Physicochemical Properties of the Soluble Dietary Fiber from Laminaria japonica and Its Role in the Regulation of Type 2 Diabetes Mice.

Laminaria japonica is a large marine brown alga that is annually highly productive. However, due to its underutilization, its potential value is substantially wasted. For example, a lot of Laminaria japonica cellulose remains unused during production of algin. The soluble dietary fiber (SDF) was prepared from the byproducts of Laminaria japonica, and its physicochemical properties were explored. SDF exhibits good water-holding, oil-holding, water-absorbing swelling, glucose and cholesterol absorption capacity, and inhibitory activity of α-amylase and α-glucosidase. In addition, the beneficial effects of SDF in diabetic mice include reduced body weight, lower blood glucose, and relieved insulin resistance. Finally, the intestinal flora and metabolomic products were analyzed from feces using 16S amplicon and LC-MS/MS, respectively. SDF not only significantly changed the composition and structure of intestinal flora and intestinal metabolites, but also significantly increased the abundance of beneficial bacteria Akkermansia, Odoribacter and Bacteroides, decreased the abundance of harmful bacteria Staphylococcus, and increased the content of bioactive substances in intestinal tract, such as harmine, magnolol, arachidonic acid, prostaglandin E2, urimorelin and azelaic acid. Taken together, these findings suggest that dietary intake of SDF alleviates type 2 diabetes mellitus disease, and provides an important theoretical basis for SDF to be used as a functional food.

The potential therapeutic effects of Trifolium alexandrinum extract, hesperetin and quercetin against diabetic nephropathy via attenuation of oxidative stress, inflammation, GSK-3ß and apoptosis in male rats.

Diabetic nephropathy (DN) is one of the manifestations of systemic microangiopathy in diabetes. Trifolium alexandrinum extract (TAE) contains biologically active phenolic compounds such as hesperetin (HES) and quercetin, possess various pharmacological properties, including anti-inflammatory, and anti-oxidative potentials. The present study aimed to assess the therapeutic effects and mechanisms underlying the anti-diabetic, antioxidant, and anti-inflammatory effects of HES and quercetin extracted from TAE, and TAE in STZ-induced DN. Male albino rats (170 ± 10 g) were divided into group (1); control rats and groups (2-5); diabetic/HFD were intraperitoneal (i.p.) injected with STZ (35 mg/kg), diabetic rats were randomly classified into STZ, STZ + HES (40 mg/kg), STZ + quercetin (50 mg/kg), and STZ + TAE (200 mg/kg) groups. After 5 weeks, blood and kidney samples were collected for further biochemical, western blotting and histopathological studies. Serum renal functions, renal oxidative status biomarkers and proinflammatory cytokines were determined. The results revealed that there were significant increases in urea, BUN, creatinine, ALP, total protein, albumin, and globulin with a significant decrease in Na+ and K+ levels, as well as significant elevation in TBARS, TGF-ß, TNF-α, IL-6 and the expression levels of GSK-3ß, as well as significant decline in TAC, GSH and CAT levels in STZ-treated group compared to the control rats. The previous deleterious alterations were significantly ameliorated after the treatment of diabetic rats with HES, quercetin and TAE. In conclusion, our data demonstrated that HES, quercetin and TAE could be used as potent therapeutic agents to counter DN through antioxidant, anti-inflammatory, and antidiabetic effects.

Glavonoid-rich oil supplementation reduces stearoyl-coenzyme A desaturase 1 expression and improves systemic metabolism in diabetic, obese KK-Ay mice.

AIMS: Glavonoid-rich oil (GRO) derived from ethanol extraction of licorice (Glycyrrhiza glabra Linne) root has been reported to have beneficial effects on health. In this study, we aimed to determine the effect of long-term administration of GRO on metabolic disorders and to elucidate the molecular mechanism. MAIN METHODS: Female obese, type 2 diabetic KK-Ay mice were fed diets supplemented with 0.3% or 0.8% GRO (w/w) for 4-12 weeks. Mice were euthanized and autopsied at 20 weeks old. The effects of GRO on lipid and glucose metabolism were evaluated by measuring physiological and biochemical markers using mRNA sequencing, quantitative reverse-transcription PCR, and western blot analyses. KEY FINDINGS: Compared to mice fed the control diet, GRO-supplemented mice had reduced body and white adipose tissue weights, serum levels of triglycerides and cholesterol, and improved glucose tolerance, while food intake was not affected. We found remarkable reductions in the gene expression levels of stearoyl-coenzyme A desaturase 1 (Scd1) and pyruvate dehydrogenase kinase isoenzyme 4 (Pdk4) in the liver, in addition to decreased expression of fatty acid synthase (Fasn) in inguinal white adipose tissue (iWAT). These results suggest that GRO supplementation improves lipid profiles via reduced de novo lipogenesis in the liver and white adipose tissue. Glucose metabolism may also be improved by increased glycolysis in the liver. SIGNIFICANCE: Our analysis of long-term supplementation of GRO in obese and diabetic mice should provide novel insight into preventing insulin resistance and metabolic syndromes.

Opuntia dillenii (Ker Gawl.) Haw., Seeds Oil Antidiabetic Potential Using In Vivo, In Vitro, In Situ, and Ex Vivo Approaches to Reveal Its Underlying Mechanism of Action.

Opuntia dillenii Ker Gawl. is one of the medicinal plants used for the prevention and treatment of diabetes mellitus (DM) in Morocco. This study aims to investigate the antihyperglycemic effect of Opuntia dillenii seed oil (ODSO), its mechanism of action, and any hypoglycemic risk and toxic effects. The antihyperglycemic effect was assessed using the OGTT test in normal and streptozotocin (STZ)-diabetic rats. The mechanisms of action were explored by studying the effect of ODSO on the intestinal absorption of d-glucose using the intestinal in situ single-pass perfusion technique. An Ussing chamber was used to explore the effects of ODSO on intestinal sodium-glucose cotransporter 1 (SGLT1). Additionally, ODSO's effect on carbohydrate degrading enzymes, pancreatic α-amylase, and intestinal α-glucosidase was evaluated in vitro and in vivo using STZ-diabetic rats. The acute toxicity test on mice was performed, along with a single-dose hypoglycemic effect test. The results showed that ODSO significantly attenuated the postprandial hyperglycemia in normal and STZ-diabetic rats. Indeed, ODSO significantly decreased the intestinal d-glucose absorption in situ. The ex vivo test (Ussing chamber) showed that the ODSO significantly blocks the SGLT1 (IC50 = 60.24 µg/mL). Moreover, ODSO indu\ced a significant inhibition of intestinal α-glucosidase (IC50 = 278 ± 0.01 µg/mL) and pancreatic α-amylase (IC50 = 0.81 ± 0.09 mg/mL) in vitro. A significant decrease of postprandial hyperglycemia was observed in sucrose/starch-loaded normal and STZ-diabetic ODSO-treated rats. On the other hand, ODSO had no risk of hypoglycemia on the basal glucose levels in normal rats. Therefore, no toxic effect was observed in ODSO-treated mice up to 7 mL/kg. The results of this study suggest that ODSO could be suitable as an antidiabetic functional food.

Dietary low ratio of n-6/n-3 polyunsaturated fatty acids improve type 2 diabetes mellitus via activating brown adipose tissue in male mice.

The ratio n-6/n-3 polyunsaturated fatty acids (PUFA) has been caused widespread discussion. However, the best ratio and mechanism of n-6/n-3 PUFA in type 2 diabetes mellitus (T2DM) are largely unknown. This study investigated the effects of different ratio of n-6/n-3 PUFA diets on brown adipose tissue (BAT) and T2DM in mice. Results showed that compared with high ratio of n-6/n-3 PUFA (50:1) diet, lower ratio of n-6/n-3 PUFA (1:1 and 5:1) diets significantly increased BAT mass by 67.55% and 60.49%, decreased the fasting blood glucose (24.87% and 20.64%), total cholesterol (32.9% and 23.84%), triglyceride (33.51% and 29.62%), low-density lipoprotein cholesterol (19.23% and 17.38%), and increased glucose tolerance by 21.99% and 15.52%. Further, qRT-PCR analyses indicated that lower ratio of n-6/n-3 PUFA diets activated BAT, increased the expression of Ucp1, ß-3AR, PPAR-γ, cAMP, GLU1, HSL, LPL, and PGC-1α, further improved lipid and glucose metabolism in T2DM mice. In conclusion, this study substantiated that the lower ratio of n-6/n-3 PUFA (1:1 and 5:1) improve symptoms associated with T2DM via activating BAT. PRACTICAL APPLICATION: Dietary ratio of n-6/n-3 polyunsaturated fatty acids is essential for the improvement of chronic diseases. Our current study showed that 1:1 or 5:1 ratio of n-6/n-3 polyunsaturated fatty acids had better efficiency for type 2 diabetes mellitus via activating brown adipose tissue when compared with 1:50. This finding provided useful guidance for the daily diet of patients with diabetes.

Oral administration of mangiferin ameliorates diabetes in animal models: a meta-analysis and systematic review.

Although mangiferin has a number of documented beneficial effects, there are no systematic reviews or meta-analyses of its effects in diabetic animal models. To investigate the effects of oral administration of mangiferin on blood glucose levels, body weight, and total cholesterol and triglycerides levels in diabetic animal models, a meta-analysis was conducted and the underlying mechanisms were reviewed. Studies from 6 databases (PubMed, Web of Science, Embase, Cochrane Library, and CNKI (China National Knowledge Infrastructure), and Wanfang Med) were searched from inception to April 2020. After article screening, a total of 19 articles were included in this meta-analysis. The meta-analysis was performed using RevMan 5.3 and STATA 14.0 software. The overall pooled estimate of standardized mean difference (SMD) of mangiferin's effect on blood glucose was -1.27 (95% confidence interval [CI]: -1.71, -0.82, P < .00001). Body weight increased in lean diabetic animals with an SMD of 1.41 (95% CI: 0.57, 2.25; P = .001), while it decreased in obese diabetic animals with an SMD of -0.92 (95% CI: -1.69, -0.14; P = .02). Mangiferin intake reduced serum total cholesterol and triglycerides levels with SMDs of -1.02 (95% CI: -1.43, -0.61; P < .001) and -1.24 (95% CI: -1.70, -0.79; P < .001), respectively. The meta-analysis suggests that oral intake of mangiferin has a significant antidiabetic effect in animal models, and the systematic review suggested that this function might be attributed to its anti-inflammatory and antioxidative properties, as well as to its function of improving glycolipid metabolism and enhancing insulin signaling.

Transcriptomic analysis links diverse hypothalamic cell types to fibroblast growth factor 1-induced sustained diabetes remission.

In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the mediobasal hypothalamus (MBH) was recently implicated as the brain area responsible for this effect. To better understand the cellular response to FGF1 in the MBH, we sequenced >79,000 single-cell transcriptomes from the hypothalamus of diabetic Lepob/ob mice obtained on Days 1 and 5 after icv injection of either FGF1 or vehicle. A wide range of transcriptional responses to FGF1 was observed across diverse hypothalamic cell types, with glial cell types responding much more robustly than neurons at both time points. Tanycytes and ependymal cells were the most FGF1-responsive cell type at Day 1, but astrocytes and oligodendrocyte lineage cells subsequently became more responsive. Based on histochemical and ultrastructural evidence of enhanced cell-cell interactions between astrocytes and Agrp neurons (key components of the melanocortin system), we performed a series of studies showing that intact melanocortin signaling is required for the sustained antidiabetic action of FGF1. These data collectively suggest that hypothalamic glial cells are leading targets for the effects of FGF1 and that sustained diabetes remission is dependent on intact melanocortin signaling.

Effects of Different n6/n3 PUFAs Dietary Ratio on Cardiac Diabetic Neuropathy.

We studied the influence of experimentally induced DM1, in combination with different dietary n6:n3 polyunsaturated fatty acid (PUFA) ratios on different types of nerve fibers in rat myocardium, in order to reveal whether protective/unfavorable effects of different PUFAs on myocardial function in diabetic patients could be a (partial) repercussion of their effect on the changes in cardiac innervation. The control group (c) and diabetic group (stz) were fed with an n6/n3 ratio of ≈7; the diet of the stz+n6 group had an n6/n3 ratio ≈60, while the diet for the stz+DHA group contained 2.5% of fish oil (containing 16% eicosapentaenoic acid-EPA and 19% docosahexaenoic acid-DHA), n6/n3 ratio of ≈1. DM1 was induced by i.p. injection of streptozotocin (55 mg/kg) and rats were euthanized 30 days after induction. Immunohistochemistry was used for the detection and quantification of different types of neuronal fibers in the cardiac septum. We found changes in cardiac innervations characteristics for the initial phase of experimental DM1, which manifested as an increase in total number and area density of all neuronal fibers, measured by Pgp9.5 immunoreactivity. By detailed analysis, we found that this increase consisted mostly of heavy myelinated NF200 immunoreactive fibers and TH immunoreactive sympathetic fibers, while the density of ChAT immunoreactive parasympathetic fibers decreased. In the deep (middle) part of the myocardium, where rare fibers (of all studied types) were found, significant differences were not found. Surprisingly, we found a more consistent protective effect of n6 PUFAs, in comparison to n3 PUFAs supplementation. These results may provide a better understanding of the potential impacts of different PUFA ratios in the diet of diabetic patients on cardiac innervation and genesis and outcome of diabetic autonomic cardiomyopathy.

Anti-Diabetic Obesity Effects of Wasabia Japonica Matsum Leaf Extract on 45% Kcal High-Fat Diet-Fed Mice.

The present study examined the effects of Wasabi leaf (WL) on 45% Kcal high-fat diet (HFD)-fed mild diabetic obese mice. In particular, the hepatoprotective (i.e., liver weight, histopathology of liver, serum aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyltransferase) effects of 12 weeks of continuous oral administration of 250 mg/kg metformin, and 200, 100, or 50 mg/kg WL were investigated. In addition, the hypolipidemic (i.e., serum triglyceride, total cholesterol, high-density lipoprotein-cholesterol, and low-density lipoprotein levels), hypoglycemic (i.e., glycated hemoglobin, blood glucose and insulin levels, pancreatic weight, and immunohistochemical-histopathological analysis of the pancreas), and anti-obesity effects (i.e., body weight, mean food consumption, total and abdominal body fat mass, periovarian fat weight, and histopathology of the periovarian and abdominal wall adipocytes) were monitored. The liver and general antioxidant defense systems were also assessed by lipid metabolism-related gene expression. All diabetes manifestations and related complications, including obesity and non-alcoholic fatty liver disease (NAFLD), were dose-dependently reduced after 84 days of oral treatment with metformin or each of the three dosages of WL. In particular, 50 mg/kg WL showed effective suppression effects against HFD-induced diabetes and related complications of obesity, NAFLD, and hyperlipidemia, comparable to the effects of metformin.

Effects of Anthocyanin Extracts from Bilberry (Vaccinium myrtillus L.) and Purple Potato (Solanum tuberosum L. var. 'Synkeä Sakari') on the Plasma Metabolomic Profile of Zucker Diabetic Fatty Rats.

This study compared the effects of the nonacylated and acylated anthocyanin-rich extracts on plasma metabolic profiles of Zucker diabetic fatty rats. The rats were fed with the nonacylated anthocyanin extract from bilberries (NAAB) or the acylated anthocyanin extract from purple potatoes (AAPP) at daily doses of 25 and 50 mg/kg body weight for 8 weeks. 1H NMR metabolomics was used to study the changes in plasma metabolites. A reduced fasting plasma glucose level was seen in all anthocyanin-fed groups, especially in the groups fed with NAAB. Both NAAB and AAPP decreased the levels of branched-chain amino acids and improved lipid profiles. AAPP increased the glutamine/glutamate ratio and decreased the levels of glycerol and metabolites involved in glycolysis, suggesting improved insulin sensitivity, gluconeogenesis, and glycolysis. AAPP decreased the hepatic TBC1D1 and G6PC messenger RNA level, suggesting regulation of gluconeogenesis and lipogenesis. This study indicated that AAPP and NAAB affected the plasma metabolic profile of diabetic rats differently.

Effect of γ-aminobutyric acid-rich yogurt on insulin sensitivity in a mouse model of type 2 diabetes mellitus.

This study aimed to investigate the effect of a γ-aminobutyric acid (GABA)-rich yogurt fermented with Streptococcus thermophilus fmb-5 on insulin sensitivity in high-fat and low-dose streptozotocin-induced type 2 diabetes mellitus mice. To study the ability of the yogurt to enhance insulin sensitivity, diabetic mice were treated with 0.5, 1, or 2 g/L of GABA yogurt once a day from wk 1 to 12. Compared with results in untreated diabetic mice, treatment with different dosages of GABA yogurt was associated with increased serum insulin and fat coefficient (fat weight relative to body weight) levels, decreased blood urea nitrogen, kidney coefficient (kidney weight relative to body weight), glucose area under the curve levels, and insulin sensitivity index, but did not alter blood glucose level or body weight. The highest dosage of GABA yogurt had a greater beneficial effect with respect to insulin resistance than the lower dosages. In particular, dietary supplementation of the high dosage of GABA yogurt favorably regulated HOMA-ß (homeostasis model assessment of ß-cell function), total cholesterol, high-density lipoprotein cholesterol, fat coefficient, and improved islet cells morphology. These results demonstrated that 2 g/L GABA yogurt could ameliorate insulin sensitivity. The GABA-rich yogurts appeared to be responsible for health-beneficial effects in this mouse model of diabetes.

Lactobacillus plantarum And Inulin: Therapeutic Agents to Enhance Cardiac Ob Receptor Expression and Suppress Cardiac Apoptosis in Type 2 Diabetic Rats.

BACKGROUND: T2DM may cause increased levels of oxidative stress and cardiac apoptosis through elevated blood glucose. The present study investigated the effects of Lactobacillus plantarum (L. plantarum) as a probiotic strain and inulin as a prebiotic supplement on cardiac oxidative stress and apoptotic markers in type 2 diabetes mellitus (T2DM) rats. METHODS: A high-fat diet and a low dose of streptozotocin were used to induce type 2 diabetes. The rats were divided into six groups which were supplemented with L. plantarum, inulin, or their combination for 8 weeks. RESULTS: The results showed improved activity of cardiac antioxidant parameters including total antioxidant capacity (TAC), superoxide dismutase (SOD), and glutathione peroxidase (GPx) (P < 0.001, P < 0.01, and P < 0.01, respectively) and decreased level of cardiac malondialdehyde (MDA) concentration (P < 0.05). These changes were accompanied with increased protein expression of cardiac obesity receptor (Ob-R) (P = 0.05) and reduced apoptotic markers such as tumor necrosis factor-alpha (TNF-α), Fas ligand (FasL), and caspase proteins (P < 0.001, P = 0.003, and P < 0.01, respectively) in T2DM rats after concurrent L. plantarum and inulin supplementation. Moreover, a remarkable correlation of cardiac Ob-R and oxidative stress parameters with cardiac apoptotic markers was observed (P < 0.01). CONCLUSION: The concurrent use of L. plantarum and inulin seems to be beneficial, as they can lead to decreased heart complications of T2DM via reducing cardiac apoptotic markers.

Addition of olive oil to diet of rats with mild pre-gestational diabetes impacts offspring ß-cell development.

Maternal diabetes impairs fetal development and increases the risk of metabolic diseases in the offspring. Previously, we demonstrated that maternal dietary supplementation with 6% of olive oil prevents diabetes-induced embryo and fetal defects, in part, through the activation of peroxisome proliferator-activated receptors (PPARs). In this study, we examined the effects of this diet on neonatal and adult pancreatic development in male and female offspring of mothers affected with pre-gestational diabetes. A mild diabetic model was developed by injecting neonatal rats with streptozotocin (90 mg/kg). During pregnancy, these dams were fed a chow diet supplemented or not with 6% olive oil. Offspring pancreata was examined at day 2 and 5 months of age by immunohistochemistry followed by morphometric analysis to determine number of islets, α and ß cell clusters and ß-cell mass. At 5 months, male offspring of diabetic mothers had reduced ß-cell mass that was prevented by maternal supplementation with olive oil. PPARα and PPARγ were localized mainly in α cells and PPARß/δ in both α and ß cells. Although Pparß/δ and Pparγ RNA expression showed reduction in 5-month-old male offspring of diabetic rats, Pparß/δ expression returned to control levels after olive-oil supplementation. Interestingly, in vitro exposure to oleic acid (major component of olive oil) and natural PPAR agonists such as LTB4, CPC and 15dPGJ2 also significantly increased expression of all Ppars in αTC1-6 cells. However, only oleic acid and 15dPGJ2 increased insulin and Pdx-1 expression in INS-1E cells suggesting a protective role in ß-cells. Olive oil may be considered a dietary supplement to improve islet function in offspring of affected mothers with pre-gestational diabetes.

Olive oil supplementation prevents extracellular matrix deposition and reduces prooxidant markers and apoptosis in the offspring´s heart of diabetic rats.

Maternal diabetes induces fetal programming of cardiovascular diseases. Diabetes induced-cardiac fibrosis is a process that may start in utero and may be related to the prooxidant/proinflammatory environment. The aim of this study was to investigate the effect of a maternal diet enriched in olive oil on the levels of components and regulators of the extracellular matrix, on prooxidant markers and on apoptosis rate in the heart of 21-day-old offspring of diabetic rats. Maternal diabetes was induced by neonatal administration of streptozotocin. During pregnancy, diabetic and control rats were fed with diets supplemented or not with 6% olive oil. The heart of the offspring was studied at 21 days of age. We found increased deposition of collagen IV and fibronectin in the offspring´s heart of diabetic rats, which was prevented by the maternal diets enriched in olive oil. Increases in connective tissue growth factor were also prevented by the maternal diets enriched in olive oil. Prooxidant markers as well as apoptosis, which were increased in the heart of the offspring of diabetic rats, were prevented by the maternal olive oil dietary treatment. Our findings identified powerful effects of a maternal diet enriched in olive oil on the prevention of increased extracellular matrix deposition and increased prooxidant markers in the heart of 21-day-old offspring of diabetic rats.

Effect on Adipose Tissue of Diabetic Mice Supplemented with n-3 Fatty Acids Extracted from Microalgae.

BACKGROUND: Type 2 Diabetes Mellitus (T2DM) is considered a chronic noncommunicable disease in which oxidative stress is expected as a result of hyperglycaemia. One of the most recent approaches is the study of microalgae fatty acids and their possible antioxidant effect. OBJECTIVE: This study aimed to analyse the effect of supplementation with n-3 fatty acids extracted from microalgae on the total antioxidant capacity (TAC) and lipid peroxidation of adipose tissue and plasma from diabetic (db/db) and healthy (CD1) mice. METHODS: Mice were supplemented with lyophilized n-3 fatty acids extracted from microalgae or added to the diet, from week 8 to 16. TAC assay and Thiobarbituric Acid Reactive Substances assay (TBARS) were performed on adipose tissue and plasma samples. RESULTS: The supplementation of lyophilized n-3 fatty acids from microalgae increased the total antioxidant capacity in adipose tissue of diabetic mice (615.67µM Trolox equivalents vs 405.02µM Trolox equivalents from control mice, p<0.01) and in the plasma of healthy mice (1132.97±85.75µM Trolox equivalents vs 930.64±32µM Trolox equivalents from modified diet mice, p<0.01). There was no significant effect on lipid peroxidation on both strains. CONCLUSION: The use of n-3 fatty acids extracted from microalgae could be a useful strategy to improve total antioxidant capacity in T2DM.

Eicosapentaenoic acid prevents salt sensitivity in diabetic rats and decreases oxidative stress.

OBJECTIVES: Salt sensitivity (SS) is associated with increased cardiovascular risk in patients with Type 2 diabetes mellitus (T2-DM) due to an increase in renal oxidation. ω-3 polyunsaturated fatty acids have shown antioxidant effects, but a typical Western diet contains limited content. In particular, ω-3 polyunsaturated fatty acids are able to activate nuclear factor erythroid 2-related factor 2 (Nrf-2) to prevent diabetes mellitus-related complications by mitigating oxidative stress. Therefore, we hypothesized that eicosapentaenoic acid (EPA; ω-3) modulates SS in rats with T2-DM by decreasing renal oxidative stress via Nrf-2 activation and enhancing the antiinflammatory response via interleukin (IL) 6 modulation. METHODS: Three-month-old male rats (n = 40) were fed with a Normal Na-diet (NNaD) and randomly selected into four groups: Healthy Wistar nondiabetic rats (Wi), diabetic controls (eSS), arachidonic acid-treated eSS (AA; ω-6), and EPA-treated eSS (ω-3). After 1 year, rats were placed in metabolic cages for 7 d and fed a NNaD, followed by a 7-d period with a High Na-diet (HNaD). Systolic blood pressure, body weight, serum IL-6 and reactive oxygen species (ROS) levels were determined at the end of each 7-d period. Glycated hemoglobin (HbA1c), triacylglycerol, creatinine, and cholesterol levels were determined. ROS levels and Nrf-2 expression in kidney lysates were also assayed. Histologic changes were evaluated. A t test or analysis of variance was used for the statistical analysis. RESULTS: After a HNaD, systolic blood pressure increased in both the control eSS and AA groups, but not in the EPA and Wi groups. However, HbA1c levels remained unchanged by the treatments, which suggests that the observed beneficial effect was independent of HbA1c levels. The IL-6 levels were higher in the eSS and AA groups, but remained unaltered in EPA and Wi rats after a HNaD diet. Interestingly, EPA protected against serum ROS in rats fed the HNaD, whereas AA did not. In kidney lysates, ROS decreased significantly in the EPA group compared with the eSS group, and Nrf-2 expression was consistently higher compared with the AA and eSS groups. Diabetic rats presented focal segmental sclerosis, adherence to Bowman capsule, and mild-to-moderate interstitial fibrosis. EPA and AA treatment prevented kidney damage. CONCLUSIONS: An adequate ω3-to-ω6 ratio prevents SS in diabetic rats by a mechanism that is independent of glucose metabolism but associated with the prevention of renal oxidative stress generation. These data suggest that EPA antioxidant properties may prevent the development of hypertension or kidney damage.

Maternal diets enriched in olive oil regulate lipid metabolism and levels of PPARs and their coactivators in the fetal liver in a rat model of gestational diabetes mellitus.

In a rat model of gestational diabetes mellitus (GDM) programmed in the offspring of neonatal streptozotocin-induced (nSTZ) diabetic rats, lipids are accumulated in the fetal liver in a sex-dependent way. Here, we evaluated whether maternal diets enriched in olive oil in rats that will develop GDM ameliorate lipid metabolic impairments in the fetal livers. Pregnant offspring of control and nSTZ diabetic rats (F0) were fed a 6% olive oil-supplemented diet throughout the F1 gestation. We evaluated maternal metabolic parameters as well as lipid content, expression of lipid metabolizing enzymes and protein expression of PLIN2, PPARs and PPAR coactivators in the fetal livers. The offspring of nSTZ diabetic rats developed GDM regardless of the maternal treatment. Hypertriglyceridemia in GDM rats was prevented by the olive oil-enriched maternal treatment. In the livers of male fetuses of GDM rats, the maternal olive oil-supplemented diet prevented lipid overaccumulation and prevented the increase in PPARγ and PPARδ levels. In the livers of female fetuses of GDM rats, the maternal olive oil supplementation prevented the increase in PPARδ levels and the reduction in PGC1α levels, but did not prevent the reduced lipid content. Control and GDM rats showed a reduction of lipid metabolic enzymes in the fetal livers, which was associated with reduced levels of the PPAR coactivators PGC-1α and SRC-1 in males and of SRC-1 in females. These results suggest powerful effects of a maternal olive oil-supplemented diet in the fetal liver, possibly providing benefits in the fetuses and offspring from GDM rats.

Dietary zinc restriction promotes degeneration of the endocrine pancreas in mice.

Zinc is a key component of several proteins, interacting with the pancreatic hormones insulin and amylin. The role of zinc in insulin oligomerization and crystallinity is well established, although the effects of dietary zinc restriction on both energetic metabolism and ß-pancreatic hormonemia and morphology remain unexplored. Here we report the effects of dietary zinc restriction on the endocrine pancreas and metabolic phenotype of mice. Nontransgenic male Swiss mice were fed a low-zinc or control diet for 4 weeks after weanling. Growth, glycemia, insulinemia and amylinemia were lower and pancreatic islets were smaller in the intervention group despite the preserved insulin crystallinity in secretory granules. We found strong immunostaining for insulin, amylin and oligomers in apoptotic pancreatic islet. High production of ß-pancreatic hormones in zinc-restricted animals counteracted the reduced islet size caused by apoptosis. These data suggest that zinc deficiency is sufficient to promote islet ß-cell hormonal disruption and degeneration.

Comparison of the hypoglycemic and antithrombotic (anticoagulant) actions of whole bovine and camel milk in streptozotocin-induced diabetes mellitus in rats.

People with diabetes are at higher risk of fatal thromboembolic accidents in the cerebral and coronary circulations, especially stroke and ischemic heart disease. We have previously described the hypoglycemic, hypolipidemic, and anticoagulant activity of orally administered camel milk in streptozotocin-induced diabetic rats. In the present study in the same animal model, we extended these observations by comparing camel milk and the more available and widely consumed bovine milk with respect to their antidiabetic and antithrombotic actions. Rats were rendered diabetic by intraperitoneal streptozotocin (65 mg/kg), and then camel milk or bovine milk was administered orally for 8 wk. We evaluated the changes in body weight, fasting blood glucose, glucose tolerance, blood coagulation profile, and platelet function. Diabetic rats developed weight loss, hyperglycemia, glucose intolerance, inhibition of platelet aggregation responses to arachidonic acid and adenosine diphosphate, a marked decrease (>50%) in plasma fibrinogen levels, and short activated partial thromboplastin time. Treatment with camel milk or bovine milk reversed these abnormalities, resulting in weight gain, decreased blood glucose levels, and improved glucose tolerance. Despite the more remarkable antidiabetic action of camel milk, treatment with bovine milk was more effective in correcting plasma fibrinogen levels and restoring inhibited platelet aggregation responses. Long-term administration of camel milk or bovine milk counteracted streptozotocin-induced metabolic manifestations in rats, maintained platelet function, and abolished coagulopathy-associated fibrinogen consumption. Notably, the antidiabetic effect of camel milk was more pronounced than that of bovine milk, but bovine milk exhibited more potent anticoagulant activity than camel milk. These findings should encourage further clinical trials to assess the efficiency of camel milk and bovine milk or their derived peptides as food supplements or potential nonpharmacological therapies for dysglycemia and the vascular complications of diabetes mellitus.

Beneficial treatment effects of dietary nitrate supplementation on testicular injury in streptozotocin-induced diabetic male rats.

RESEARCH QUESTION: Do low doses of dietary nitrate help to attenuate the progression of diabetic reproductive disorders in streptozotocin-induced diabetic male rats? DESIGN: Fifty male Wistar rats were divided into five groups: controls receiving distilled water; controls receiving 100 mg/l nitrate in distilled water; diabetic rats receiving distilled water; diabetic rats receiving insulin 2-4 U/day of neutral protamine hagedorn insulin; and diabetic rats receiving 100 mg/l nitrate in distilled water. Diabetes was induced by 45 mg/kg streptozotocin. Nitrate and insulin treatment were started 4 weeks after diabetes induction for 8 weeks. Serum insulin, nitrogen oxide, stereology of testis, apoptosis, sperm parameters, and mRNA expression of Pdcd4, Pacs2, p53 and miR-449a were assessed at the end of the study. RESULTS: Blood glucose, apoptotic index of seminiferous tubules and expression of p53, Pdcd4, and Pacs2 mRNA were significantly higher in the diabetic rats (P < 0.001). Decreased body weight, serum insulin and nitrogen oxide level, and miR-449a were observed in the diabetic group (P < 0.01 for insulin; P < 0.001 for others). Most sperm parameters and stereological results differed between diabetic and control rats; nitrate recovered almost all these alterations, including dead spermatozoa, sperm motility grade, sperm deformity index, spermatozoa with damaged DNA, malformations in abnormal spermatozoa, total volume of seminiferous tubule, germinal epithelium, capsule, lumen, interstitial tissue, seminiferous tubule diameter, germinal epithelium height, the number of spermatogenic, Sertoli and Leydig cells. CONCLUSIONS: Treatment with sodium nitrate could modulate apoptosis, which is a major cause of diabetic testicular disorder. These experiments suggest that nitric oxide plays an important role in the function of the reproductive system.