Tetrahydrocurcumin Upregulates the Adiponectin-AdipoR Pathway and Improves Insulin Signaling and Pancreatic β-Cell Function in High-Fat Diet/Streptozotocin-Induced Diabetic Obese Mice.
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ABSTRACT:
SUBMITTER: Tsai YZ
PROVIDER: S-EPMC8707974 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Glucagon-like peptide 1 (GLP-1) mimetics have been approved as an adjunct therapy for glycemic control in type 2 diabetic patients for the increased insulin secretion under hyperglycemic conditions. Recently, it is reported that such agents elicit neuroprotective effects against diabetes-associated cognitive decline. However, there is an issue of poor compliance by multiple daily subcutaneous injections for sufficient glycemic control due to their short duration, and neuroprotective actions were not fully studied, yet. In this study, using the prepared exendin-4 fusion protein agent, we investigated the pharmacokinetic profile and the role of this GLP-1 mimetics on memory deficits in a high-fat diet (HFD)/streptozotocin (STZ) mouse model of type 2 diabetic mellitus. After induction of diabetes, mice were administered weekly by intraperitoneal injection of GLP-1 mimetics for 6 weeks. This treatment reversed HFD/STZ-induced metabolic symptoms of increased body weight, hyperglycemia, and hepatic steatosis. Furthermore, the impaired cognitive performance of diabetic mice was significantly reversed by GLP-1 mimetics. GLP-1 mimetic treatment also reversed decreases in GLP-1/GLP-1 receptor expression levels in both the pancreas and hippocampus of diabetic mice; increases in hippocampal inflammation, mitochondrial fission, and calcium-binding protein levels were also reversed. These findings suggest that GLP-1 mimetics are promising agents for both diabetes and neurodegenerative diseases that are associated with increased GLP-1 expression in the brain.
| S-EPMC7076426 | biostudies-literature
Project description:IntroductionHydroxychloroquine (HCQ) is a common disease modifying therapy for the treatment of rheumatoid arthritis (RA). Prior research suggests that HCQ may reduce the risk of diabetes mellitus in patients with RA. To investigate the mechanism of this effect, we examined the effect of HCQ on insulin resistance, insulin sensitivity, and pancreatic β-cell secretion of insulin in non-diabetic, obese subjects.MethodsWe recruited 13 obese, non-diabetic subjects without systemic inflammatory conditions for an open-label longitudinal study of HCQ 6.5 mg per kilogram per day for six weeks. Subjects underwent an oral glucose tolerance test at three time points: 0 weeks (pre-treatment with HCQ), 6 weeks (at the end of the HCQ treatment), and 12 weeks (6 weeks post HCQ-treatment). The Matsuda Insulin Sensitivity Index (ISI), HOMA-IR, and HOMA-B were compared across time-points.ResultsThe mean age of the cohort was 49 years, 77% females and median body mass index was 36.1 kg/m2. After 6 weeks of HCQ therapy, ISI increased from a median (interquartile range) of 4.5 (2.3-7.8) to 8.9 (3.7-11.4) with a p-value of 0.040, and HOMA-IR decreased from a median of 2.1 (1.6-5.4) to 1.8 (1.02-2.1) with a p-value of 0.09. All these variables returned toward baseline at week 12.ConclusionHCQ use for 6 weeks in non diabetic obese subjects was associated with a significant increase in ISI and trends toward reduced insulin resistance and insulin secretion. These data suggest that HCQ, a common medication used to treat RA, possesses beneficial effects upon insulin sensitization. Further study of the insulin sensitizing effects of HCQ in patients with RA is warranted.
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Project description:Protein consumption influences glucose homeostasis, but the effect depends on the type and origin of proteins ingested. The present study was designed to determine the effect of herring milt protein hydrolysate (HPH) on insulin function and glucose metabolism in a mouse model of diet-induced obesity. Male C57BL/6J mice were pretreated with a low-fat diet or a high-fat diet for 6 weeks. Mice on the high-fat diet were divided into four groups where one group continued on the high-fat diet and the other three groups were fed a modified high-fat diet where 15%, 35%, and 70%, respectively, of casein was replaced with an equal percentage of protein derived from HPH. After 10 weeks, mice that continued on the high-fat diet showed significant increases in body weight, blood glucose, insulin, and leptin levels and exhibited impaired oral glucose tolerance, insulin resistance, and pancreatic ?-cell dysfunction. Compared to mice fed the high-fat diet, the 70% replacement of dietary casein with HPH protein reduced body weight, semi-fasting blood glucose, fasting blood glucose, insulin, leptin, and cholesterol levels and improved glucose tolerance, homeostasis model assessment of insulin resistance (HOMA-IR), and homeostasis model assessment of ?-cell function (HOMA-?) indices. The 35% replacement of dietary casein with HPH protein showed moderate effects, while the 15% replacement of dietary casein with HPH protein had no effects. This is the first study demonstrating that replacing dietary casein with the same amount of protein derived from HPH can prevent high-fat-diet-induced obesity and insulin resistance.
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Project description:Obesity is a common chronic metabolic disease that is harmful to human health and predisposes the affected individuals to a cluster of pathologies. Insulin resistance (IR) is one of the most frequent complications of obesity. Hydroxytyrosol (HT) may reduce obesity and IR in high-fat diet (HFD)-fed mice; however, the mechanism underlying is still unknown. Systemic low-grade inflammation and intestinal dysfunction are thought to be associated with obesity and IR. In this study, we found that HFD feeding for 8 weeks altered the intestinal microbiota, injured intestinal barrier function, increased endotoxin release into the blood, enhanced the expression of inflammatory factors (TNF-α, IL-1β, IL-6) and lipid accumulation in liver, caused obesity, and aggravated IR via the JNK/IRS (Ser 307) pathway in HFD mice. We also found that HT gavage could reverse those effects and the beneficial effects of HT were transferable through fecal microbiota transplantation. Our data indicate that HT can improve obesity and IR by altering the composition of the intestinal microbiota and improving integrity of the intestinal wall. We propose that HT replenishment may be used as a dietary intervention strategy to prevent obesity and IR.
| S-EPMC6410680 | biostudies-literature
Project description:Diabetic ulcers bring about high morbidity and mortality in patients and cause a great economic burden to society as a whole. Since existing treatments cannot fulfil patient requirements, it is urgent to find effective therapies. In this study, the wound healing effect of topical notoginsenoside R1 (NR1) treatment on diabetic full-thickness wounds in type II diabetes mellitus (T2DM) was induced by the combination of a high-fat diet and streptozotocin (STZ) injection. NR1 significantly increased the wound closure rate, enhanced extracellular matrix (ECM) secretion, promoted collagen growth, increased platelet endothelial cell adhesion molecule-1 (CD31) expression, and decreased cleaved caspase-3 expression. RNA-Seq analysis identified ECM remodeling and inflammation as critical biological processes and Timp1 and Mmp3 as important targets in NR1-mediated wound healing. Further experiments showed that NR1-treated wounds demonstrated higher expression of tissue inhibitor of metalloproteinase 1 (TIMP1) and transforming growth factor-β1 (TGFβ1) and lower expression of matrix metallopeptidase 9 (MMP9), matrix metallopeptidase 3 (MMP3), interleukin-1β (IL-1β), and interleukin-6 (IL-6) than diabetic wounds. These investigations promote the understanding of the mechanism of NR1-mediated diabetic wound healing and provide a promising therapeutic drug to enhance diabetic wound healing.
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Project description:BackgroundC1q/tumor necrosis factor-related protein 1 (CTRP1) is an adipokine secreted by adipose tissue, related to chondrocyte proliferation, inflammation, and glucose homeostasis. However, the therapeutic effects on metabolic disorders and the underlying mechanism were unclear. Here, we investigated the functions and mechanisms of CTRP1 in treating obesity and diabetes.MethodsThe plasmid containing human CTRP1 was delivered to mice by hydrodynamic injection, which sustained expression of CTRP1 in the liver and high protein level in the blood. High-fat diet (HFD) fed mice and STZ-induced diabetes model were used to study the effects of CTRP1 on obesity, glucose homeostasis, insulin resistance, and hepatic lipid accumulation. The lipid accumulation in liver and adipose tissue, glucose tolerance, insulin sensitivity, food intake, and energy expenditure were detected by H&E staining, Oil-Red O staining, glucose tolerance test, insulin tolerance test, and metabolic cage, respectively. The metabolic-related genes and signal pathways were determined using qPCR and western blotting.ResultsWith high blood circulation, CTRP1 prevented obesity, hyperglycemia, insulin resistance, and fatty liver in HFD-fed mice. CTRP1 also improved glucose metabolism and insulin resistance in obese and STZ-induced diabetic mice. The metabolic cage study revealed that CTRP1 reduced food intake and enhanced energy expenditure. The mechanistic study demonstrated that CTRP1 upregulated the protein level of leptin in blood, thermogenic gene expression in brown adipose tissue, and the gene expression responsible for lipolysis and glycolysis in white adipose tissue (WAT). CTRP1 also downregulated the expression of inflammatory genes in WAT. Overexpression of CTRP1 activated AMPK and PI3K/Akt signaling pathways and inhibited ERK signaling pathway.ConclusionThese results demonstrate that CTRP1 could improve glucose homeostasis and prevent HFD-induced obesity and fatty liver through upregulating the energy expenditure and reducing food intake, suggesting CTRP1 may serve as a promising target for treating metabolic diseases.
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Project description:Background:One common feature of chronic diseases, such as cancer, diabetes and chronic kidney disease (CKD), is the disruption of iron metabolism and increase in labile iron pool, which can result in excessive production of harmful oxidative stress. The proper management of iron metabolism in this situation can be a valuable tool to ameliorate pathological events. Materials and Methods:In the previous studies, the anti-neoplastic effects of BCc1, a nanochelating-based nanomedicine with iron-chelating property, were demonstrated in cell culture, animal models and clinical trials. In the present study, the therapeutic effects of BCc1 in animal model of diabetic kidney disease (DKD), induced by streptozotocin injection (35 mg/kg) and high-fat diet consumption, were evaluated. Results:The results showed that BCc1 significantly decreased HOMA-IR index, uric acid, blood urea nitrogen, malondialdehyde and 8-isoprostane. In addition, it reduced urinary albumin excretion rate and albumin-to-creatinine ratio in comparison to DKD control rats. This nanomedicine had no negative impact on liver iron content, hemoglobin level, red blood cell count, hematocrit and mean corpuscular volume, while it significantly decreased aspartate aminotransferase and alanine aminotransferase compared to DKD control group. Moreover, the histopathological assessment indicated that lesser glomerular basement membrane and wrinkling, mesangial matrix expansion and pathological changes in proximal cortical tubules were seen in the kidney samples of BCc1-treated rats. Conclusion:In conclusion, BCc1 as an iron-chelating agent shows promising impacts in DKD animal model, which can ameliorate biochemical and pathological events of this disease.
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Project description:Intestinal microbiota is closely associated with various metabolic diseases such as type 2 diabetes (T2D), and microbiota is definitely affected by diet. However, more work is required to gain detailed information about gut metagenome and their associated impact with diet in T2D patients. We used a streptozotocin-high-fat diet (HFD) to induce a T2D mouse model and investigated the effect of standard chow diet and HFD on the composition and function of gut microbiota. We found that a HFD could worsen the diabetes status compared with a standard diet. 16S rRNA gene sequencing revealed that a HFD caused a large disturbance to the microbial structure and was linked to an increased ratio of Firmicutes to Bacteroidetes. A HFD increased the bacteria of the Ruminococcaceae and Erysipelotrichaceae family and decreased the bacteria of S24-7 and Rikenellaceae. Meanwhile, a HFD decreased the abundance of Parabacteroidesdistasonis and Eubacteriumdolichum, both of which have previously been reported to alleviate obesity and metabolic dysfunctions. Moreover, PICRUSt-predicted KEGG pathways related to membrane transport, lipid metabolism, and xenobiotics biodegradation and metabolism were significantly elevated in HFD-fed T2D mice. Our results provide insights into dietary and nutritional approaches for improving host metabolism and ameliorating T2D.
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Project description:Adiponectin has emerged as a potential therapy for type 2 diabetes mellitus, but the molecular mechanism by which adiponectin reverses insulin resistance remains unclear. Two weeks of globular adiponectin (gAcrp30) treatment reduced fasting plasma glucose, triglyceride (TAG), and insulin concentrations and reversed whole-body insulin resistance, which could be attributed to both improved insulin-mediated suppression of endogenous glucose production and increased insulin-stimulated glucose uptake in muscle and adipose tissues. These improvements in liver and muscle sensitivity were associated with ∼50% reductions in liver and muscle TAG and plasma membrane (PM)-associated diacylglycerol (DAG) content and occurred independent of reductions in total ceramide content. Reductions of PM DAG content in liver and skeletal muscle were associated with reduced PKCε translocation in liver and reduced PKCθ and PKCε translocation in skeletal muscle resulting in increased insulin-stimulated insulin receptor tyrosine1162 phosphorylation, IRS-1/IRS-2-associated PI3-kinase activity, and Akt-serine phosphorylation. Both gAcrp30 and full-length adiponectin (Acrp30) treatment increased eNOS/AMPK activation in muscle and muscle fatty acid oxidation. gAcrp30 and Acrp30 infusions also increased TAG uptake in epididymal white adipose tissue (eWAT), which could be attributed to increased lipoprotein lipase (LPL) activity. These data suggest that adiponectin and adiponectin-related molecules reverse lipid-induced liver and muscle insulin resistance by reducing ectopic lipid storage in these organs, resulting in decreased plasma membrane sn-1,2-DAG-induced nPKC activity and increased insulin signaling. Adiponectin mediates these effects by both promoting the storage of TAG in eWAT likely through stimulation of LPL as well as by stimulation of AMPK in muscle resulting in increased muscle fat oxidation.
| S-EPMC7768680 | biostudies-literature
Project description:The prevalence of obesity and insulin-resistance is on the rise, globally. Cannabis have been shown to have anti-diabetic/obesity properties, however, the effect mediated at various fat depots remains to be clarified. The aim of this study was to (1) investigate the anti-diabetic property of an oral cannabis administration in an obese and streptozotocin-induced diabetic rat model and (2) to determine and compare the effect mediated at the peritoneal and intramuscular fat level. Cannabis concentration of 1.25 mg/kg body weight (relative to THC content) was effective in reversing insulin-resistance in the rat model, unlike the other higher cannabinoid concentrations. At the peritoneal fat level, gene expression of fat beigeing markers, namely Cidea and UCP1, were significantly increased compared to the untreated control. At the intramuscular fat level, on the other hand, CE1.25 treatment did not promote fat beigeing but instead significantly increased mitochondrial activity, relative to the untreated control. Therefore, these findings indicate that the mechanism of action of oral cannabis administration, where glucose and lipid homeostasis is restored, is not only dependent on the dosage but also on the type of fat depot investigated.
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