of rats was recorded before and after the study period of 28 days.. In the acute study, both doses of the extract showed a significant reduction in the blood glucose level compared with the control but less significant than glibenclamide. In the chronic study, all treatments showed a significant blood glucose reduction in diabetic rats. The extract and glibenclamide not only prevented a further body weight loss but also maintained the body weight during the study period.. The result of the study concluded that I. digitata exhibits a considerable hypoglycemic activity, which could be due to the presence of flavonoids and β-sitosterol as active principles, although the mechanism of action remains to be determined. Thus, the plant can be the key contributor in the treatment of diabetes as an alternative medicine.

Topics: Administration, Oral; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Flavonoids; Glyburide; Hypoglycemic Agents; Ipomoea; Plant Extracts; Rats; Rats, Wistar; Sitosterols; Streptozocin; Time Factors

We investigated how liver fat content (LFC) influences cholesterol metabolism by quantifying liver fat using proton magnetic resonance spectroscopy and by measuring the serum concentrations of lathosterol, a marker of cholesterol synthesis, and sitosterol and campesterol, two markers of cholesterol absorption. We also evaluated whether this relationship could be modified by statin therapy. The study was conducted in 263 patients with type 2 diabetes, 137 of whom (52.0%) received statin therapy.. One hundred and sixty-five patients (62.7%) had steatosis (LFC>5.5%). We performed specific analyses in patients without statin therapy and in patients treated with statin therapy. In both groups, the lathosterol to cholesterol ratio correlated positively with LFC, and in multivariate analysis, the lathosterol to cholesterol ratio was associated with LFC independently of age, gender and BMI. Sitosterol and campesterol concentrations were not associated with LFC.. Our study suggests that in patients with type 2 diabetes, LFC is associated with an increase in cholesterol synthesis that is independent of obesity or diabetes mellitus. Statin therapy does not modify this relationship.

Topics: Aged; Biomarkers; Cholesterol; Diabetes Mellitus, Type 2; Dyslipidemias; Fatty Liver; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Linear Models; Liver; Magnetic Resonance Spectroscopy; Male; Middle Aged; Multivariate Analysis; Non-alcoholic Fatty Liver Disease; Phytosterols; Risk Factors; Sitosterols; Treatment Outcome

Topics: Aged; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; ATP-Binding Cassette Transporters; Case-Control Studies; Cholesterol; Cholesterol, Dietary; Chylomicrons; Diabetes Mellitus, Type 2; Female; Gene Expression Regulation; Humans; Lipoproteins; Male; Membrane Proteins; Membrane Transport Proteins; Middle Aged; RNA, Messenger; Sitosterols

Plasma plant sterol concentrations (an index of cholesterol absorption efficiency) and plasma lathosterol concentration (an index of cholesterol synthesis rate) were measured in 52 patients with non-insulin dependent diabetes mellitus (NIDDM) and 36 non-diabetic controls. Plasma plant sterol concentrations were significantly (P less than 0.01) lower in diabetic patients (campesterol: men -36%, women -48%; betasitosterol: men -35%, women -42%). Fasting serum insulin levels were inversely correlated with plasma plant sterol concentrations in diabetic patients (campesterol: r = -0.347, P = 0.012; betasitosterol: r = -0.345, P = 0.012) and in non-diabetic men (campesterol: r = -0.578, P = 0.039; betasitosterol: r = -0.702, P = 0.008). Serum insulin levels were also correlated significantly with plasma lathosterol concentration in diabetic patients (r = 0.295, P = 0.034). The results of this study suggest that absorption of plant sterols and possibly cholesterol from the diet may be reduced in hyperinsulinemic diabetics.

Topics: Adult; Aged; Cholesterol; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Male; Middle Aged; Phytosterols; Sitosterols