Attenuation Of Hyperglycemia Research Articles

Enhanced hepatoprotective effects of empagliflozin and vitamin D dual therapy against metabolic dysfunction-associated steatohepatitis in mice by boosted modulation of metabolic, oxidative stress, and inflammatory pathways.

Although single treatment with sodium-glucose cotransporter-2 inhibitors (SGLT2i) or vitamin D3 (VD3) inhibited metabolic dysfunction-associated steatohepatitis (MASH) development in diabetic patients, their combination hasnot been explored previously. Hence, this study investigated the hepatoprotective effects of SGLT2i (empagliflozin) and/or VD3 against MASH in type 2 diabetic mice. Forty Mice were assigned into negative (NC) and positive (PC) controls, SGLT2i, VD3, and SGLT2i + VD3 groups. All animals, except the NC group, received high-fructose/high-fat diet (8 weeks) followed by diabetes induction. Diabetic mice then received another cycle of high-fructose/high-fat diet (4 weeks) followed by 8 weeks of treatment (five times/week) with SGLT2i (5.1 mg/kg/day) and/or VD3 (410 IU/Kg/day). The PC group demonstrated hyperglycaemia, dyslipidaemia, elevated liver enzymes, and increased non-alcoholic fatty liver disease activity score (NAS) with fibrosis. Hepatic glucose transporting molecule (SGLT2) with lipogenesis (SREBP-1/PPARγ), oxidative stress (MDA/H2O2), inflammation (IL1β/IL6/TNF-α), fibrosis (TGF-β1/α-SMA), and apoptosis (TUNEL/Caspase-3) markers alongside the PI3K/AKT/mTOR pathway increased in the PC group. Conversely, hepatic insulin-dependent glucose transporter (GLUT4), lipolytic (PPARα/INSIG1), antioxidant (GSH/GPx1/SOD1/CAT), and anti-inflammatory (IL-10) molecules with the inhibitor of PI3K/AKT/mTOR pathway (PTEN) decreased in the PC group. Whilst SGLT2i monotherapy outperformed VD3, their combination showed the best attenuation of hyperglycaemia, dyslipidaemia, and fibrosis with the strongest modulation of hepatic glucose-transporting and lipid-regulatory molecules, PI3K/AKT/mTOR pathway, and markers of oxidative stress, inflammation, fibrosis, and apoptosis. This study is the first to reveal boosted hepatoprotection for SGLT2i and VD3 co-therapy against diabetes-induced MASH, possibly via enhanced metabolic control and modulation of hepatic PI3K/AKT/mTOR, anti-inflammatory, anti-oxidative, and anti-fibrotic pathways.

Attenuation of Hyperglycemia in Diabetic Rats Assisted by Immobilized Probiotic in Sodium Alginate.

Diabetes mellitus type 2 (DM2) is the most common chronic disease worldwide, characterized mainly by increased glucose concentration in the blood and affecting several organs' functionality. The daily consumption of probiotic bacteria can help control diabetes and reduce the damage caused. Cell immobilization techniques are a powerful tool that provides physical cell protection to such probiotic bacteria against gastrointestinal conditions. We suggest that cell immobilization could be a significant vector for delivering a high quantity of viable probiotics to the gut, helping attenuate hyperglycemia in diabetic rats. Seventy male Wistar rats were used in this work. Nicotinamide was administrated via intraperitoneal injection 15 minutes before inducing type 2 diabetes (DM2), followed by a second intraperitoneal injection of streptozotocin to induce DM2. Rats were divided into seven groups. For 45days, a specific treatment was applied to each group. The group of rats, supplied with immobilized Lactobacillus casei, showed a serum glucose concentration of 137mg/dL, which was close to the one observed in the groups of healthy rats (117mg/dL) and rats treated with metformin (155mg/dL). The diabetic rats without treatment presented a higher serum glucose concentration (461mg/dL). In the rats treated with immobilized L. casei, there was no biochemical parameter alteration, and the cell morphology of the analyzed tissues was similar to those of the healthy group. The consumption of immobilized L. casei could allow a high quantity of viable probiotics to be delivered to the gut, reducing serum glucose concentration by up to 70% compared to diabetic rats and reducing organ damage caused by diabetes.

Biochanin-A Protects Rats from Diabetes-associated Cardiorenal Damage by Attenuating Oxidative Stress through Activation of Nrf-2/HO-1 Pathway

The current study is designed to evaluate the cardiorenal protective efficacy of the Biochanin-A (BCA) against high-fat-diet (HFD) and streptozotocin (STZ)-induced diabetes in rats. BCA (10mg/kg body weight) was administered to the diabetic rats for a period of 30 days and evaluated its effect on hyperglycemic markers, formation of lipid peroxidation, nitric oxide production and antioxidant enzymes such as superoxide dismutase, catalase and glutathione mediated enzymes. Further, we assessed the impact of BCA on nuclear factor erythroid 2-related factor-2 (Nrf-2) and heme oxygenase-1 (HO-1) along with antioxidant enzymes mRNA expressions by RT-PCR. BCA administration to diabetic rats resulted in attenuation of hyperglycemia and oxidative stress in both the kidney and heart. Further, BCA enhanced the endogenous antioxidant activities in the kidney and heart and up-regulated their corresponding mRNA expressions. In addition, BCA treatment produced notable up-regulation of Nrf-2 and HO-1 mRNA expressions in the cardiac and renal tissue of diabetic rats. In conclusion, the current study revealed that BCA could protect from diabetes-induced complications such as cardiomyopathy and nephropathy by activating the Nrf-2/HO-1 pathway and enhancing the endogenous antioxidant state in the kidney and heart.

Empagliflozin Treatment Attenuates Hepatic Steatosis by Promoting White Adipose Expansion in Obese TallyHo Mice.

Sodium-glucose co-transporters (SGLTs) serve to reabsorb glucose in the kidney. Recently, these transporters, mainly SGLT2, have emerged as new therapeutic targets for patients with diabetes and kidney disease; by inhibiting glucose reabsorption, they promote glycosuria, weight loss, and improve glucose tolerance. They have also been linked to cardiac protection and mitigation of liver injury. However, to date, the mechanism(s) by which SGLT2 inhibition promotes systemic improvements is not fully appreciated. Using an obese TallyHo mouse model which recapitulates the human condition of diabetes and nonalcoholic fatty liver disease (NAFLD), we sought to determine how modulation of renal glucose handling impacts liver structure and function. Apart from an attenuation of hyperglycemia, Empagliflozin was found to decrease circulating triglycerides and lipid accumulation in the liver in male TallyHo mice. This correlated with lowered hepatic cholesterol esters. Using in vivo MRI analysis, we further determined that the reduction in hepatic steatosis in male TallyHo mice was associated with an increase in nuchal white fat indicative of “healthy adipose expansion”. Notably, this whitening of the adipose came at the expense of brown adipose tissue. Collectively, these data indicate that the modulation of renal glucose handling has systemic effects and may be useful as a treatment option for NAFLD and steatohepatitis.

Characterizing Hepatic Inflammation upon SGLT2 Inhibition in Diabetic TallyHo Mice

By 2030, Diabetes is estimated to become the 7th leading cause of death worldwide with roughly 90‐95% of all cases attributed to Type 2 diabetes (T2D). A common comorbidity of T2D is Non‐Alcoholic Fatty Liver Disease (NAFLD), characterized by the presence of lipid accumulation with or without hepatic steatosis (NASH). While the pathogenesis of NAFLD and NASH is not entirely understood, it is associated with insulin resistance, inflammation, and hyperlipidemia. Recently, sodium‐glucose co‐transporter 2 (SGLT2) inhibitors have emerged as a treatment option for patients with T2D. This drug effectively blocks renal glucose reabsorption and in turn, improves glycemic control. It is also associated with positive renal and cardiovascular outcomes. Given the attenuation of hyperglycemia, we sought to determine if SGLT2 inhibitors also offer protection from the development of NAFLD and NASH. To test this, spontaneously diabetic male and female TallyHo mice were maintained on either a control or high milk fat diet (60%) for 24‐weeks in the continued presence or absence of Empagliflozin, one of the most well‐characterized SGLT2 inhibitors on the market. As expected, at the conclusion of 24 weeks, blood glucose values were significantly lowered in the male mice treated with Empagliflozin. We also detected a reduction in hepatic lipid accumulation by both MRI and biochemical analysis. To determine if these protective effects correlated with a reduction in inflammation, we performed a large‐scale screen of more than 60 inflammatory markers on both plasma and livers collected from the high‐fat diet‐fed male mice. The data revealed that Empagliflozin attenuates systemic inflammation; we detected a downregulation in circulating pro‐inflammatory cytokines (CD30 ligand, IL‐1α, IL‐4, IL‐9, TIMP1, TPO) and an upregulation in MIP‐1γ, an anti‐inflammatory cytokine (p<0.05 for all cytokines). In contrast, we observed indications of increased inflammation in the Empagliflozin‐treated livers. Protein expression of cleaved caspase, the active form of the inflammatory‐driven protein, was elevated when compared to non‐treated milk fat diet‐fed mice (which was already elevated compared to normal chow controls). In addition, we noted heightened levels of five pro‐inflammatory cytokines (IL‐3, IL‐6, CCL2, M‐CSF, CCL1) while there was downregulation of another three (p40/p70, TNFSF8, CCL3; p<0.05). Efforts are currently underway to confirm the expression of these common inflammatory markers and to elucidate the mechanism behind the dysregulated hepatic inflammatory pathway upon SGLT2 inhibition.

A Dioxidovanadium Complex cis-[VO2 (obz) py] Attenuates Hyperglycemia in Streptozotocin (STZ)-Induced Diabetic Male Sprague-Dawley Rats via Increased GLUT4 and Glycogen Synthase Expression in the Skeletal Muscle.

Vanadium has demonstrated antihyperglycemic effects in diabetes mellitus (DM) but is, however, associated with toxicity. Therefore, new vanadium complexes envisaged to possess heightened therapeutic potency while rendering less toxicity are being explored. Accordingly, the aim of the study was to investigate the effects of a dioxidovanadium (V) complex, cis-[VO2 (obz) py], on selected glucose metabolism markers in streptozotocin (STZ)-induced diabetic rats. STZ-induced diabetic rats were treated orally with cis-[VO2 (obz) py] (10, 20, and 40 mg/kg) twice every 3rd day for 5 weeks. Blood glucose concentrations, body weight, and food and water intake were monitored weekly, for 5 weeks. Rats were then euthanized after which blood, liver, and muscle tissues were collected for biochemical analysis. The administration of dioxidovanadium complex significantly decreased blood glucose concentrations throughout the 5-week period in comparison with the diabetic control (DC). The attenuation of hyperglycemia was accompanied by an increased glycogen concentration in both liver and muscle tissues in the treated groups. Furthermore, a significant increase was observed in the expression of glucose transporter type 4 (GLUT4) in the skeletal muscle tissues and glycogen synthase in the liver tissues. These findings indicate that our vanadium complex cis-[VO2 (obz) py] may exert antihyperglycemic effects through increased glucose uptake, glycogen synthesis, and increased GLUT4 and glycogen synthase expression.

Attenuation of hyperglycemia and amadori products by aminoguanidine in alloxan-diabetic rabbits occurs via enhancement in antioxidant defenses and control of stress.

The micro- and macro-complications in diabetes mellitus (DM) mainly arise from the damage induced by Amadori and advanced glycation end products, as well as the released free radicals. The primary goal of DM treatment is to reduce the risk of micro- and macro-complications. In this study, we looked at the efficacy of aminoguanidine (AG) to prevent the production of early glycation products in alloxan-diabetic rabbits. Type1 DM was induced in rabbits by a single intravenous injection of alloxan (90 mg/kg body weight). Another group of rabbits was pre-treated with AG (100 mg/kg body weight) prior to alloxan injection; this was followed by weekly treatment with 100 mg/kg of AG for eight weeks. Glucose, insulin, and early glycation products (HbA1C and fructosamine) were measured in control, diabetic and AG treated diabetic rabbits. The effects of hyperglycemia on superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (Gpx), reduced glutathione (rGSH), nitric oxide, lipid peroxides, and protein carbonyl were investigated. Alloxan-diabetic rabbits had lower levels of SOD, CAT, Gpx, and rGSH than control rabbits. Nitric oxide levels were considerably greater. AG administration restored the activities of SOD, CAT, Gpx enzymes up to 70–80% and ameliorated the nitric oxide production. HbA1c and fructosamine levels were considerably lower in AG-treated diabetic rabbits. The observed control of hyperglycemia and amadori adducts in alloxan-diabetic rabbits by AG may be attributed to decrease of stress and restoration of antioxidant defenses.

Chromatographic fractions from Chrysophyllum albidum stem bark boost antioxidant enzyme activity and ameliorate some markers of diabetes complications

Background and aimDiabetes, with hyperglycaemia as hallmark, is a global crisis that reduces the antioxidant status and produces complications when poorly managed. The development of complications can be indicated by inflammation, lipid peroxidation and the accumulation of glycation adducts. Thus, the attenuation of hyperglycaemia and boosting of antioxidants status is key in ameliorating markers of diabetes complications. This work evaluated the potency of Chrysophyllum albidum stem bark on some markers of diabetes complications. Experimental procedureA total of 100 female rats (180.80 ± 8.50 g) were assigned into ten groups of ten animals each; control received 1.0 ml of distilled water while those in groups DC, RD, F1, F3, F4, F5, F7, F9, F10 were induced into diabetes by intraperitoneal administration of 120 mg/kg body weight of alloxan and were orally administered distilled water, glibenclamide, 2.5 mg/kg of the chromatographic fractions 1, 3, 4, 5, 7, 9, and 10 respectively, once daily for 14 days. F7 was profiled for its bioactive constituents and the pancreas histology of the rats were examined. ResultsChromatographic fractions F5 and F7 significantly decreased fasting blood glucose, glycosylated haemoglobin, C-reactive protein, total cholesterol, triglycerides, atherogenic index, malondialdehyde while insulin, high density lipoprotein, catalase, superoxide dismutase activities significantly increased. Fraction F7 revealed eight compounds and restored the distorted pancreas. ConclusionFraction F7 ameliorated the markers of diabetes complications considered in this study better than F5, restored the compromised pancreas and can be explored as lead candidate for production of drug for the management of diabetes.

Acute dapagliflozin administration exerts cardioprotective effects in rats with cardiac ischemia/reperfusion injury

BackgroundA sodium-glucose co-transporter 2 (SGLT-2) inhibitor had favorable impact on the attenuation of hyperglycemia together with the severity of heart failure. However, the effects of acute dapagliflozin administration at the time of cardiac ischemia/reperfusion (I/R) injury are not established.MethodsThe effects of dapagliflozin on cardiac function were investigated by treating cardiac I/R injury at different time points. Cardiac I/R was instigated in forty-eight Wistar rats. These rats were then split into 4 interventional groups: control, dapagliflozin (SGLT2 inhibitor, 1 mg/kg) given pre-ischemia, at the time of ischemia and at the beginning of reperfusion. Left ventricular (LV) function and arrhythmia score were evaluated. The hearts were used to evaluate size of myocardial infarction, cardiomyocyte apoptosis, cardiac mitochondrial dynamics and function.ResultsDapagliflozin given pre-ischemia conferred the maximum level of cardioprotection quantified through the decrease in arrhythmia, attenuated infarct size, decreased cardiac apoptosis and improved cardiac mitochondrial function, biogenesis and dynamics, leading to LV function improvement during cardiac I/R injury. Dapagliflozin given during ischemia also showed cardioprotection, but at a lower level of efficacy.ConclusionsAcute dapagliflozin administration during cardiac I/R injury exerted cardioprotective effects by attenuating cardiac infarct size, increasing LV function and reducing arrhythmias. These benefits indicate its potential clinical usefulness.

Activated protein C reverses epigenetically sustained p66Shc expression in plaque-associated macrophages in diabetes

Impaired activated protein C (aPC) generation is associated with atherosclerosis and diabetes mellitus. Diabetes-associated atherosclerosis is characterized by the hyperglycaemic memory, e.g., failure of disease improvement despite attenuation of hyperglycaemia. Therapies reversing the hyperglycaemic memory are lacking. Here we demonstrate that hyperglycaemia, but not hyperlipidaemia, induces the redox-regulator p66Shc and reactive oxygen species (ROS) in macrophages. p66Shc expression, ROS generation, and a pro-atherogenic phenotype are sustained despite restoring normoglycemic conditions. Inhibition of p66Shc abolishes this sustained pro-atherogenic phenotype, identifying p66Shc-dependent ROS in macrophages as a key mechanism conveying the hyperglycaemic memory. The p66Shc-associated hyperglycaemic memory can be reversed by aPC via protease-activated receptor-1 signalling. aPC reverses glucose-induced CpG hypomethylation within the p66Shc promoter by induction of the DNA methyltransferase-1 (DNMT1). Thus, epigenetically sustained p66Shc expression in plaque macrophages drives the hyperglycaemic memory, which—however—can be reversed by aPC. This establishes that reversal of the hyperglycaemic memory in diabetic atherosclerosis is feasible.

Taurine and pioglitazone attenuate diabetes-induced testicular damage by abrogation of oxidative stress and up-regulation of the pituitary-gonadal axis.

Chronic hyperglycemia is associated with impairment of testicular function. The current study aimed to investigate the protective effects and the possible mechanisms of taurine and pioglitazone against diabetes-induced testicular dysfunction in rats. Diabetes was induced by streptozotocin injection. Both normal and diabetic rats received taurine (100 mg/kg) or pioglitazone (10 mg/kg) orally and daily for 6 weeks. Diabetic rats showed a significant (P < 0.001) increase in glycosylated hemoglobin, glucose, homeostasis model of insulin resistance, and pro-inflammatory cytokines. Serum insulin, testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were significantly (P < 0.001) decreased in diabetic rats. Taurine and pioglitazone alleviated hyperglycemia, decreased pro-inflammatory cytokines, and increased circulating levels of insulin, testosterone, LH, and FSH. Gene and protein expression of LH and FSH receptors and cytochrome P450 17α-hydroxylase (CYP17) was significantly (P < 0.001) down-regulated in testes of diabetic rats, an effect which was significantly increased after administration of taurine and pioglitazone. In addition, taurine and pioglitazone significantly decreased lipid peroxidation and DNA damage, and enhanced activity of the antioxidant enzymes in testes of diabetic rats. In conclusion, taurine and pioglitazone exerted protective effects against diabetes-induced testicular damage through attenuation of hyperglycemia, inflammation, oxidative stress and DNA damage, and up-regulation of the pituitary/gonadal axis.

Attenuation of hyperglycemia and hyperlipidemia in high calorie fed/streptozotocin-treated rats by hydromethanolic extract of &lt;i&gt;Padina tetrastromatica&lt;/i&gt;

In the present study, the effect of defatted hydromethanolic extract of Padina tetrastromatica on carbohydrate metabolism and serum lipid profile were evaluated. Diabetes mellitus was induced in male Wistar rats by feeding high calorie/energy diet for two months followed by a single intraperitoneal injecttion of streptozotocin. Diabetic rats were administered with the extract intragastrically at doses of 150, 300, 450, and 600 mg/kg body weight daily for 45 days. Treatment with graded doses showed a dose dependent reduction in blood glucose and glycated hemoglobin levels. Treatment significantly increased the activity of hexokinase, glucose-6-phosphate dehydrogenase and glycogen content while there was significant reduction in the activity of glucose-6-phosphatase and fructose-1,6-bisphosphatase. Serum lipid profile was also brought back to near normal levels in a dose dependent manner. The present study clearly indicates the antihyperglycemic and hypolipidemic effects of P. tetrastromatica at an optimum dose of 450 mg/kg body weight.

Abstract 423: A Combination of Metformin, Quercetin, and Curcumin Restores HDL Function and Improves Atherosclerosis Burden in LDLr-/-/ob.ob leptin-/- and LDLr-/- Mice by attenuating Insulin Resistance, Hyperglycemia, and Low-grade Inflammation

Cardiovascular disease risk in diabetics is 2-4 fold greater compared to non-diabetics. While dyslipidemia poorly explains excess risk in diabetics, glucose intolerance leads to increased macrophage infiltration, arterial stiffness, and modifies vascular tone. Enhanced lipid peroxidation in diabetes mellitus contributes to increased formation of free radicals, leading to accelerated glycation and oxidative stress, which causes HDL modification. The objective of the present study was to: a) investigate HDL function and atherosclerosis burden in animal model of diabetes, hyperlipidemia, and low-grade inflammation; and b) evaluate regression of preformed lesions following treatment with a proprietary formulation (COMB) of metformin (MET) with anti-oxidant and anti-inflammatory agents, quercetin and curcumin. We used LDLr-/-/leptin-/-ob/ob (DKO) and LDLr-/- (SKO) mice fed Western Diet for 10 weeks to develop lesion formation followed by treatment with MET (150 mpk) or COMB for 6 weeks (bid). Lipid profile, lesion formation, and OGTT were measured. We also measured HDL functionality by ABCA1-dependent cholesterol efflux in the serum, and in a separate cohort, cholesterol efflux using 3H-cholesterol-loaded J774 cells. Atherosclerotic lesion formation in DKO was greater (27%) compared to SKO. Impaired glucose tolerance, insulin resistance, and proinflammatory index was found to be associated with HDL functionality and atherosclerosis burden. Treatment with COMB attenuated hyperglycemia, insulin resistance and inflammation, and restored HDL function and promoted lesion regression (-24% in DKO, and -15% in SKO). COMB showed greater efficacy compared to MET, demonstrating the benefit of controlling glycemia and inflammation to restore HDL function and enhance lesion regression. Preliminary results in diabetics (n=10) and age and sex matched non-diabetic individuals (n=10) showed impairment in ABCA1-mediated cholesterol efflux in the serum of diabetics (-18% vs control). In summary, these data suggest that HDL dysfunction in diabetes mellitus is one of the risk factors of atherosclerotic lesion formation, and attenuation of hyperglycemia, oxidative stress, and inflammation may improve HDL function and promote lesion regression.

Monascin improves diabetes and dyslipidemia by regulating PPARγ and inhibiting lipogenesis in fructose-rich diet-induced C57BL/6 mice

Monascin (MS) is a yellow compound isolated from Monascus-fermented products that has pancreatic protective, anti-inflammatory, anti-oxidative, and hypolipidemic activity. We recently found that MS also acts as a peroxisome proliferator-activated receptor-gamma (PPARγ) agonist, thereby promoting insulin sensitivity in C2C12 cells. However, the attenuation of hyperglycemia by MS treatment in vivo remains uncertain. In the present study, both MS and pioglitazone significantly down-regulated blood glucose and hyperinsulinemia in fructose-rich diet (FRD)-induced C57BL/6 mice (8 weeks). In addition, inhibitions of inflammatory factor production, serum dyslipidemia, and hepatic fatty acid accumulation by MS and pioglitazone were attenuated by GW9662 (PPARγ antagonist). These results were mediated by MS-suppressing FRD-elevated lipogenic transcription factors, including sterol regulatory element-binding protein-1c (SREBP-1c), carbohydrate response element-binding protein (ChREBP), PPARγ coactivator-1α (PGC-1α), and PPARγ coactivator-1β (PGC-1β). Taken together, de novo lipogenesis results in hyperlipidemia and hyperglycemia by fructose induction thereby leading to diabetes development; we found that MS may inhibit lipogenesis in FRD-induced mice. These findings suggest that MS acts as an antidiabetic agent and thus may have therapeutic potential for prevention of diabetes.

Attenuation of experimentally induced diabetic neuropathy in association with reduced oxidative-nitrosative stress by chronic administration of &amp;lt;i&amp;gt;Momordica charantia&amp;lt;/i&amp;gt;

Momordica Charantia (MC) is one of the most famous traditional plant worldwide, used for the treatment of diabetes and its complications. In the present study possible protective effect of MC in Streptozotocin (STZ) induced diabetic neuropathy in mice was evaluated. STZ induced diabetic mice were orally administered MC at various doses (200 - 800 mg/kg) for six weeks. Diabetes induced neuropathic pain was assessed by hot plate test, formalin test and tail flick test at the beginning and end of the study. Serum TBARS, NO and SOD levels were estimated at the end of the study as the markers of oxidative-nitrosative stress. Rotarod test was employed to assess the effect of treatment on motor coordination. The results showed that STZ induced diabetes significantly decreased the pain threshold as was indicated by increased flinching in formalin test and decreased withdrawal latency in hot plate and tail flick tests. Oxidative-nitrosative stress was significantly increased in diabetic animals. Chronic administration of MC significantly attenuated diabetes induced increase in flinches and decrease in withdrawal latency without impacting sensory and motor functions. MC administration also exhibited dose dependant reduction of hyperglycemia and serum TBARS, NO and SOD levels in diabetic mice. The results suggest that long term use of MC protects against diabetes induced neuropathy in association with attenuation of hyperglycemia and oxidative-nitrosative stress.

PPARγ Agonist Pioglitazone Reverses Memory Impairment and Biochemical Changes in a Mouse Model of Type 2 Diabetes Mellitus

Pioglitazone, known as a peroxisome proliferator-activated receptor γ (PPARγ) agonist, is used to treat type 2 diabetes mellitus (T2DM). T2DM has been associated with reduced performance on numerous domains of cognitive function. Here, we investigated the effects of pioglitazone on memory impairment in a mouse model with defects in insulin sensitivity and secretion, namely high-fat diet (HFD) streptozotocin (STZ)-induced diabetic mice. ICR mice were fed with HFD for 4 weeks and then injected with a single low dose of STZ followed by continued HFD feeding for an additional 4 weeks. Pioglitazone (18 mg/kg, 9 mg/kg body weight) was orally administered for 6 weeks once daily. Y-maze test and Morris water maze test (MWM) were employed for testing learning and memory. Serum glucose, serum insulin, serum triglyceride, brain β-amyloid peptide (Aβ), brain β-site amyloid precursor protein cleaving enzyme (BACE1), brain nuclear factor κB (NF-κB), and brain receptor for advanced glycation end products (RAGE) were also tested. The STZ/HFD diabetic mice, characterized by hyperglycemia, hyperlipemia and hypoinsulinemia, performed poorly on Y-maze and MWM hence reflecting impairment of learning and memory behavior with increases of Aβ40/Aβ42, BACE1, NF-κB, and RAGE in brain. Treatment of PPARγ agonist, pioglitazone (18 or 9 mg/kg body weight), significantly reversed diabetes-induced impairment of learning and memory behavior, which is involved in decreases of Aβ40/Aβ42 via inhibition of NF-κB, BACE1 and RAGE in brain as well as attenuation of hyperglycemia, hyperlipemia, and hypoinsulinemia. It is concluded that PPARγ agonist pioglitazone may be considered as potential pharmacological agents for the management of cognitive dysfunction in T2DM.

La greffe de myoblastes dans le muscle squelettique améliore la tolérance au glucose dans un modèle de souris diabétique

Aims/hypothesis We aimed to demonstrate the feasibility and efficacy of intra-muscular transplantation of human skeletal myoblasts (hSkMs) for attenuation of hyperglycaemia and improvement of insulin sensitivity using a mouse model of type 2 diabetes mellitus.

Time Point Is Important for Effects of Syngeneic Bone Marrow Transplantation for Type 1 Diabetes in Mice

Objectives Autologous hematopoietic stem cell transplantation (HSCT) has recently become a novel therapy for patients with new-onset type 1 diabetes (T1D). However, the optimal time points for HSCT are still unknown. Methods By using multiple low-dose streptozotocin (STZ)-induced T1D mice models, we performed syngeneic bone marrow transplantation (syn-BMT) in diabetic mice at various time points new-onset day 3 ( n = 12); new-onset day 10 ( n = 13); later-onset day 20 ( n = 12); and day 40 ( n = 7), respectively. At 120 days after syn-BMT, we examined pancreata histology, serum insulin, and CD4 +CD25 +FoxP3 + T regulatory lymphocytes (Tregs). Results Our previous results showed that syn-BMT can overcome diabetes when performed on day 10, but not at day 40. Our new data showed BMT only attenuated diabetes when done on day 3 or day 20. Moreover, the percentage of Tregs in the spleen correlated with the attenuation of hyperglycemia. Significance These results indicated that syn-BMT should be performed, when diabetes is neither too new-onset nor too late-stage. Tregs represent one mechanism for syn-BMT-induced restoration of immune tolerance in STZ-diabetic mice.

The citrus fruit flavonoid naringenin suppresses hepatic glucose production from Fao hepatoma cells

Hepatic gluconeogenesis is the major source of fasting hyperglycemia. Here, we investigated the role of the citrus fruit flavonoid naringenin, in the attenuation of hepatic glucose production from hepatoma (Fao) cells. We show that naringenin, but not its glucoside naringin, suppresses hepatic glucose production. Furthermore, unlike insulin-mediated suppression of hepatic glucose production, incubation of hepatocytes with the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor Ly294002 had no effect on the ability of naringenin to suppress hepatic glucose production. Further, naringenin did not increase phosphorylation of Akt at Ser473 or, Thr308, indicating this down-stream target of PI3-kinase is also not a player in naringenin-mediated suppression of hepatic glucose production. Importantly, like the dimethylbiguanide, metformin, naringenin significantly decreased cellular ATP levels without increasing cell cytotoxicity. Together, these results suggest that the aglycone, naringenin, has a role in the attenuation of hyperglycemia and may exert this effect in a manner similar to the drug, metformin.

Attenuation of hyperglycemia and associated biochemical parameters in STZ-induced diabetic rats by dietary supplementation of potato peel powder

Background Both dietary fiber and polyphenols have been reported to exert antihyperglycemic effect. Potato peel (PP), a waste by product of potato processing, is found to be a good source of both dietary fiber and polyphenols. The current study examined the attenuating influence of dietary potato peel (PP) powder on hyperglycemia and various oxidative stress-associated biochemical parameters in diabetic rats. Methods Streptozotocin (STZ)-induced diabetic male Wistar rats were used as experimental models. The rats were divided into nondiabetic (control), diabetic, potato-peel-supplemented (5% and 10%) and diabetic-PP (5% and 10%)-supplemented groups and were maintained for 4 weeks on the experimental regime. The modulatory role of PP was assessed by determining its effect on blood glucose, urine output, body weight gain, lipid peroxidation, reduced glutathione, serum aminotransferases, lipid profiles, selected antioxidant enzymes in liver/kidney and selected eye lens parameters. Results Diabetic rats fed with PP-powder-supplemented diet for 4 weeks showed a significant decrease in blood glucose levels. Incorporation of PP powder reduced significantly the hypertrophy of both liver and kidney of STZ-diabetic rats and also normalized the activities of serum ALT and AST, hepatic and renal MDA and GSH, as well as activities of various antioxidant enzymes in liver and kidney of diabetic rats. Furthermore, PP powder in the diet also appeared to attenuate the eye lens damage associated with the diabetic condition. Conclusion Potato peel powder supplementation in diet was found to effectively attenuate diabetic alterations in rats.