High-fat Diet Low-dose Streptozotocin Research Articles

Ameliorative Effects of Lactobacillus paracasei L14 on Oxidative Stress and Gut Microbiota in Type 2 Diabetes Mellitus Rats.

Bioprospecting of more novel probiotic strains has attained continuous interest. This study aimed to investigate the beneficial effects of Lactobacillus paracasei strain L14, an isolate from a traditional Chinese dairy product, on type 2 diabetes mellitus (T2DM) rats. Preventive supplementation of strain L14 showed excellent anti-diabetic effects on high-fat diet/low-dose streptozotocin (HFD/STZ)-induced T2DM rats. It significantly reduced hyperglycemia, protected pancreatic β-cell and liver function, and ameliorated oxidative stress while considerably improving dyslipidemia and inflammation. Furthermore, the strain modulated the gut microbiota to alleviate gut dysbiosis. Interestingly, most of these biochemical parameters could even restore to normal levels by the intervention of strain L14. The whole-genome sequencing of L14 was performed to provide a critical molecular basis for its probiotic activities. Genes related to antioxidant systems and other beneficial microbial metabolites like exopolysaccharides (EPS) biosynthesis were found. This study demonstrates that probiotic L. paracasei L14 has good potential for applications in functional food and pharmaceutical industries.

1193-P: Investigating the Role of Intestinal L-Cell Secretagogin in Circadian GLP-1 Secretion in a Mouse Model of Type 2 Diabetes

The intestinal L-cell hormone Glucagon-like Peptide-1 (GLP-1) increases glucose-dependent insulin secretion and is thus used in the treatment of T2D. GLP-1 secretion from the L-cell exhibits a circadian pattern in rodents and varies by time-of-day in humans. We have shown that KD of the SNARE-regulatory protein, secretagogin (SCGN) prevents time-dependent GLP-1 release. SCGN KD in ß-cells also decreases insulin secretion and SCGN levels are reduced in T2D islets. We thus hypothesized that SCGN is decreased in the L-cell in T2D, causing alterations in the physiological pattern of GLP-1 secretion. High-fat diet, low-dose streptozotocin (HFD-STZ) mice, a model of T2D, exhibited increased fasting glucose (5.5 vs. 15.6 mmol/L; p<0.001) and decreased ß-cell area (by 75%, p<0.001). Unexpectedly, oral glucose tolerance tests conducted in 4-hour intervals through the 24-hr day showed that HFD-STZ mice exhibit a 10x increase in GLP-1 responses (400 vs. 4000 pg/ml*60 min, p<0.001) and exhibit an anti-phasic rhythm to controls. Basal GLP-1 levels remained unchanged between HFD-STZ and controls. Unexpectedly, insulin responses were not reduced in HFD-STZ mice, suggesting that increased GLP-1 levels could act as a compensatory mechanism. HFD-STZ mice also exhibited hyperglucagonemia compared to control, with increased glucagon secretion across timepoints following glucose administration (–243 vs. 800 pg/ml*60 min, p<0.001). RT-qPCR of intestinal mucosa showed an anti-phasic Scgn rhythm in the HFD-STZ model, with a 1.5-fold increase in average expression across timepoints (p<0.05), which could explain the drastically increased GLP-1 secretion. These data show that GLP-1 secretion is both increased and arrhythmic in a murine model of T2D, and that this occurs in association with an unanticipated increase in Scgn expression. Further investigation into the role of SGCN in the L-cell may serve as an avenue for therapeutics aimed at increasing endogenous GLP-1 release. Disclosure A. Biancolin: None. P. L. Brubaker: None. Funding Canadian Institutes of Health Research (PJT-15308)

Improvement of cognitive function, glucose and lipid homeostasis and serum osteocalcin levels by liraglutide in diabetic rats.

Glucose and lipid abnormalities, oxidative stress (OXS) and reduced brain-derived neurotrophic factor (BDNF) are involved in cognitive dysfunction in diabetes. Glucagon like peptide 1 (GLP1) receptors modulate glucose and lipid metabolism, cognitive function and serum osteocalcin. On the other hand, osteocalcin modulates cognitive function and glucose and lipid metabolism. This study investigated whether the GLP 1 agonist liraglutide improves cognitive function via modulation of serum osteocalcin and glucose and lipid metabolism. Effects of 4weeks liraglutide treatment (100µg/Kg/d and 300µg/Kg/d) on changes in cognitive function and bone homeostasis, induced by high fat diet/low-dose streptozotocin (HFD-STZ), were determined in rats. Cognitive function was assessed using Morris water maze (MWM) test. Serum and bone biochemical parameters were determined. Liraglutide dose-dependently improved cognitive function in diabetic rats (reduced escape latency, and increased time spent in target quadrant in MWM test, compared to diabetic control). Glucose and lipid abnormalities and the associated changes in serum BDNF and oxidative stress makers were improved. Serum BDNF and glutathione were significantly increased, whereas malondialdehyde level was reduced. Serum osteocalcin was significantly increased and correlated with improvement in cognitive dysfunction. Serum and bone receptor activator of nuclear factor κB ligand (RANKL)/osteoprotegerin ratios were significantly reduced by liraglutide treatment. Improvement of cognitive dysfunction by liraglutide involves modulation of glucose and lipid metabolism and serum osteocalcin. GLP1 agonists may provide an alternative metabolic approach for cognitive dysfunction in diabetes.

Dapagliflozin Ameliorates Glycemic State, Lipid Profile and Renal Functions in Type 2 Diabetic Rats

Background: Diabetic kidney disease is the leading cause of chronic kidney disease worldwide. Sodium glucose cotransporter-2 inhibitors may provide a recent solution with better control. Aim: to study the effect of dapagliflozin on glycemic state, lipid profile, renal functions, renal histopathology and some underlying possible mechanisms in type 2 diabetic rats. Methods: Fifty adult male albino rats were divided into five groups: Non-diabetic, diabetic non-treated, diabetic metformin-treated, diabetic dapagliflozin-treatedand diabetic combined metformin & dapagliflozin-treated. Type 2 diabetes was induced by high fat diet-low dose streptozotocin. Metformin or dapagliflozin were given. RBF and RVR were measured. Fasting serum glucose, HbA1c, serum insulin, lipid profile, renal function tests, TAC, MDA and TNF-α were measured then HOMA-IR, LDL-C & creatinine clearance were calculated. Histopathological examination of kidney sections was performed. Results:Hyperglycemia, hyperinsulinemia, insulin resistance, dyslipidemia, impairment of renal functions, altered oxidative and inflammatory modulators status, and changes in renal morphology were observed in diabetic rats. Individual treatment with metformin or dapagliflozin significantly improved those parameters however, better improvement in renal functions was observed in dapagliflozin as compared to metformin-treated groups. Diabetic combined metformin & dapagliflozin-treated group revealed significant improvement in glycemic state, renal function, TNF-α and oxidative stress as compared to dapagliflozin-treated group. Conclusion: Although metformin is better than dapagliflozin in glycemic control, dapagliflozin is more renoprotective than metformin. Combined dapagliflozin and metformin treatment resulted in significant improvement in glycemic state and renal functions in diabetic rats which is better than individual treatment. dapagliflozin had a complementary effect to metformin treatment in T2DM.

Effect of endurance exercise on oxidative stress marker malondialdehyde in type 2 diabetic mice.

Diabetes is associated with oxidative stress and has a significant role in the pathophysiology of the disease and its complications. Exercise training is a powerful therapeutic approach in diabetes and has protective effects against the progress of its complications. Objectives: The aim of this study was to investigate the effect of an endurance exercise program on the oxidative stress marker malondialdehyde (MDA) in high fat diet-low dose streptozotocin induced type 2 diabetic mouse model. Study Design: Randomized Control trial. Setting: Department of Physiology, Akhtar Saeed Medical and Dental College, Lahore. Period: August 2017 to August 2018. Material & Methods: 60 male albino mice were fed a high fat diet containing 60% kCal as fat for 4 weeks. This was followed by intra peritoneal injection of 40mg/kg body weight streptozotocin, given on three consecutive days. Mice with fasting blood glucose more than 250mg/dl after a week were considered diabetic. Half the mice underwent an exercise program which comprised of a 20 minute swimming session per day, with a 6% body weight load attached to the tail of mice, 3 days a week, for 4 weeks. The level of MDA was estimated in both groups using TBARs method. Results: Mean malondialdehyde level was significantly (p˂0.05) reduced in diabetic mice that underwent endurance exercise training. Conclusion: This study highlights the important role of endurance exercise in reducing oxidative stress in diabetes.

Effect of Perillyl Alcohol (POH) A Monoterpene on Lipid Peroxidation and Antioxidant Status in High Fat Diet-Low Dose STZ Induced Type 2 Diabetes in Experimental Rats

Aim: The plan of this study was to assess the protective activity of Perillyl alcohol (POH) on the levels of lipid peroxidation (LPO) by-products and antioxidant defense systems in the plasma and other tissues of normal and High Fat Diet-Low Dose Streptozotocin (STZ) induced type 2 diabetes in wistar rats. Materials and Methods: The experimental diabetes was induced in animals by High Fat Diet-Low Dose STZ (35 mg/kg i.p.) injection, and treatment with Perillyl alcohol at the dose of (50mg/kg b.w and 100mg/kg b.w) was continued for 30 days. At the end of treatment period, oxidative stress parameters like lipid peroxidation by-products; enzymatic antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and non-enzymic antioxidants including reduced glutathione, Vitamin C and Vitamin E were measured in the plasma and tissues of experimental rats. Results: In untreated diabetic rats an increase was seen in the levels of lipid peroxidation by-products and significant decrease was seen in antioxidant enzymes. Oral administration of Perillyl alcohol a monocyclic monoterpene to diabetic rats for 30 days caused a significant reduction in the levels of lipid peroxidation by-products and an increase in the activities of antioxidant enzymes, when the same were compared with the untreated diabetic group. Conclusion: The result of this study indicates that Perillyl alcohol has anti lipid peroxidation and antioxidant status potential in experimental diabetes.

Improving hepatic mitochondrial biogenesis as a postulated mechanism for the antidiabetic effect of Spirulina platensis in comparison with metformin.

Various nutritional and medicinal potencies have been accredited to metabolites from the cyanobacteria, Spirulina platensis (Arthrospira platensis) sp. Hence, our study was designed to examine whether the Spirulina supplementation would possess beneficial effects in type 2 diabetes mellitus (T2DM) in comparison with metformin. High-fat diet/low-dose streptozotocin (HFD/STZ) model was adopted and the diabetic rats were orally treated with metformin (200 mg/kg) or Spirulina (250 or 500 or 750 mg/kg) for 30 days. Spirulina ameliorated the HFD/STZ-induced elevation of fasting blood glucose, insulin, and hepatic enzymes. Moreover, Spirulina successfully rectified disrupted serum lipid profile and exhibited an anti-inflammatory effect via tumor necrosis factor-α and adiponectin modulation. On the molecular level, Spirulina reduced the expression of hepatic sterol regulatory element binding protein-1c (SREBP-1c), confirming its lipotropic effect. Furthermore, Spirulina amended compromised hepatic mitochondrial biogenesis signaling by significantly increasing peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), mitochondrial transcription factor A (Tfam), and mitochondrial DNA (mtDNA) copy number. On almost all parameters, the highest dose of Spirulina showed the best effects, which were comparable to that of metformin. To our knowledge, our study is the first to attribute the various aspects of the effect of Spirulina to the SREBP-1c and PGC-1α/Tfam/mtDNA pathways in liver. The present results clearly proved that Spirulina modulated glucose/lipid profile and exhibited prominent anti-inflammatory properties through SREBP-1c inhibition and hepatic mitochondrial biogenesis enhancement. Thus, Spirulina can be considered as an add-on to conventional antidiabetic agents and might influence the whole dynamics of the therapeutic approaches in T2DM.

Antidiabetic effects of Mangifera indica Kernel Flour-supplemented diet in streptozotocin-induced type 2 diabetes in rats.

Our previous report showed that Mangifera indica kernel flour (MIKF) is a rich source of pharmacologically important flavonoids and phenolic acids; and that its methanolic extract inhibits some key enzymes linked to the pathology and complications of type 2 diabetes (T2D) in vitro. Hence, this study evaluated the antidiabetic effects of 10% and 20% MIKF‐supplemented diets in T2D in rats. T2D was induced in rats using a high‐fat diet (HFD), low‐dose streptozotocin (HFD/STZ) model, by feeding the rats with HFD for 2 weeks followed by single dose administration of STZ (40 mg/kg body weight, intraperitoneally). The diabetic rats were later fed the MIKF‐supplemented diets, or administered with metformin (25 mg/kg b.w.) for 21 days; the control rats were fed basal diet during this period. Intake of the MIKF‐supplemented diets resulted in significant (P < 0.05) improvement in the fasting blood glucose, hepatic glycogen, glycosylated hemoglobin, lipid profile, plasma electrolytes, hepatic and pancreatic malonaldehyde, and the liver function markers of the diabetic rats, compared with the diabetic control rats. The ameliorative effect of 20% MIKF‐supplemented was comparable (P > 0.05) with that of metformin administration in the diabetic rats. It is concluded that M. indica kernel flour has antidiabetic effects in T2D rats, and could therefore be a promising nutraceutical therapy for the management of T2D and its associated complications.

Phenolics composition and antidiabetic property of Brachystegia eurycoma seed flour in high-fat diet, low-dose streptozotocin-induced type 2 diabetes in rats

ObjectiveTo quantify some major pharmacologically important flavonoids and phenolic acids in Brachystegia eurycoma seed flour (BESF) and evaluate its antidiabetic activity in type 2 diabetic rats. MethodFlavonoids and phenolic acids were quantified using a reverse-phase high pressure liquid chromatrography coupled with diode array detection. Type 2 diabetes was induced in rats using high-fat diet, low-dose streptozotocin (HFD/STZ) model, by feeding the rats with HFD for 2 weeks followed by single dose administration of STZ (40 mg/kg body weight, intraperitoneally). The diabetic rats were later fed BESF-supplemented (10% and 20%) diets, or administered with metformin (25 mg/kg b.w.) for 21 days; the control rats were fed basal diet during this period. After the dietary regimen, the rats were sacrificed, and their blood, liver and pancreas samples were collected for biochemical assays. ResultsThe flavonoids (catechin, rutin, quercitrin, quercetin and kaempferol) and phenolic acids (gallic acid, caffeic, chlorogenic and ellagic acid) were abundant in BESF. BESF-supplemented diets (BESF-SD) significantly (P < 0.05) decreased the levels of fasting blood glucose (FBG); ameliorated the lipid profile, and significantly (P < 0.05) increased the hepatic glycogen of the diabetic rats. BESF-SD also significantly (P < 0.05) attenuated the oxidative stress induced by STZ in the liver and pancreas of the diabetic rats. The ameliorative effects of 20% BESF-SD compared (P > 0.05) with metformin administration in some of the biomarkers. ConclusionThe flavonoids and phenolic acids in BESF may have acted synergistically to produce the observed antidiabetic effects. BESF could therefore be an effective and affordable dietary therapy for the management of T2DM; and an excellent source for drug discovery.

Ellagic acid, an NF-κB inhibitor, ameliorates renal function in experimental diabetic nephropathy

Diabetic nephropathy (DN) is a serious complication confronted by diabetic patients. Available data indicate that the development of DN is linked to inflammation. In this context, nuclear factor-kappa B (NF-κB) has received much attention. Ellagic acid (2,3,7,8-tetrahydroxy-chromeno[5,4,3-cde]chromene-5,10-dione), found abundantly in plant extracts and fruits, possesses numerous medicinal properties. We investigated the nephroprotective effects of oral treatment of ellagic acid in high fat diet/low dose streptozotocin (HFD/STZ)-induced type 2 diabetic Wistar albino rats. Ellagic acid treatment for 16weeks post induction of diabetes significantly attenuated renal dysfunction and oxidative stress. Ellagic acid significantly inhibited the renal NF-кB activation. Moreover, ellagic acid significantly lowered renal pathology and suppressed transforming growth factor-beta (TGF-β) and fibronectin expressions in renal tissues. Ellagic acid also significantly reduced the serum levels of pro-inflammatory cytokines, interleukin-1beta (IL-1β), IL-6 and tumor necrosis factor-alpha (TNF-α). In cultured rat NRK 52E proximal tubular epithelial cells, ellagic acid treatment inhibited high glucose-induced activation of NF-κB and pro-inflammatory cytokine synthesis. These results suggest that ellagic acid exhibited renal protective effect in diabetic rats partly through antihyperglycemia which was accompanied by attenuation of inflammatory processes via inhibition of NF-κB pathway.