Decreased Fasting Blood Glucose Research Articles

Investigation of anti-diabetic effect of a novel coenzyme Q10 derivative.

Introduction: The rising incidence of type 2 diabetes has seriously affected international public health. The search for more drugs that can effectively treat diabetes has become a cutting-edge trend in research. Coenzyme Q10 (CoQ10) has attracted much attention in the last decade due to its wide range of biological activities. Many researchers have explored the clinical effects of CoQ10 in patients with type 2 diabetes. However, CoQ10 has low bio-availability due to its high lipophilicity. Therefore, we have structurally optimized CoQ10 in an attempt to exploit the potential of its pharmacological activity. Methods: A novel coenzyme Q10 derivative (L-50) was designed and synthesized by introducing a group containing bromine atom and hydroxyl at the terminal of coenzyme Q10 (CoQ10), and the antidiabetic effect of L-50 was investigated by cellular assays and animal experiments. Results: Cytotoxicity results showed that L-50 was comparatively low toxicity to HepG2 cells. Hypoglycemic assays indicated that L-50 could increase glucose uptake in IR-HepG2 cells, with significantly enhanced hypoglycemic capacity compared to the CoQ10. In addition, L-50 improved cellular utilization of glucose through reduction of reactive oxygen species (ROS) accumulated in insulin-resistant HepG2 cells (IR-HepG2) and regulation of JNK/AKT/GSK3β signaling pathway, resulting in hypoglycemic effects. Furthermore, the animal experiments demonstrated that L-50 could restore the body weight of HFD/STZ mice. Notably, the findings suggested that L-50 could improve glycemic and lipid metabolism in HFD/STZ mice. Moreover, L-50 could increase fasting insulin levels (FINS) in HFD/STZ mice, leading to a decrease in fasting blood glucose (FBG) and hepatic glycogen. Furthermore, L-50 could recover triglycerides (TG), total cholesterol (T-CHO), lipoprotein (LDL-C) and high-density lipoprotein (HDL-C) levels in HFD/STZ mice. Discussion: The addition of a bromine atom and a hydroxyl group to CoQ10 could enhance its anti-diabetic activity. It is anticipated that L-50 could be a promising new agent for T2DM.

Omega-3 fatty acids supplementation improves early-stage diabetic nephropathy and subclinical atherosclerosis in pediatric patients with type 1 diabetes: A randomized controlled trial

Numerous studies have evaluated the beneficial effects of omega-3 fatty acids on inflammatory, autoimmune and renal diseases. However, data about the effects of omega-3 fatty acids on diabetic kidney disease in type 1 diabetes mellitus (T1DM) are lacking. This randomized-controlled trial assessed the effect of oral omega-3 supplementation on glycemic control, lipid profile, albuminuria level, kidney injury molecule-1 (KIM-1) and carotid intima media thickness (CIMT) in pediatric patients with T1DM and diabetic nephropathy. Seventy T1DM patients and diabetic nephropathy were enrolled with a mean age 15.2±1.96 years and median disease duration 7 years. Patients were randomly assigned into two groups; intervention group which received oral omega-3 fatty acids capsules (1g daily). The other group received a matching placebo and served as a control group. Both groups were followed-up for 6 months with assessment of fasting blood glucose (FBG), HbA1c, fasting lipids, urinary albumin creatinine ratio (UACR), KIM-1 and CIMT. After 6 months, omega-3 fatty acids adjuvant therapy for the intervention group resulted in a significant decrease in FBG, HbA1c, triglycerides, total cholesterol, LDL-cholesterol, UACR, KIM-1 and CIMT, whereas, HDL-cholesterol was significantly higher post-therapy compared with baseline levels and compared with the control group (p<0.05). Baseline KIM-1 levels were positively correlated to HbA1c, UACR and CIMT. Supplementation with omega-3 fatty acids was safe and well-tolerated. Omega-3 fatty acids as an adjuvant therapy in pediatric T1DM patients with diabetic nephropathy improved glycemic control, dyslipidemia and delayed disease progression and subclinical atherosclerosis among those patients. This trial was registered under ClinicalTrials.gov Identifier no. NCT05980026.

The effect of lyophilized dried cornelian cherry (Cornus mas L.) intake on anthropometric and biochemical parameters in women with insulin resistance: A randomized controlled trial.

The aim of this study was to determine the effect on the anthropometric and biochemical parameters for women with insulin resistance when lyophilized dried cornelian cherry (Cornus mas L., CM) was added to medical nutrition therapy (MNT). The study was conducted with 84 women aged 18-45, who had been diagnosed with insulin resistance. Participants were randomized into four groups: MNT + 20 g lyophilized dried CM group (DCm, n = 22), MNT group (D, n = 21), only 20 g lyophilized dried CM group (Cm, n = 21), and the control group (C, n = 20). All participants were followed for 12 weeks. While pre- and post-intervention biochemical parameters were recorded from patient files, anthropometric measurements and food consumption records were takenevery 15 days. Pre-intervention groups were homogeneously distributed. Post-intervention, among the groups, all anthropometric measurements were similar between the DCm and D, while the percentage of decrease in insulin resistance-related parameters was approximately two times greater in DCm than in D (p < .05). When the Cm and C were compared, it was found that all post-intervention anthropometric measurements were similar, but the percentage of decrease in fasting blood glucose, fasting insulin, and HOMA-IR (Homeostasis Model Assessment-Insulin Resistance) values were greater in C (p < .05). In this study, it was concluded that CM consumption resulted with a decrease in insulin resistance-related biochemical parameters independent of body weight change. Nevertheless, MNT has positive effects on women with insulin resistance, and adding lyophilized dried CM to MNT improves insulin resistance-related parameters and may be beneficial for preventing the development of diabetes.

Transcriptomics Reveals the Mechanism of Rosa roxburghii Tratt Ellagitannin in Improving Hepatic Lipid Metabolism Disorder in db/db Mice.

A complex metabolic disorder, type 2 diabetes, was investigated to explore the impact of ellagitannin, derived from Rosa roxburghii Tratt (RTT), on liver lipid metabolism disorders in db/db mice. The findings demonstrated that both RTT ellagitannin (C1) and RTT ellagic acid (C4) considerably decelerated body mass gain in db/db mice, significantly decreased fasting blood glucose (FBG) levels, and mitigated the aggregation of hepatic lipid droplets. At LDL-C levels, C1 performed substantially better than the C4 group, exhibiting no significant difference compared to the P (positive control) group. An RNA-seq analysis further disclosed that 1245 differentially expressed genes were identified in the livers of experimental mice following the C1 intervention. The GO and KEGG enrichment analysis revealed that, under ellagitannin intervention, numerous differentially expressed genes were significantly enriched in fatty acid metabolic processes, the PPAR signaling pathway, fatty acid degradation, fatty acid synthesis, and other lipid metabolism-related pathways. The qRT-PCR and Western blot analysis results indicated that RTT ellagitannin notably upregulated the gene and protein expression levels of peroxisome proliferator-activated receptor alpha (PPARα) and peroxisome proliferator-activated receptor gamma (PPARγ). In contrast, it downregulated the gene and protein expression levels of sterol regulatory element-binding protein (SREBP), recombinant fatty acid synthase (FASN), and acetyl-CoA carboxylase (ACC). Therefore, RTT ellagitannin can activate the PPAR signaling pathway, inhibit fatty acid uptake and de novo synthesis, and ameliorate hepatic lipid metabolism disorder in db/db mice, thus potentially aiding in maintaining lipid homeostasis in type 2 diabetes.

A-047 Role of the Gut Microbiota in the Efficacy of Dietary Intervention With Flavonoid-Containing Foods in Obesity

Abstract Background Flavonoids are an active component of plant-based diets that have been investigated for their beneficial antioxidant properties in high fat diet induced obesity animal models and human intervention trials. Certain bacterial members of the gut microbiota have been reported that transform flavonoids into monophenolic acids. Our goal is to characterize the microbiome link between a flavonoid-rich diet and improved metabolic parameters characteristic of obesity. We hypothesize that flavonoid supplemented diets are most effective in presence of microbiota capable of monophenolic acids formation, and that these bacterial metabolites are a main bioactive compound responsible for the improved metabolic parameters. Methods To test our hypothesis, males and females C57BL/6 mice were fed a high fat control diet, or the same diet supplemented with 1% berry extract, or 1% monophenolic acid for 12 weeks. Separate experimental groups received either regular drinking water or antibiotic water to suppress their gut microbial community. We monitored metabolic parameters, including body weight, lean and fat mass, glucose and insulin tolerance, histological assessment of liver cell, quantification of liver injury biomarkers, and transcriptional changes in metabolically active peripheral tissues. Results For insulin tolerance test, mice on high fat diet with regular water, or antibiotic water control mice had a comparable increase in insulin resistance, demonstrated by the increase in glucose levels after injecting insulin. Similarly, the groups of mice on high fat diet with 1% monophenolic acid and regular water, or antibiotic water, had improved insulin sensitivity, presented as a decrease in glucose levels after insulin injection. Consistent with our hypothesis, mice on high fat diet supplemented with 1% berry extract had an improved insulin sensitivity, and this effect was dependent on an intact microbiome. This suggests that the gut microbiota are required to metabolize the berry extract to produce bioactive metabolites that improve insulin tolerance. We also observed a significant decrease in fasting blood glucose, an improvement in the expression for genes involved in lipid and glucose metabolism, and a noticeable reduction in hepatic steatosis in both 1% monophenolic acid and 1% berry extract with high fat diet group, compared to the high fat diet control group. Conclusion By feeding the mice a flavonoid rich diet, with the presence of an intact gut microbiota, we can improve the metabolic parameters associated with metabolic diseases. Our work will open the door for new benign approaches for treatment, such as dietary flavonoid supplementation with concomitant gut microbial probiotic therapy.

Black mulberry extract inhibits hepatic adipogenesis through AMPK/mTOR signaling pathway in T2DM mice

Ethnopharmacological relevanceBlack mulberry (Morus nigra L.) is an ancient dual-use plant resource for medicine and food. It is widely used in Uyghur folklore for hypoglycemic treatment and is a folkloric plant medicine with regional characteristics. However, the mechanism of Morus nigra L. treatment in diabetes mellitus has not been fully understood, especially from the perspective of hepatic lipid accumulation is less reported. Objective of this studyThis study was to explore the potential of Morus nigra L. fruit ethyl acetate extract (MNF-EA) to reduce blood sugar levels by preventing the production of hepatic lipogenesis and to provide more evidence for the use of MNF-EA as an adjuvant therapy for type 2 diabetes mellitus (T2DM). Materials and methodsIn this study, the chemical composition of MNF-EA was first analyzed and characterized using UPLC-Q-TOF-MS technique. A series of in vitro studies were performed with HepG2-IR cells and oleic acid (OA)-induced HepG2 cells, including MTT assay, glucose uptake assay, oil red O staining and Western blot analysis. The STZ-HFD co-induced T2DM mice were employed for in vivo research, including physical indices, biochemical analysis, histopathological examination, and Western blot analysis. ResultsThe 19 compounds in MNF-EA were identified by UPLC-Q-TOF-MS technique. Insulin resistance (IR) and lipid droplet accumulation in HepG2 cells were greatly improved by MNF-EA treatment, which had no appreciable side effects at the dosage used. In T2DM mice, MNF-EA decreased fasting blood glucose (FBG), saved body weight, and significantly improved oral glucose tolerance (OGTT) and IR status. In addition, MNF-EA treatment also improved lipid metabolism disorders and liver function in T2DM mice. Histopathological sections showed that MNF-EA treatment reduced hepatic steatosis. Mechanistic studies suggest that MNF-EA acted through the AMPK/mTOR pathway. ConclusionsThese results suggest that MNF-EA has great potential to reverse the metabolic abnormalities associated with T2DM by regulating the AMPK/mTOR signaling pathway. Therefore, we believe that MNF is a promising medicinal and food-homologous agent to improve T2DM.

Preparation of Nanoemulsions with Low-Molecular-Weight Collagen Peptides from Sturgeon Fish Skin and Evaluation of Anti-Diabetic and Wound-Healing Effects in Mice.

This study aims to isolate collagen peptides from waste sturgeon fish skin, and prepare nanoemulsions for studying their anti-diabetic and wound-healing effects in mice. Collagen peptides were extracted and purified by acetic acid with sonication, followed by two-stage hydrolysis with 0.1% pepsin and 5% flavourzyme, and ultrafiltration with 500 Da molecular weight (MW) cut-off dialysis membrane. Animal experiments were performed with collagen peptides obtained by pepsin hydrolysis (37 kDa) and pepsin plus flavourzyme hydrolysis (728 Da) as well as their nanoemulsions prepared at two different doses (100 and 300 mg/kg/day). The mean particle size of low-MW and low-dose nanoemulsion, low-MW and high-dose nanoemulsion, high-MW and low-dose nanoemulsion and high-MW and high-dose nanoemulsion was, respectively, 16.9, 15.3, 28.1 and 24.2 nm, the polydispersity index was 0.198, 0.215, 0.231 and 0.222 and zeta potential was -61.2, -63.0, -41.4 and -42.7 mV. These nanoemulsions were highly stable over a 90-day storage period (4 °C and 25 °C) and heating at 40-100 °C (0.5-2 h). Experiments in mice revealed that the low-MW and high-dose nanoemulsion was the most effective in decreasing fasting blood glucose (46.75%) and increasing wound-healing area (95.53%). Collectively, the sturgeon fish skin collagen peptide-based nanoemulsion is promising for development into a health food or wound-healing drug.

Impacts of Extra Virgin Olive Oil Consumption on Glycemic Control in Patients with Metabolic Syndrome

The purpose of this study was to observe the impacts of extra virgin olive oil on glycemic control in patients with metabolic syndrome (MetS). A total number of 70 patients of both genders with MetS were selected with the age varying from 35 to 55 years. Among them, 35 patients who had consumed 25 ml of extra virgin olive oil daily for 12 weeks were included in the study group (Group B). Another 35 patients who did not consume extra virgin olive oil, were enrolled as the control group (Group A) for comparison. Levels of fasting blood glucose (FBG) and glycosylated hemoglobin (HbA1c) were measured in both the control and study groups at baseline and after 12 weeks. EVOO consumption group showed a statistically significant decrease in fasting blood glucose (p =.003) and glycosylated hemoglobin (p &lt;0.001) in comparison to a control group who did not consume extra virgin olive oil. Regular consumption of extra virgin olive oil improves glycemic status in patients with metabolic syndrome.

A sulfonamide chalcone AMPK activator ameliorates hyperglycemia and diabetic nephropathy in db/db mice

Diabetic nephropathy (DN) is a serious complication of diabetes mellitus (DM), which currently lacks effective treatments. AMP-activated protein kinase (AMPK) stimulation by chalcones, a class of polyphenols abundantly found in plants, is proposed as a promising therapeutic approach for DM. This study aimed to identify novel chalcone derivatives with improved AMPK-stimulating activity in human podocytes and evaluate their mechanisms of action as well as in vivo efficacy in a mouse model of DN. Among 133 chalcone derivatives tested, the sulfonamide chalcone derivative IP-004 was identified as the most potent AMPK activator in human podocytes. Western blot analyses, intracellular calcium measurements and molecular docking simulation indicated that IP-004 activated AMPK by mechanisms involving direct binding at allosteric site of calcium-dependent protein kinase kinase β (CaMKKβ) without affecting intracellular calcium levels. Interestingly, eight weeks of intraperitoneal administration of IP-004 (20 mg/kg/day) significantly decreased fasting blood glucose level, activated AMPK in the livers, muscles and glomeruli, and ameliorated albuminuria in db/db type II diabetic mice. Collectively, this study identifies a novel chalcone derivative capable of activating AMPK in vitro and in vivo and exhibiting efficacy against hyperglycemia and DN in mice. Further development of AMPK activators based on chalcone derivatives may provide an effective treatment of DN.

Metabolic Adaptations to Morning Versus Afternoon Training: A Systematic Review and Meta-analysis.

Some physiological responses such as circulating glucose as well as muscle performance show a circadian rhythmicity. In the present study we aimed to quantitatively synthesize the data comparing the metabolic adaptations induced by morning and afternoon training. PubMed, SCOPUS, and Web of Science databases were systematically searched for studies comparing the metabolic adaptations (> 2weeks) between morning and afternoon training. A meta-analysis was performed using random-effects models with DerSimonian-Laird methods for fasting blood glucose, hemoglobin A1c (HbAc1), homeostatic model assessment (HOMA), insulin, triglycerides, total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL). We identified 9 studies with 11 different populations (n = 450 participants). We found that afternoon exercise was more effective at reducing circulating triglycerides [standardized mean difference (SMD) - 0.32; 95% confidence interval (CI) - 0.616 to - 0.025] than morning training. Moreover, afternoon tended to decrease fasting blood glucose (SMD - 0.24; 95% CI - 0.478 to 0.004) to a greater extent than morning training. Metabolic adaptations to exercise may be dependent on the time of day. Morning training does not show superior effects to afternoon exercise in any of the analyzed outcomes. However, afternoon training is more effective at reducing circulating triglyceride levels and perhaps at reducing fasting blood glucose than morning training. The study was preregistered at PROSPERO (CRD42021287860).

Exploring the Antidiabetic Effect of Lupenone in Rats with Type 1 Diabetes and its Underlying Mechanism Based on Network Pharmacology

Lupenone has been reported to possess numerous medicinal values and gives a positive antidiabetic effect. But the mechanism of preventing and treating type 1 diabetes has not been elucidated in type 1 diabetic rats. This study investigated the effects and mechanism of action of lupenone in preventing and treating type 1 diabetes by network pharmacology and diabetic rats. The blood glucose, glycosylated hemoglobin (HbA1c), insulin, and inflammatory factors in the pancreas of rats with type 1 diabetes were measured, and histopathological changes were observed after treatment with lupenone. The pharmacological network of ‘component-target-disease’ was constructed on diabetic rats. Gene function enrichment, the Kyoto Encyclopedia of Genes and Genomes pathway analysis, and molecular docking were performed. The results showed that lupenone can decrease fasting blood glucose and HbA1c levels, increase insulin content and interleukin (IL)-4, IL-10, and decrease IL-6, transforming growth factor β and tumor necrosis factor α levels in the pancreas. Furthermore, ten targets were identified, and 50 signal pathways closely related to type 1 diabetes and inflammation were screened by network pharmacology, including insulin resistance, type II diabetes, type I diabetes, insulin signal pathway, mitogen activated protein kinase (MAPK) signal pathway, and tumor necrosis factor (TNF) signal pathway. The docking affinity of potential targets and lupenone were between -3.3 and -9.8, among which caspase-3 (CASP3), cyclin-dependent kinase 4 (CDK4), inhibitor of kappaB kinase beta (IKBKB), transforming growth factor beta-1 (TGFB1), and TNF had high binding abilities. Thus, lupenone has the potential to be developed as a new drug for treating type 1 diabetes.

Functional properties of β-glucan extracted from Algerian barley, and its effect on different parameters of overfed rats

This paper aims to propose a preventive strategy for obesity using barley β-glucan, which is a soluble dietary fiber contnent in cereals. In this study, the effect of barley β-glucan in the prevention of induced obesity in Wistar rats is highlighted. For that, 24 male rats were divided into 4 groups, the 1st group presented control and received a standard diet (CT), the 2nd received a standard diet supplemented with 5% of barley β-glucan (CT + BG), the 3rd received a high-fat diet (HFD), and the 4th received the same high-fat diet supplemented with 5% of barley β-glucan (HFD + BG). After 12 weeks of diet, the rats were sacrificed and the biochemical and microbiological assays were carried out. The obtained results show that a highly significant increase (p < 0.001) is observed in body weight, epididymal and subcutaneous adipose tissue in the HFD group compared to the CT group. Further, a highly significant decrease is observed (p < 0.001) in total cholesterol, triglycerides, and low density lipoprotein cholesterol (LDL-C) in the HFD + BG group compared to the HFD group. Barley β-glucan balanced the ecophysiology of the intestinal microbiota reducing significantly (p < 0.001) the level of pathogenic bacteria in the colon and jejunum and increasing the beneficial bacteria. The supplementation with 5% of barley β-glucan for 12 weeks also decreased fasting blood glucose and the Hemoglobin A1C (HBA1C). Therefore this miraculous molecule could be used as a therapeutic element to treat dyslipidemia as well as the imbalance of the microbiota linked to obesity.

STUDY OF VITAMIN D3-FORTIFIED GOAT KEFIR ON PLASMA FIBRINOGEN LEVELS OF DIABETIC RATTUS NORVEGICUS RATS

ABSTRACTBackground: Diabetes mellitus is often associated with the occurrence of complications. Haemostatic factors, especially hyperfibrinogenaemia, is a common cause of the complication. Goat kefir and vitamin D3 may act as an antioxidant and anti-inflammation agent which can repair pancreatic beta cells.Objectives: This study aimed to analyse the effect of vitamin D3-fortified goat milk and plasma fibrinogen levels in diabetic rats. Materials and Methods: This study was an experimental study with pre-post only group design. The samples were 21 male rats divided into four groups; negative control (K-), positive control (K +), treated with unfortified goat kefir (P1), and treated with vitamin D3-fortified goat kefir (P2). The 35-day intervention was conducted, the goat kefir dose was 2 ml/200 g BW/day and the vitamin D dose 600 IU. Fasting blood glucose and plasma fibrinogen were assessed pre- and post-intervention. Blood glucose level was evaluated by GOD-PAP method, while plasma fibrinogen was assessed by Enzyme-Linked Immunosorbent Assay (ELISA) method. The data were analysed with paired t-test and One-Way ANOVA. Results: There were not significant difference levels of fibrinogen between groups. The intervention groups both showed an insignificant decrease of plasma fibrinogen. The plasma fibrinogen of group treated with vitamin D3-fortified goat kefir went down to 13.47 mg/dl from 16.49 mg/dl (p = 0.49). Meanwhile, the group treated with unfortified goat kefir showed a decrease from 26.81 mg/dl to 24.94 mg/dl (p=0.83). On the other hand, there was a significant decrease in fasting blood glucose in the group treated with vitamin D3-fortified goat kefir from 181.75 mg/dl to 116.25 mg/dl (p=0.03).Conclusion Our results demonstrate that administration of vitamin D3-fortified goat kefir can decrease fasting blood glucose but not in plasma fibrinogen. Keywords : Diabetes Mellitus; Fastin blood glucose; Fibrinogen; Goat kefir; Vitamin D3 Fortification

181-OR: Pancreatic Gene Therapy Durably Improves Glycemia and Delays Disease Progression in a Murine Model of Type 2 Diabetes

Beta-cell (β-cell) failure is a root cause of the progression of type 2 diabetes (T2D). GLP-1 receptor agonists (GLP1RA) have proven clinical efficacy and improve β-cell function. However, systemic side effects limit patient adherence and long-term efficacy. Localized pancreatic GLP1RA production may engender durable islet cell benefit while diminishing side effects. We developed a novel adeno-associated virus (AAV) gene therapy delivery platform to enable local and durable production of therapeutic proteins by the pancreas. We assessed to what degree a β-cell restricted GLP1RA gene therapy impacts disease progression in the db/db mouse compared to semaglutide (Sema). To establish a baseline for chronically administered systemic GLP1RA, Sema (10 nmol/kg) or vehicle were given daily to 5-week-old mice for 10 weeks (n=8/group). Sema treated mice had a 64% decrease in fasting blood glucose (FBG; p&amp;lt;0.0001) and a 3.5-fold increase in fasting insulin (FI; p=0.01) across the time course. Glucose tolerance was significantly improved during IPGTT at weeks 3, 6, and 9 (p&amp;lt;0.001). To determine the impact of a single dose GLP1RA gene therapy, 1) β-cell restricted AAV-GLP1RA, 2) AAV control, or 3) vehicle were given to 5-week-old mice (n=8/group). Remarkably, AAV-GLP1RA treatment decreased FBG levels by 70% (p&amp;lt;0.0001) and elevated FI by 1.9-fold (p&amp;lt;0.01) compared to controls for 10 weeks. Glucose tolerance was improved during IPGTT at weeks 3, 5, 7, and 9 (p&amp;lt;0.01). AAV-GLP1RA protein was undetectable in serum and restricted to the islet, suggesting improved glycemic control was due to intra-islet GLP1RA production and signaling. These results demonstrate that a single dose β-cell restricted GLP1RA gene therapy can comparably improve glycemia and delay disease progression in a murine model of T2D when compared to chronic systemic GLP1RA administration. These data provide proof of concept that a gene therapy has the potential to durably treat metabolic diseases, including T2D. Disclosure A.L.Fitzpatrick: Employee; Fractyl Health, Inc. E.Cozzi: Employee; Fractyl Health, Inc. J.Wainer: Employee; Fractyl Health, Inc. R.Reese: Employee; Fractyl Health, Inc. N.Khanna: Employee; Fractyl Health, Inc. J.Caplan: Employee; Fractyl Health, Inc. H.Rajagopalan: Employee; Fractyl Health, Inc. J.A.West: Employee; Fractyl Health, Inc. Funding Fractyl Health, Inc.

Menthol confers neuroprotection through Nrf2/ARE pathway in diabetic encephalopathy

Background: Chronic, long-standing hyperglycemia in diabetes results in diabetic encephalopathy (DE). It is hallmarked by cognitive dysfunction accelerated by hyperglycemia-induced oxidative stress. Objective: This study explored the neuroprotective potency of menthol in experimental diabetes.Methodology: Streptozotocin at a dose of 40 mg/kg body weight was injected into eighteen male Sprague- Dawley rats intraperitoneally to induce diabetes. The animals were kept without treatment for a period of 30 days for the development of DE. The cognitive deficit was confirmed by the Morris water maze test. Menthol (50 mg/kg body weight) was administered orally for 60 days. The behavioral test was conducted after 60 days of treatment. Results obtained were compared to diabetic rats fed with metformin (100 mg/kg body weight). Animals were then sacrificed to get blood and brain tissue for various biochemical examinations.Results:Treatment with menthol improved cognitive performance in diabetic rats. In addition, menthol significantly decreased fasting blood glucose, HbA1c, renal toxicity markers, and lipid peroxidation products. Menthol enhances the levels of plasma insulin and antioxidant enzymes. It also upregulated the mRNA expression of Bcl-2, Nrf2, Glo-1, and γ-GCS while diminishing the expression of Bax, cytochrome c, and caspase-3. Conclusion:Menthol promotes neuroprotection by abating cognitive deficits, attenuating hyperglycemia, regulating oxidative stress, and curtailing apoptosis through Nrf2/ARE signaling. Keywords: Diabetic encephalopathy, Menthol, apoptosis, Nrf2/ARE pathway

Ameliorative effects of phlorotannin-rich fraction of Sargassum tenerrimum in high-fat diet and low dose streptozotocin-induced metabolic changes and oxidative stress in diabetic rats

Introduction: Type 2 diabetes mellitus (T2D) is a progressing polygenic disease demanding a multitargeted treatment strategy. Sargassum tenerrimum (ST) is a marine brown alga with potentially bioactive chemicals that could be used as innovative biotherapeutics for diabetes treatment. The current research examined the potential of the phlorotannin-rich fraction from S. tenerrimum (PST) to mitigate diabetes in Wistar albino rats induced with high-fat diet (HFD) and streptozotocin (STZ) administration. Methods: Diabetic rats were given PST (200 and 400 mg/kg) or metformin (250 mg/kg) orally three weeks, and followed by the measurements of insulin, glycemic factors, biological markers of oxidative stress, tumor necrosis factor-alpha (TNF-α), as well as hepatic and pancreatic histopathological changes. Results: PST treatment significantly decreased fasting blood glucose, insulin resistance, lipid profile, hepatic profile, and TNF- α levels and improved serum insulin and glucose tolerance in diabetic rats. In the skeletal muscles of diabetic rats, PST led to a significant rise in antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) reductase, and a decrease in lipid peroxidation. Furthermore, PST treatment significantly reduced pancreatic-cell damage and hepatic fatty accumulation. PST was more efficacious at 400 mg/kg exhibiting a dose-dependent effect. Conclusion: PST improves glucolipid metabolism in HFD and STZ-induced diabetic rats, probably by reducing hyperglycemia, insulin resistance, dyslipidemia, oxidative stress, inflammation, and damage to pancreatic and hepatic architectures. The findings suggest that PST has a curative impact on diabetes mellitus type 2 and represents a new subject of study for the treatment of diabetes naturally.

Sulfosuccinimidyl oleate ameliorates the high-fat diet-induced obesity syndrome by reducing intestinal and hepatic absorption.

Background: A high-fat Western diet is a risk factor for obesity and steatosis. Reducing intestinal absorption of a high-fat diet (HFD) is a feasible strategy to control obesity. Sulfosuccinimidyl oleate (SSO) inhibits intestinal fatty acid transport. Therefore, the aim of this study was to investigate the effects of SSO on HFD-induced glucose and lipid metabolism in mice and its possible underlying mechanisms. Methods: Male C57/BL were fed a HFD (60% calories) for 12weeks and were administered an oral dose of SSO (50mg/kg/day). The expression of lipid absorption genes (CD36, MTTP, and DGAT1) and the serum levels of triglycerides (TGs), total cholesterol (TC), and free fatty acids (FFAs) were detected. Lipid distribution in the liver was detected by oil red and hematoxylin and eosin staining. In addition, serum levels of inflammatory factors, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were measured to detect side effects. Results: SSO was effective in the treatment of obesity and metabolic syndrome induced by HFD in mice. It attenuated the assembly of intestinal epithelial chylomicrons by inhibiting intestinal epithelial transport and absorption of fatty acids, thereby reducing the gene expression levels of MTTP and DGAT1, resulting in decreased plasma TG and FFA levels. At the same time, it inhibited the transport of fatty acids in the liver and improved the steatosis induced by a HFD. The results of oil red staining showed that SSO treatment can reduce lipid accumulation in the liver by 70%, with no drug-induced liver injury detected on the basis of interleukin-6, C-reactive protein, ALT, and AST levels. In addition, SSO treatment significantly improved insulin resistance, decreased fasting blood glucose levels, and improved glucose tolerance in HFD-fed mice. Conclusion: SSO is effective in the treatment of obesity and metabolic syndrome induced by a HFD in mice. SSO reduces intestinal fatty acid absorption by reducing the inhibition of intestinal CD36 expression, followed by decreased TG and FFA levels, which attenuates HFD-induced fatty liver.

The combination of metformin with morin alleviates hepatic steatosis via modulating hepatic lipid metabolism, hepatic inflammation, brown adipose tissue thermogenesis, and white adipose tissue browning in high-fat diet-fed mice

AimThe valuable effects of metformin (MET) and morin (MOR) in the improvement of NAFLD have been proposed, nevertheless, their combination impacts were not investigated so far. We determined the therapeutic effects of combined MET and MOR treatment in high-fat diet (HFD)-induced Non-alcoholic fatty liver disease (NAFLD) mice. MethodsC57BL/6 mice were fed on an HFD for 15 weeks. Animals were allotted into various groups and supplemented with MET (230 mg/kg), MOR (100 mg/kg), and MET + MOR (230 mg/kg + 100 mg/kg). Key findingsMET in combination with MOR reduced body and liver weight in HFD-fed mice. A significant decrease in fasting blood glucose and improvement in glucose tolerance was observed in HFD mice treated with MET + MOR. Supplementation with MET + MOR led to a decline in hepatic triglyceride levels and this impact was associated with diminished expression of fatty-acid synthase (FAS) and elevated expression of carnitine palmitoyl transferase 1 (CPT1) and phospho-Acetyl-CoA Carboxylase (p-ACC). Moreover, MET combined with MOR alleviates hepatic inflammation through the polarization of macrophages to the M2 phenotype, decreasing the infiltration of macrophages and lowering the protein level of NF-kB. MET and MOR in combination reduce the size and weight of epididymal white adipose tissue (eWAT), and subcutaneous WAT (sWAT), whereas improves cold tolerance, BAT activity, and mitochondrial biogenesis. Combination therapy results in stimulating brown-like adipocyte (beige) formation in the sWAT of HFD mice. SignificanceThese results suggest that the combination of MET and MOR has a protective effect on hepatic steatosis, which may use as a candidate therapeutic for the improvement of NAFLD.

Erythropoietin ameliorates cognitive dysfunction in mice with type 2 diabetes mellitus via inhibiting iron overload and ferroptosis

Type 2 diabetes mellitus (T2DM) is strongly associated with an increased risk of developing cognitive dysfunction. Numerous studies have indicated that erythropoietin (EPO) has neurotrophic effects. Ferroptosis has been reported to be associated with diabetic cognitive dysfunction. However, the impact of EPO on T2DM-associated cognitive dysfunction and its protective mechanism remain unclear. To evaluate the effects of EPO on diabetes-associated cognitive dysfunction, we constructed a T2DM mouse model and found that EPO not only decreased fasting blood glucose but also ameliorated hippocampal damage in the brain. The Morris water maze test indicated that EPO improved cognitive impairments in diabetic mice. Moreover, a ferroptosis inhibitor improved cognitive dysfunction in mice with T2DM in vivo. Furthermore, a ferroptosis inhibitor, but not other cell death inhibitors, mostly rescued high-glucose damaged PC12 cell viability. EPO had a similar effect as the ferroptosis inhibitor, which increased cell viability in the presence of a ferroptosis inducer. In addition, EPO reduced lipid peroxidation, iron levels, and regulated ferroptosis-related expression of proteins in vivo and in vitro. These findings indicate that EPO ameliorates T2DM-associated cognitive dysfunction, which might be related to decreasing iron overload and inhibiting ferroptosis.

Role of yoga in type 2 diabetes mellitus

Type 2 Diabetes Mellitus (T2DM) has become most common problem worldwide. Yoga provides best means of self-improvement and gaining full potential of one’s body, mind &amp; soul. It has been proved that pranayama and certain Asana’s help in lowering blood glucose, balancing blood pressure and calms nervous system. The asanas improve the sensitivity of β-cells to glucose, improves insulin secretion, and improves glucose uptake. Hence, Yogic asanas are important for preventing and curing many ailments. The effect of yogic practices in diabetics has to be investigated well. To assess the effect of yoga on blood glucose levels and anthropometric parameters before and after doing yoga in T2DMpatients. A total of 100 T2DM diabetic patients in age group 30-60 years were taken. Effect of Yoga on fasting Blood glucose (FBG), Post prandial blood glucose (PPBG), HbA1c levels and serum insulin were assessed. Anthropometric parameters like BMI and waist hip ratio were also assessed. There was significant decrease in FBG, PPBG and HbA1c levels with p value&amp;#60;0.001 after doing yoga. There was also significant improvement in serum insulin levels and decrease in BMI &amp; waist hip ratio. A significant improvement in the blood glucose levels occurred in subjects who practiced Yoga. There was also lowering of the drug requirement.