Combination Of High-fat Diet Research Articles

Protective effects of losartan on some type 2 diabetes mellitus-induced complications in Wistar and spontaneously hypertensive rats.

Diabetes mellitus type 2 (T2DM) is characterized by resistance of insulin receptors and/or inadequate insulin secretion resulting in metabolic and structural complications including vascular diseases, arterial hypertension and different behavioral alterations. We aimed to study the effects of the antihypertensive angiotensin AT1 receptor antagonist losartan on the T2DM-induced changes of exploratory behavior, anxiety, nociception and short term memory in normotensive Wistar and spontaneously hypertensive rats (SHRs). The experimental model of T2DM induced by a combination of high fat diet and streptozotocin, decreased exploratory activity and increased the level of carbonylated proteins in selected brain structures in both strains; as well it increased corticosterone level, pain threshold, anxiety-like behavior, and decline short term memory only in SHRs. Losartan treatment alleviated some of the T2DM- induced metabolic complications, abolished the T2DM-induced hypo activity, and normalized the corticosterone level, carbonylated proteins in brain, nociception and memory. Losartan did not exert effect on the anxiety behavior in both strains. We showed that T2DM exerted more pronounced negative effects on the rats with comorbid hypertension as compared to normotensive rats. Overall effects on the studied behavioral parameters are related to decreased exploration of the new environment, increased anxiety-like behavior, and decline in short-term memory. The systemic sub-chronic treatment with an angiotensin AT1 receptor antagonist losartan ameliorated most of these complications.

Type 2 diabetes mellitus alters cardiac mitochondrial content and function in a non-obese mice model.

Type 2 diabetes mellitus (T2DM) is associated with an increase of premature appearance of several disorders such as cardiac complications. Thus, we test the hypothesis that a combination of a high fat diet (HFD) and low doses of streptozotocin (STZ) recapitulate a suitable mice model of T2DM to study the cardiac mitochondrial disturbances induced by this disease. Animals were divided in 2 groups: the T2DM group was given a HFD and injected with 2 low doses of STZ, while the CNTRL group was given a standard chow and a buffer solution. The combination of HFD and STZ recapitulate the T2DM metabolic profile showing higher blood glucose levels in T2DM mice when compared to CNTRL, and also, insulin resistance. The kidney structure/function was preserved. Regarding cardiac mitochondrial function, in all phosphorylative states, the cardiac mitochondria from T2DM mice presented reduced oxygen fluxes when compared to CNTRL mice. Also, mitochondria from T2DM mice showed decreased citrate synthase activity and lower protein content of mitochondrial complexes. Our results show that in this non-obese T2DM model, which recapitulates the classical metabolic alterations, mitochondrial function is impaired and provides a useful model to deepen study the mechanisms underlying these alterations.

Polysaccharides from Armillariella tabescens mycelia ameliorate insulin resistance in type 2 diabetic mice.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by hyperglycemia mainly due to insulin resistance. The objective of this study was to investigate the effects of polysaccharides from Armillariella tabescens mycelia (AT) on insulin resistance in mice fed a high-fat diet in combination with streptozotocin to induce T2DM. Following treatment with different doses of AT, hyperglycemia and lipid metabolism dysfunction, insulin resistance, and hepatic function-related indices were markedly ameliorated; the histopathological alterations, oxidative stress, and inflammatory reaction in hepatic tissue were also alleviated; most importantly, AT inhibited the expression of hepatic thioredoxin-interacting protein (TXNIP) to repress the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation and activated the 5'AMP-activated protein kinase (AMPK) pathway in a dose-dependent manner in T2DM mice. In conclusion, these findings revealed that the hypoglycemic and hypolipidemic activities of AT were associated with the alleviation of insulin resistance through repression of the TXNIP/NLRP3 inflammasome pathway and activation of the AMPK pathway.

Therapeutic Effects of the Anti-diabetic Polyherbal Drug Diawell in Combination with Metformin on Liver and Lipid Parameters in Type 2 Diabetic Rats

Type 2 diabetes is one of the most important diseases worldwide. It affects several organ systems including the liver and lipid metabolism. Many herbal formulations have shown anti-diabetic potential, however, their safety and efficacy remain a debate in the medical community.
 Aim: This study evaluates the therapeutic effects of the anti-diabetic polyherbal drug diawell in combination with metformin on liver enzyme and lipid profile in type 2 diabetic rats.
 Methodology: A total of 35 male Wistar albino rats weighing between 120-220 g were used for this study. The rats were placed on high fat diet, and diabetes was induced by a single intraperitoneal injection of freshly prepared streptozotocin (STZ) (45 mg/kg body wt). Fasting plasma glucose (FPG) was determined using the glucose oxidase method. Total Cholesterol (TC), Triglyceride (TG) and High density lipoprotein cholesterol (HDL-C) were determined using enzymatic methods. Low density lipoprotein cholesterol (LDL-C) was calculated using the Friedewald equation. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined using Reitman-Frankel method, while alkaline phosphatase (ALP) was determined using the colorimetric phenolphthalein method. Liver sections were stained using haematoxylin and eosin (H&E) staining technique, and phytochemical analysis was also done on the herbal tablet.
 Results: The results show no significant differences in mean TC levels in all groups. TG level was significantly higher in the diabetic control when compared to the negative control. There were no significant differences in TG levels in the metformin group, and diawell group when compared to the diabetic control. TG levels in the combination group (metformin + diawell) was significantly lower versus the diabetic control, and showed no significant difference compared to the negative control. HDL-C was significantly higher in the negative control when compared to the diabetic control and the treatment groups. There were no significant differences in HDL-C levels in all the treatment groups, when compared to the diabetic control. LDL-C levels were significantly lower in the negative control compared to the diabetic control and treatment groups. There were no significant differences in LDL-C levels in all the treatment groups, when compared to the diabetic control. The diabetic control had significantly higher ALT, AST and ALP levels compared to the negative control and treatment groups. All the treatment groups showed no significant differences in ALT and AST levels compared to the negative control. Liver sections of the negative control showed normal histoarchitecture. The diabetic control showed inflammation and fatty deposition. The treatment groups showed a nearly normal histoarchitecture, with fatty deposits.
 Conclusion: High fat diet in combination with 45 mg/kg of STZ produced significant diabetes in the Wistar rats with dyslipidaemia and elevated liver enzyme levels. Metformin and the polyherbal tablet diawell had no impact on the lipid levels as it did not correct the dyslipidaema, however, the treatments showed hepatoprotective potentials and restored liver enzyme levels to normal. Lipid lowering drugs should be included in the management of type 2 diabetes, and there should be proper evaluation of anti-diabetic herbal products.

Urinary Bladder Weight and Function in a Rat Model of Mild Hyperglycemia and Its Treatment With Dapagliflozin.

Hypertrophy and dysfunction of the urinary bladder are consistently observed in animal models of type 1 and less consistently in those of type 2 diabetes. We have tested the effects of mild hyperglycemia (n = 10 per group) in a randomized, blinded study and, in a blinded pilot study, of type 2 diabetes (n = 6 per group) and its treatment with dapagliflozin (1 mg/kg per day) on weight, contraction, and relaxation of the rat bladder. Based on a combination of high-fat diet and a low dose of streptozotocin, animals in the main study reached a mean peak blood glucose level of about 300 mg/dl, which declined to 205 mg/dl at study end. This was associated with a small, if any, increase in bladder weight. In a pooled analysis of all animals of the main and the pilot study, we detected a correlation of moderate strength between blood glucose and bladder weight (r 2 = 0.2013; P = 0.0003 for Pearson correlation coefficient). Neither the main nor the pilot study found evidence for an altered contractility (responses to carbachol or KCl) or relaxation (responses to isoprenaline, fenoterol, CL 316,243, or forskolin). Treatment with dapagliflozin in the absence of hyperglycemia increased diuresis in the main study by 43% relative to control and increased bladder weight by 15% in the pooled groups of both studies (post hoc analysis). We conclude that mild hyperglycemia has no major effects on bladder hypertrophy or function.

Abstract 867: NAD + Repletion Reverses HFpEF by Attenuating Myocardial Metabolic Dysfunction

Background: Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent clinical condition associated with significant morbidity, mortality and health care expenses. Yet, no effective treatment has been identified. We recently demonstrated that concomitant metabolic and hypertensive stress in mice elicited by a combination of high fat diet (HFD) and constitutive nitric oxide synthase inhibition by N [w] -nitro-l-arginine methyl ester (L-NAME) faithfully recapitulates the numerous and myriad features of human HFpEF (paper in press at Nature ). Methods: Wild type C57Bl6 mice were fed with HFD and L-NAME via drinking water for 5-8 weeks. Myocardial mitochondrial morphology was assessed by electron microscopy. Mitochondrial function was assessed by measuring oxygen consumption rates using an oxygen electrode. Protein expression and modification were assessed by Western blotting and immunoprecipitation. Results: Using this novel mouse model, we discovered significant impairment of mitochondrial fatty acid oxidation (FAO) associated with hyperacetylation of key FAO enzymes in HFpEF myocardium. Mechanistically, downregulation of Sirtuin3, the major mitochondrial deacetylase, and deficiency of its co-substrate nicotinamide adenine dinucleotide (NAD + ), culminated in mitochondrial protein hyperacetylation. Strikingly, supplementation with nicotinamide riboside (NR), a NAD + precursor, led to dramatic improvement of mitochondrial function, and importantly, amelioration of the HFpEF phenotype. Conclusion: In summary, we have unveiled that protein hyperacetylation-mediated mitochondrial dysfunction is a crucial mechanism of HFpEF pathogenesis. This is, to our knowledge, the first study identifying a specific signature of metabolic remodeling in HFpEF heart. We also demonstrated the therapeutic effect of NAD + repletion in a preclinical HFpEF model. In next steps, confirming this benefit in a clinical trial is warranted.

Metabolic Syndrome Exacerbates Pulmonary Hypertension due to Left Heart Disease.

Pulmonary hypertension (PH) due to left heart disease (LHD), or group 2 PH, is the most prevalent form of PH worldwide. PH due to LHD is often associated with metabolic syndrome (MetS). In 12% to 13% of cases, patients with PH due to LHD display vascular remodeling of pulmonary arteries (PAs) associated with poor prognosis. Unfortunately, the underlying mechanisms remain unknown; PH-targeted therapies for this group are nonexistent, and the development of a new preclinical model is crucial. Among the numerous pathways dysregulated in MetS, inflammation plays also a critical role in both PH and vascular remodeling. We hypothesized that MetS and inflammation may trigger the development of vascular remodeling in group 2 PH. Using supracoronary aortic banding, we induced diastolic dysfunction in rats. Then we induced MetS by a combination of high-fat diet and olanzapine treatment. We used metformin treatment and anti-IL-6 (interleukin-6) antibodies to inhibit the IL-6 pathway. Compared with sham conditions, only supracoronary aortic banding+MetS rats developed precapillary PH, as measured by both echocardiography and right/left heart catheterization. PH in supracoronary aortic banding+MetS was associated with macrophage accumulation and increased IL-6 production in lung. PH was also associated with STAT3 (signal transducer and activator of transcription 3) activation and increased proliferation of PA smooth muscle cells, which contributes to remodeling of distal PA. We reported macrophage accumulation, increased IL-6 levels, and STAT3 activation in the lung of group 2 PH patients. In vitro, IL-6 activates STAT3 and induces human PA smooth muscle cell proliferation. Metformin treatment decreased inflammation, IL-6 levels, STAT3 activation, and human PA smooth muscle cell proliferation. In vivo, in the supracoronary aortic banding+MetS animals, reducing IL-6, either by anti-IL-6 antibody or metformin treatment, reversed pulmonary vascular remodeling and improve PH due to LHD. We developed a new preclinical model of group 2 PH by combining MetS with LHD. We showed that MetS exacerbates group 2 PH. We provided evidence for the importance of the IL-6-STAT3 pathway in our experimental model of group 2 PH and human patients.

Differential effect of high fat diet (HFD) on the cardiac muscle of adult and aged female mice and the possible protective role of artichoke treatment: Histomorphometric and ultrastructural study

Background: Coexistence of hyperlipidemia and aging is a highly serious condition that massively deteriorates cardiacfunction. Artichoke is a well-known antioxidant commonly used in long-lived countries diet. Recent researches showed itshypolipidemic and antiaging effects.Objective: This work aimed to investigate the histopathological effects of high fat diet (HFD) on adult mice cardiac muscle, toaddress and compare the extent of myocardial damage in aged mice and to assess beneficial effects of artichoke in mitigatingthese effects.Materials and Methods: A total of 42 adult (Group I) and aged (Group II) female mice (3 and 26 months old respectively)were divided into six equal subgroups (7 per each); Groups Ia and IIa: adult and aged control, Groups Ib and IIb: adult andaged HFD groups were fed diet enriched with 1.5% cholesterol and 10% lard oil for 6 weeks. Groups Ic and IIc: adult andaged artichoke treated group, were received HFD for 6 weeks as HFD groups concomitant with artichoke extract at a dose of1.5 gm/kg once daily via gastric tube.Results: Adult HFD laden cardiac myocytes showed loss of cross striations, inflammatory cell infiltrate, increase collagencontent, myofiber focal degeneration,disruption of myofibrils, sarcomeres and T tubule system, lipid vacuolation, mitochondrialdamage and nuclear pyknosis. These effects were the worst in aged HFD fed animals. Artichoke markedly improved thesechanges in both adult and aged mice.Conclusion: combination of HFD and aging caused more extensive insults on cardiac myocytes than each factor alone.Artichoke is highly efficient in ameliorating these insults.

Effects of dietary supplementation of Chrysophyllum albidum fruit pulp powder on some biochemical parameters in a type 2 diabetes rat model

Chrysophyllum albidum (C. albidum) is an indigenous fruit, found predominantly in African countries. The fleshy pulp of the fruit is widely consumed by the populace and used in folklore for diabetes management. The present study was carried out to assess the effects of dietary supplementation of Chrysophyllum albidum fruit pulp powder (CAPP) on biochemical parameters in a type 2 diabetes rat model, induced by a combination of high-fat diet and low-dose streptozotocin (35 mg kg −1) for 14 days. Diabetic rats were placed on dietary regimen containing 5–10% Chrysophyllum albidum fruit pulp powder (CAPP) supplemented diet. The results revealed that there was no significant (P > 0.05) difference in the average feed intake and weight changes between the rat groups. Furthermore, supplementation with CAPP gradually reduced blood glucose level in diabetic rat compared to control diabetic rats without CAPP supplementation. Moreover, reduced activities of α-amylase and α-glucosidase were observed in CAPP and metformin-treated rat groups when compared to control diabetic rats without CAPP supplementation. In addition, CAPP showed significantly (P < 0.05) elevated levels of antioxidant status (reduced glutathione, superoxide dismutase, catalase, glutathione peroxidase and glutathione-S-transferase) while significantly (P < 0.05) reduced malondialdehyde level. Histologically, a pale stained cellular architecture in pancreas depicting an atrophy and decreased size of islet of Langerhans were observed in control diabetic rats without CAPP supplementation while CAPP and metformin-treated rat groups showed a preserved cellular morphology with increased size of islet of Langerhans. The results suggest that the C. albidum fruit pulp diet may attenuate hyperglycemia and oxidative stress in the type 2 diabetic condition and therefore provides pharmacological basis for the folkloric use of this fruit as a therapy for the management of oxidative stress induced pathologies.

Folate receptor positive macrophages in rat models for OA: phenotype switch in response to anti-inflammatory medication

Purpose: Folate-based radiotracers have been used to visualize macrophages in a range of inflammatory diseases, including RA and OA, and have shown that folate receptor-expressing macrophages accumulate at the site of inflammation. Macrophages are thought to arise from monocytes that migrate from the bloodstream to the site of inflammation or injury and then mature to the appropriate pro-inflammatory or anti-inflammatory phenotype. Methods: From previous work using folate-SPECT imaging in both animal models and in patients with OA we know that folate receptor-expressing macrophages are present in OA affected joints. We have performed studies with a variety of rat models using folate-SPECT imaging in OA: running at various intensities, papain injections combined with running (Figure 1), high-fat diet, placement of grooves on femoral condyles and a combination of high fat diet + grooves (Figure 2). In all models cartilage damage, osteophytosis and synovial inflammation was assessed by histology. Results: We observed that folate uptake is increased with increasing OA severity, and seems to correlate with synovial membrane inflammation. This has led to the hypothesis that the folate-SPECT scan could be a useful tool to monitor disease severity in vivo. Interestingly, two subsequent studies with anti-inflammatory medication in the papain-groove model showed folate uptake increased up to three-fold after treatment with local delivery of either triamcinolone acetonide or celecoxib in the knee joint (Figure 1). This increase was not associated with increased disease severity, but rather with reduced osteophyte formation and increased cartilage thickness. Further in vitro evaluation confirmed that triamcinolone acetonide induces an anti-inflammatory folate-positive phenotype in macrophages during the early stages of maturation but also showed that the folate receptor is not specifically expressed in anti-inflammatory macrophages.Together these results suggest that as new monocytes arrive in the joint at the site of inflammation and mature into macrophages, they become active folate expressing pro-inflammatory macrophages. When anti-inflammatory medication is administered intra-articularly, the newly arrived monocytes mature instead to anti-inflammatory macrophages with possibly even higher folate expression (Figure 3). Conclusions: In conclusion, the folate receptor may be a useful tool to monitor macrophage activation during OA development and progression. However, folate-based imaging cannot distinguish between macrophage phenotypes and the use of anti-inflammatory medication could thus result in unexpectedly high uptake of folate by (anti-inflammatory) macrophages.Figure 2Relative activity on folate SPECT in the high-fat diet model in the grooved vs the sham operated knee.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3Corticosteroids drive macrophages towards an anti-inflammatory phenotype, but only during the early stages of maturation.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

High‐Fat Diet Exacerbates Diabetic Kidney Injury in Mice Lacking eNOS

Diabetic nephropathy is the leading cause of chronic kidney disease and end stage renal disease. It has been shown that deficiency in endothelial nitric oxide synthase (eNOS), and/or reduced eNOS activity is associated with diabetic nephropathy progression in humans. This study was designed to examine whether high fat diet (HFD) would enhance diabetic kidney injury in eNOS deficient mice. To induce diabetes, six‐week old eNOS deficient mice were placed on normal diet (ND) or HFD (42% from fat). Two weeks later, half of them were rendered diabetic with alloxan. Proteinuria/albuminuria and urinary levels of kidney injury markers were measured in control and diabetic animals 4 months post alloxan injection. There is no difference in urinary total protein among four groups. HFD treatment increased urinary albumin as well as proinflammatory cytokine osteopontin, whereas urinary parameters remained normal in alloxan‐induced diabetic mice fed with normal diet. A combination of HFD and alloxan treatment resulted in a more pronounced albuminuria as well as increased glomerular and tubular damage as evidenced by an elevation of urinary synaptopodin, matrix metalloproteinase‐9 and kidney injury molecule‐1. These results demonstrate that HFD accelerates diabetic kidney injury in eNOS deficient mice. Thus eNOS deficient mice may be suitable for studying the roles of albuminuria and renal lipotoxicity in development and progression of diabetic nephropathy.Support or Funding InformationNIH (SC1DK112151), NIH/NCRR/RCMI (8G12MD007602) and (8U54MD007588)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

An Exaggerated Muscle Mechanoreflex in Type 2 Diabetic Rats Is Mediated by Potentiated Skeletal Muscle Afferent Discharge to Mechanical Stimulation

The blood pressure response to exercise is heightened in patients with type 2 diabetes (T2D). Since such elevations in blood pressure increase the risk for developing an adverse cardiovascular event, elucidating the underlying mechanisms is clinically relevant. The exercise pressor reflex (EPR) plays an important role in regulating the cardiovascular system during exercise. Our group has previously demonstrated that the EPR is exaggerated in T2D rats contributing importantly to the augmented pressor response to physical activity. However, the mechanisms responsible for this abnormal EPR function in T2D remain to be elucidated. Sensory information from working muscle is generated, in part, by stimulation of mechanically sensitive afferent neurons (i.e. the skeletal muscle mechanoreflex, a component of the EPR). In this study, it was hypothesized that the EPR dysfunction characteristic of T2D is mediated by an exaggerated muscle mechanoreflex resulting from an increase in muscle afferent responsiveness to mechanical stimulation.PURPOSEIn T2D rats, to 1) investigatethe pressor and sympathetic responses to stimulation of the muscle mechanoreflex in vivo and 2) examine neuronal discharge to mechanical stimulation in skeletal muscle thin fiber afferents in vitro.METHODSFor 14–16 weeks, rats were given either a normal diet (control group) or a high fat diet in combination with a low dose (35 mg/kg) of streptozotocin (T2D group). In vivo, we measured changes in renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) during passive stretch of hindlimb muscle in decerebrate rats. In vitro, muscle afferent neurons were mechanically activated via ramp‐shaped mechanical stimulation (0–196 mN) with the resulting action potentials assessed by obtaining single‐fiber recordings using an extensor digitorum longusmuscle‐nerve preparation.RESULTSCompared to control, induction of T2D evoked hyperglycemia (104±5 vs. 161±10 mg/dL, P&lt;0.05). Similarly, T2D elicited significant increases in plasma insulin (111±10 vs. 150±13 pmol/L, P&lt;0.05) and HOMA‐IR (3.9±0.3 vs. 9.3±1.2, P&lt;0.01). Mechanoreflex activationby passive stretch evoked significantly greater increases in RSNA and MAP in T2D (13±3 vs. 81±16 %, P&lt;0.01 and 7±3 vs. 29±7 mmHg, P&lt;0.05, respectively). Further, the response magnitude to mechanical stimulation tended to be greater in muscle afferents from T2D compared to control (20±7 vs. 40±8 spikes, P=0.10).CONCLUSIONSThese findings suggest that the muscle mechanoreflex is exaggerated in T2D resulting, at least in part, from augmentations in the responsiveness of thin muscle afferent fibers to mechanical stimuli. Importantly, these changes likely contribute significantly to the EPR overactivity manifest in T2D.Support or Funding InformationSupported by Lawson &amp; Rogers Lacy Research Fund in Cardiovascular Disease and the Southwestern School of Health Professions Interdisciplinary Research Grant Program.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Nitrosative stress drives heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a common syndrome with high morbidity and mortality for which there are no evidence-based therapies. Here we report that concomitant metabolic and hypertensive stress in mice-elicited by a combination of high-fat diet and inhibition of constitutive nitric oxide synthase using Nω-nitro-L-arginine methyl ester (L-NAME)-recapitulates the numerous systemic and cardiovascular features of HFpEF in humans. Expression of one of the unfolded protein response effectors, the spliced form of X-box-binding protein 1 (XBP1s), was reduced in the myocardium of ourrodent model and in humans with HFpEF. Mechanistically, the decrease in XBP1s resulted from increased activity of inducible nitric oxide synthase (iNOS) and S-nitrosylation of theendonuclease inositol-requiring protein 1α (IRE1α), culminating in defective XBP1 splicing. Pharmacological or genetic suppression of iNOS, or cardiomyocyte-restricted overexpression of XBP1s, each ameliorated the HFpEF phenotype. We report that iNOS-driven dysregulation of the IRE1α-XBP1 pathway is a crucial mechanism of cardiomyocyte dysfunction in HFpEF.

Impairment of Intestinal Monocarboxylate Transporter 6 Function and Expression in Diabetic Rats Induced by Combination of High-Fat Diet and Low Dose of Streptozocin: Involvement of Butyrate-Peroxisome Proliferator-Activated Receptor-γ Activation.

Generally, diabetes remarkably alters the expression and function of intestinal drug transporters. Nateglinide and bumetanide are substrates of monocarboxylate transporter 6 (MCT6). We investigated whether diabetes down-regulated the function and expression of intestinal MCT6 and the possible mechanism in diabetic rats induced by a combination of high-fat diet and low-dose streptozocin. Our results indicated that diabetes significantly decreased the oral plasma exposure of nateglinide. The plasma peak concentration and area under curve in diabetic rats were 16.9% and 28.2% of control rats, respectively. Diabetes significantly decreased the protein and mRNA expressions of intestinal MCT6 and oligopeptide transporter 1 (PEPT1) but up-regulated peroxisome proliferator-activated receptor γ (PPARγ) protein level. Single-pass intestinal perfusion demonstrated that diabetes prominently decreased the absorption of nateglinide and bumetanide. The MCT6 inhibitor bumetanide, but not PEPT1 inhibitor glycylsarcosine, significantly inhibited intestinal absorption of nateglinide in rats. Coadministration with bumetanide remarkably decreased the oral plasma exposure of nateglinide in rats. High concentrations of butyrate were detected in the intestine of diabetic rats. In Caco-2 cells (a human colorectal adenocarcinoma cell line), bumetanide and MCT6 knockdown remarkably inhibited the uptake of nateglinide. Butyrate down-regulated the function and expression of MCT6 in a concentration-dependent manner but increased PPARγ expression. The decreased expressions of MCT6 by PPARγ agonist troglitazone or butyrate were reversed by both PPARγ knockdown and PPARγ antagonist 2-chloro-5-nitro-N-phenylbenzamide (GW9662). Four weeks of butyrate treatment significantly decreased the oral plasma concentrations of nateglinide in rats, accompanied by significantly higher intestinal PPARγ and lower MCT6 protein levels. In conclusion, diabetes impaired the expression and function of intestinal MCT6 partly via butyrate-mediated PPARγ activation, decreasing the oral plasma exposure of nateglinide.

Melatonin protects against cardiac damage induced by a combination of high fat diet and isoproterenol exacerbated oxidative stress in male Wistar rats

In the current study, it was found that high fat diet (60% of total kCal) (H) or/and isoproterenol (I) exacerbated oxidative stress and caused myocardial damage. This was indicated by increased levels of LPO, PCO, abnormal mitochondria and altered activities of metabolic as well as antioxidant enzymes in myocardium of rats. Melatonin at different doses (10, 20 and 40 mg/kg) effectively protected against myocardial damage induced by H or/and I and preserved all of these altered parameters. Morphological analyses showed that combination of H and I treatment led to the extensive myofibril disintegration and neutrophil infiltration. Melatonin at the dose of 40 mg/kg almost completely prevented these pathological alterations. The mechanistical studies have uncovered that the protective effects of melatonin on the myocardial damage induced by H and I are attributed to its direct and indirect antioxidative capacity, i.e., it directly scavenges free radicals and also regulates the gene expression of antioxidant enzymes. Collectively, based on the evidences gathered from the current study, it will not be unwise to suggest that melatonin can serve as an ideal therapeutic agent for those cardiovascular diseases caused by oxidative stress.

Inhibition of Ephrin-B2 in brain pericytes decreases cerebral pathological neovascularization in diabetic rats.

We have previously shown that diabetes causes dysfunctional cerebral neovascularization that increases the risk for cerebrovascular disorders such as stroke and cognitive impairment. Pericytes (PCs) play a pivotal role in the angiogenic process through their interaction with the endothelial cells (EC). Yet, the role of PCs in dysfunctional cerebral neovascularization in diabetes is unclear. In the present study, we tested the hypothesis that the increased proangiogenic Ephrin-B2 signaling in PCs contributes to the dysfunctional cerebral neovascularization in diabetes. Type-II diabetes was induced by a combination of high fat diet and low dose streptozotocin injection in male Wistar rats. Selective in vivo Ephrin-B2 silencing in brain PCs was achieved using the stereotactic injection of adeno-associated virus (AAV) with NG2-promoter that expresses Ephrin-B2 shRNA. Neovascularization was assessed using vascular fluorescent dye stain. Novel object recognition (NOR) test was used to determine cognitive functions. Human brain microvascular pericytes HBMVPCs were grown in high glucose 25 mM and palmitate 200 uM (HG/Pal) to mimic diabetic conditions. Scratch migration and tube formation assays were conducted to evaluate PC/EC interaction and angiogenic functions in PC/EC co-culture. Diabetes increased the expression of Ephrin-B2 in the cerebrovasculature and pericytes. Concomitant increases in cerebral neovascularization parameters including vascular density, tortuosity and branching density in diabetic rats were accompanied by deterioration of cognitive function. Inhibition of Ephrin-B2 expression in PCs significantly restored cerebral vascularization and improved cognitive functions. HG/Pal increased PC/EC angiogenic properties in co-culture. Silencing Ephrin-B2 in PCs significantly reduced PC migration and PC/EC co-culture angiogenic properties. This study emphasizes the significant contribution of PCs to the pathological neovascularization in diabetes. Our findings introduce Ephrin-B2 signaling as a promising therapeutic target to improve cerebrovascular integrity in diabetes.

High-fat diet and streptozotocin in the induction of type 2 diabetes mellitus: a new proposal.

Our objective was to establish a diabetes mellitus type 2 (DM2) model in rats using a high-fat diet and streptozotocin (HF-STZ). Male Wistar rats (240-250g) were divided into a control group (commercial feed), and HF-STZ group, (66.5%-commercial feed, 13.5%-lard, and 20%-sugar). STZ (40mg/kg i.p.) or vehicle was administered on the 13th day. An oral glucose tolerance test (OGTT) was performed (2.5mg of glucose/kg v.o.) on both groups. After 39 days of treatment, blood and tissue samples were collected for analyses. The weight gain after STZ administration was lower in the HF-STZ group than in the control group with reductions in muscle mass and adipose tissue. The HF-STZ group showed hyperglycemia after STZ administration (glucose on day 39: HF-STZ: 499 ± 60; control: 134 ± 9mg/dL). Serum glucagon was 23% lower, and insulin levels were unaltered. The HOMA index was 4-times higher in the HF-STZ. The HF-STZ group showed increased post-prandial (330%) and fasting (125%) triglycerides, and while glycogen content in the liver and muscles decreased (70-80%). The area under the curve (OGTT) was 282% higher in the HF-STZ group. The combination of high-fat diet with STZ (i.p) generated rats with hyperglycemia associated with hypertriglyceridemia and introduced many other alterations present in human DM2.

Effect of supplementing chromium histidinate and picolinate complexes along with biotin on insulin sensitivity and related metabolic indices in rats fed a high-fat diet.

ScopeTo investigate the effects of chromium histidinate (CrHis) and chromium picolinate (CrPic) complex along with biotin to a high‐fat diet (HFD) fed to rats on the insulin sensitivity and the anti‐obesity properties.MethodsForty‐two Sprague–Dawley male rats were divided into six groups. The rats were fed either (a): a standard diet (Control) or (b): a HFD or (c): a HFD with biotin (HFD+B) or (d): a combination of HFD and biotin along with CrPic (HFD + B + CrPic) or (e): a combination of HFD and biotin along with CrHis (HFD + B + CrHis) or (f): a combination of HFD and biotin along with CrHis and CrPic (HFD + B + CrHis + CrPic).ResultsAdding biotin with chromium to HFD improved the glucose, insulin, HOMA‐IR, leptin, lipid profile, with HFD+B+CrHis treatment being the most effective (p = 0.0001). Serum, liver, and brain tissue Cr concentrations increased upon Cr supplementations (p = 0.0001). Supplementing CrHis along with biotin to a HFD (HFD + B + CrHis) provided the greatest levels of GLUT‐1, GLUT‐3, PPAR‐γ, and IRS‐1, but the lowest level of NF‐κB in the brain and liver tissues.ConclusionBiotin supplementation with chromium complexes, CrHis in particular, to a HFD pose to be a potential therapeutic feature for the treatment of insulin resistance.

Schistosoma mansoni Infection-Induced Transcriptional Changes in Hepatic Macrophage Metabolism Correlate With an Athero-Protective Phenotype.

Hepatic macrophages play an essential role in the granulomatous response to infection with the parasitic helminth Schistosoma mansoni, but the transcriptional changes that underlie this effect are poorly understood. To explore this, we sorted the two previously recognized hepatic macrophage populations (perivascular and Kupffer cells) from naïve and S. mansoni-infected male mice and performed microarray analysis as part of the Immunological Genome Project. The two hepatic macrophage populations exhibited remarkably different genomic profiles. However, this diversity was substantially reduced following infection with S. mansoni, and in fact, both populations demonstrated increases in transcripts of the monocyte lineage, suggesting that both populations may be replenished by monocytes following infection. Pathway analysis showed a profound alteration in global metabolic pathways, including changes to phospholipid and cholesterol metabolism, as well as amino acid biosynthesis and glucagon signaling. These changes suggest a possible mechanism for the previously reported athero-protective effects of S. mansoni infection. Indeed, we find that male ApoE null mice fed a high-fat diet in combination with S. mansoni infection have reduced plaque area and increased glucose tolerance as compared to control mice. Transcript analysis of infected and control high-fat diet fed ApoE−/− mice confirm that ApoC1, Psat1, and Gys1 are all altered by infection, suggesting that altered hepatic macrophage metabolism is associated with S. mansoni- induced protection from hyperlipidemia, atherosclerosis, and glucose intolerance. These results suggest a previously unknown and unreported role of hepatic macrophages in the modulation of whole body lipid and glucose metabolism during infection and provide a template for examining the role of immunomodulation on the long-term metabolism of the host.

Gynura divaricata rich in 3, 5\u2212/4, 5-dicaffeoylquinic acid and chlorogenic acid reduces islet cell apoptosis and improves pancreatic function in type 2 diabetic mice

BackgroundDiabetes mellitus is one of the most common chronic diseases that accompanied by severe complications. Gynura divaricata (GD), a medicinal and edible plant that is usually used for the treatment of diabetes. Therefore, this study investigates the chemical components of GD with hypoglycemic effect and the possible mechanism lowering blood sugar in T2D diabetic mice.MethodsThe methanol extract of GD was analysed by HPLC-DAD. And then mice with type 2 diabetes induced by a high-fat diet in combination with streptozotocin feed the diet containing lyophilized GD powder for 4 weeks. During this period, fasting blood glucose (FBG) levels and body weight were measured.ResultsGD was rich in four bioactive components of dicaffeoylquinic acid and chlorogenic acid. These components occupied about 2.37% in the GD powder in which the highest level was 3, 5-dicaffeoylquinic acid. Oral GD significantly reduced FBG, fasting serum insulin, and glycosylated serum protein levels, and enhanced antioxidative activities. HE-staining showed that the pathological damage in pancreatic β-cells was ameliorated. An immunohistochemical assay also showed that GD promoted marked pancreatic β-cell regeneration. GD also caused notable increase in GLUT2, GK, MafA, PDX-1, and Bcl-2 as well as reduction in Bax and caspase-3 expression as shown by western blot analysis.ConclusionsGD exerts the pronounced hypoglycaemic effect by inhibiting islet cell apoptosis and improving pancreatic function. Therefore, GD might have a potential to improve diabetes.