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Experimental research of piperine on glucose metabolism of model rats with insulin resistance syndrome
Abstract
Aim: To investigate the effect of piperine (PIP) on glucose metabolism and blood pressure (BP) of model rats with insulin resistance syndrome (IRS). Methods: Rats were fed with high-fat, high-glucose and high-salt diet to establish IRS model rats. Fasting blood glucose (FBG) and BP were observed dynamically every 4 weeks. The model rats started the treatment from the 4 th week and were treated for 8 weeks continuously. FBG (method of GOD-POD) and fasting insulin(FINS, method of RIA) were measured and insulin sensitivity index (ISI) was calculated, oral glucose tolerance test(OGTT) was observed, no invasion blood pressure instrument was used to measure BP. Results: After 8 weeks treatment, the level of ISI in PIP group increased obviously, while the levels of FBG in serum and BP were reduced significantly, and abnormal oral glucose tolerance improved accordingly. Conclusions: PIP could reduce BP and significantly improve abnormal glucose metabolism of model rats with IRS.
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In the obese adipose tissue produces proinflammatory molecules as tumor necrosis factor-α, which has local effects on adipocyte physiology and systemic effects in other organs. Many studies linking TNF-α, obesity, insulin resistance and lipid metabolism have been conducted in rats, rabbits and dogs, but the results observed in several of these studies have been conflicting and many of them have not been able to reproduce in humans, which on human makes difficult the interpretation of the effect of TNF-α on human metabolism. Objective: To conduct a systematic review of human studies which relates, TNF-α insulin resistance and lipoprotein metabolism. Methods: We searched the PubMed database for studies in humans, human tissue and human cell lines linking TNF-α, obesity, insulin resistance and lipoprotein. Results: There is a increased production of TNF-α on adipose tissue of obese. TNF-α decreases the cellular response to insulin in adipocytes, hepatocytes and human muscle cells. There is an increase of TNF-α in patients with dyslipidemia, and inactivation of TNF-α affects lipid metabolism. In human hepatocytes, TNF-α inhibits expression of APO AI, which may decrease the secretion of high density lipoproteins. TNF-α affects the excretion of cholesterol by inhibiting the enzyme cholesterol-7α-hydroxylase in hepatocytes. Conclusion: TNF-α decreases the cellular response to insulin, and has effects on the metabolism of cholesterol and lipoproteins in humans. A better understanding of the mechanisms of the inflammatory response induced obesity in humans, can lead to identifying new therapeutic targets that can prevent the complications associated with obesity.
Glucose homeostasis is closely regulated not only by insulin, but also by leptin. Both hormones act centrally, regulating food intake and adiposity in humans. Leptin has several effects on the glucose-insulin homeostasis, some of which are independent of body weight and adiposity. Those effects of leptin are determined centrally in the hypothalamus and peripherally in the pancreas, muscles and liver. Leptin has beneficial effects on the glucose-insulin metabolism, by decreasing glycemia, insulinemia and insulin resistance. The understanding of the effects of leptin on the glucose-insulin homeostasis will lead to the development of leptin-based therapies against diabetes and other insulin resistance syndromes. In these review, we summarize the interactions between leptin and insulin, and their effects on the glucose metabolism.
Piperine (1-Piperoyl piperidine) is a major alkaloid of Piper nigrum Linn. and Piper longum Linn. It is shown to possess bioavailability-enhancing activity with various structurally and therapeutically diverse drugs. The mechanism of enhancing the bioavailability, is, however, not understood. We hypothesize that piperine's bioavailability-enhancing property may be attributed to increased absorption, which may be due to alteration in membrane lipid dynamics and change in the conformation of enzymes in the intestine. Results of membrane fluidity studies using an apolar fluorescent probe, pyrene (which measures the fluid properties of hydrocarbon core), showed an increase in intestinal brush border membrane (BBM) fluidity. Piperine also stimulated Leucine amino peptidase and Glycyl-glycine dipeptidase activity, due to the alteration in enzyme kinetics. This suggests that piperine could modulate the membrane dynamics due to its apolar nature by interacting with surrounding lipids and hydrophobic portions in the protein vicinity, which may decrease the tendency of membrane lipids to act as stearic constrains to enzyme proteins and thus modify enzyme conformation. Ultra structural studies with piperine showed an increase in microvilli length with a prominent increase in free ribosomes and ribosomes on the endoplasmic reticulum in enterocytes, suggesting that synthesis or turnover of cytoskeletal components or membrane proteins may be involved in the observed effect. In conclusion, it is suggested that piperine may be inducing alterations in membrane dynamics and permeation characteristics, along with induction in the synthesis of proteins associated with cytoskeletal function, resulting in an increase in the small intestine absorptive surface, thus assisting efficient permeation through the epithelial barrier.
High fat diet is one of the important factors leading to type 2 diabetes mellitus and insulin resistant symptom. Developing a steady and applied model using high-fat diet-fed animals becomes an important part of type 2 diabetes mellitus and insulin resistant symptom researches. Whether high fat diet leads to insulin resistant symptom in experimental animals depends on the following factors: the artifactitious pattern and the fat proportion of the feed, the total amount of calories absorbed by the experimental animal, the duration of the animal model development, the breed and gender of experimental animals and the assistant medicament etc.
Aim: The aim of this study was to establish a rodent model with similar characters of human metabolic syndrome (MS). Methods: Three species mice and Wistar rats were fed with high energy chows (HEC) for 6 to 23 weeks. Animals were weighted every week. Fasting blood glucose (FBG) together with total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C) were investigated by oxidase test every two week. And fasting blood insulin (FINS) was determined by radioimmunoassay. Homeostasis model assessment of insulin resistance(HOMA-IR) was calculated as FBGxFINS/22.5. At the end of the experiment, oral glucose tolerance test (OGTT) was performed. Then animals were decapitated, and coel-fat and orchio-fat were collected and weighted to calculate the visceral fat coefficient (VFC). Results: FBG, serum TC and LDL-C significantly increased(P<0.01) after 6 weeks feed of HEC in KM mice. The mice also formed abdominal obesity and insulin resistant together with impairment of glucose tolerance (P < 0.05 or P < 0.01). Though similar to the KM mice, C57BL/6 and BALB/c mice couldn't form abdominal obesity while the latter had increased body weight(P < 0.05 or P < 0.01). Wistar rats formed hyperlipidemia from 1 to 10 week and hyperglycemia from 10 to 23 week together with insulin resistance and impaired glucose tolerance(P < 0.05 or P < 0.01). Conclusion KM mice feed with HEC for 6 weeks could successfully establish metabolic syndrome mice model which might be suitable for drug-screening, the major characters includes the formation of abdominal obesity (increase of VFC), the increase of serum TC, LDL-C, FBG and HOMA-IR, and the decrease of OGTT.
The immunotoxicological effects of piperine were investigated in Swiss male mice, gavaged at a dose of 1.12, 2.25 or 4.5 mg/kg body weight for five consecutive days. All the dose levels had no overt toxic effect and the liver gained weight normally. Treatment at highest dose, however, resulted in significant decrease in the weight of spleen, thymus and mesenteric lymph nodes, but not of peripheral lymph nodes. All the dose levels suppressed the cellular population of lymphoid organs, except for the spleen, where the doses of 1.12 and 2.25 caused an increase. Haematologically, doses of 2.25 and 4.5 mg/kg caused a significant reduction in total leucocyte counts and differential leucocyte counts showed an increase in the percentage of neutrophils. The higher doses of 2.25 and 4.5 mg/kg suppressed the mitogenic response of B-lymphocyte to lipopolysaccharide. The number of primary antibody (IgM) forming cells in the spleen and the level of primary antibody in serum, was decreased. The doses of 1.12 and 2.25 mg/kg suppressed the mitogenic response of T-lymphocytes to phytohaemagglutinin and the nitroblue tetrazolium (NBT) dye reducing activity of peritoneal exudate cells (PECs). Since the lowest dose of 1.12 mg of piperine per kg body weight had no immunotoxic effect, it may be considered as immunologically safe “no observed adverse effect level (NOAEL)” dose.
Objective: To evaluate the efficacy and safety of Yiqing Shuangjie Capsule and Tablet in treating acute upper respiratory tract infection with wind-warm syndrome.Methods: The multiple center, double-blinded, double-dummy and randomized controlled method was conducted. Three hundred and sixty patients were randomly divided into the treatment group A (n=120, treated with Yiqing Shuangjie Capsule and Chaihuang analogues), treatment group B (n=120, treated with Yiqing Shuangjie Tablet and Chaihuang analogues) and the control group (n=120, treated with Chaihuang Tablet and Yiqing Shuangjie Capsule analogues). Every drug was administered 3 pills each time. Patients in the three groups were all treated for 5 days and three times daily. The accumulated scores of syndrome, clinical symptoms, adverse effect and body temperature were recorded before and after the treatment. The safety indexes, such as routine tests of blood, urine and stool, hepatic and renal function tests and electrocardiogram (ECG) were taken before and after the treatment.Results: Three cases were excluded and eighteen cases lost to follow-up. There were 343 patients who entered to the intention-to-treat (ITT) analysis and 339 patients fitted in the per-protocol population set (PPS) analysis. After treatment, the therapeutic effects of respiratory tract infection were calculated by ITT and PPS analysis respectively. The rates of total obvious effect were 84.96% and 87.27% respectively in the treatment group A, and the total response rates were 96.46% and 97.27% respectively. The rates of total obvious effect were 85.47% and 86.20% respectively in the treatment group B, and the total response rates were 97.45% and 97.41% respectively. In the control group, the rates of total obvious effect both were 72.57%, and the total response rates both were 99.12%. There was significant difference among the three groups (P<0.05). The effects of traditional Chinese medicine syndrome were also detected by ITT and PPS analysis respectively. In the treatment group A, the total obvious effect rates were 84.07% and 85.46% respectively, and the total response rates were 96.46% and 97.27% respectively. In the treatment group B, the rates of total obvious effect were 88.89% and 89.65% respectively, and the total response rates were 97.44% and 97.41% respectively. In the control group, the rates of total obvious effect both were 72.57%, and total response rates both were 99.12%. There was also statistical significant difference among the three groups (P<0.05). ITT and PPS analysis had the same results. No adverse effect was found in the trial.Conclusion: Yiqing Shuangjie Capsule and Tablet are effective and safe in treating acute upper respiratory tract infection of wind heat syndrome without obvious adverse effect.
This study was aimed to explore underlying mechanism(s) of cardiovascular effects of piperine. Intravenous administration of piperine caused a dose-dependent (1 to 10 mg/kg) decrease in mean arterial pressure (MAP) in normotensive anesthetized rats; the next higher dose (30 mg/kg) did not cause any further change in MAP. The fall in blood pressure (BP) was followed by small increase in MAP after each dose. In Langendorrf's rabbit heart preparation, piperine caused partial inhibition and verapamil caused complete inhibition of force and rate of ventricular contractions and coronary flow. In rabbit aortic rings, piperine inhibited high K+ (80 mM) precontractions and partially inhibited phenylephrine (PE), suggesting Ca2+ channel blockade (CCB), which was further confirmed when pretreatment of tissues with piperine caused rightward shift in Ca2+ concentration-response curves, similar to verapamil. In Ca2+-free medium, piperine (1 to 30 microM) exhibited vasoconstrictor effect. In rat aorta, piperine demonstrated endothelium-independent vasodilator effect and was more potent against high K+ precontractions than PE. In bovine coronary artery preparations, piperine inhibited high K+ precontractions completely. These data indicate that piperine possesses a blood pressure-lowering effect mediated possibly through CCB, while consistent decrease in BP was restricted by associated vasoconstrictor effect. Additionally, species selectivity exists in the CCB effect of piperine.