Insulin Resistance In Diabetic Mice Research Articles

Low-intensity pulsed ultrasound ameliorates insulin resistance in type 2 diabetes mice via promoting glucagon-like peptide-1 release

Abstract Glucagon-like peptide-1 (GLP-1) is a hormone secreted by intestinal L-cells. It regulates glucose levels by boosting insulin secretion, inhibiting glucagon release, and preventing β-cell death. GLP-1 is increasingly used in managing type 2 diabetes mellitus (T2DM). This study assessed the effectiveness of low-intensity pulsed ultrasound (LIPUS), a non-pharmacological intervention, in enhancing insulin resistance in diabetic mice by stimulating GLP-1 release. T2DM was induced in C57BL/6J mice through a high-fat diet and streptozotocin injection. Mice were divided into Control, T2D-sham and T2D-LIPUS groups. The T2D-LIPUS group received LIPUS treatment with a frequency of 1MHz, intensity of 120mW/cm2, and duty cycle of 20%for 20 minutes/day, 5 days/week for 4 weeks. Glucose tolerance and insulin resistance were measured through tests. Pancreatic histology and GLP-1 expression in serum were evaluated. Results showed that T2DM increased insulin resistance, but LIPUS treatment alleviated it. GLP-1 levels significantly increased in the T2D-LIPUS group compared to the T2D-sham group, approaching the control group’s level. LIPUS also reduced apoptosis of islet β cells. These findings suggest that LIPUS stimulation of the intestine can enhance islet β-cell activity through GLP-1 regulation of the gut-pancreas axis, mitigating insulin resistance in T2DM.

Alleviative effects of the parthenolide derivative ACT001 on insulin resistance induced by sodium propionate combined with a high-fat diet and its potential mechanisms

The increasing side effects of traditional medications used to treat type II diabetes have made research into the development of safer and more effective natural medications necessary. ACT001, a derivative of parthenolide, has been shown to have good anti-inflammatory and antitumor effects; however, its role in diabetes is unclear. The short-chain fatty acid propionate is a common food preservative that has been found to cause disturbances in glucose metabolism in mice and humans. This study aimed to investigate whether sodium propionate could aggravate insulin resistance in obese mice and cause diabetes and to study the alleviative effects and potential mechanisms of action of ACT001 on insulin resistance in diabetic mice. Type II diabetic mice were adminietered sodium propionate combined with a high-fat diet (HFD + propionate) by gavage daily for four weeks. Biochemical analysis showed that ACT001 significantly affected blood glucose concentration in diabetic mice, mainly by downregulating the expression of phosphoenolpyruvate carboxykinase 2 and glucose-6-phosphatase. Meanwhile, the level of fatty acid-binding protein 4 in the liver was significantly decreased. ACT001 has a protective effect on the liver and adipose tissue of mice. In addition, the results of the running wheel experiment indicated that ACT001 alleviated the circadian rhythm disorder caused by insulin resistance to a certain extent. This study revealed the potential mechanism by which ACT001 alleviates insulin resistance and provides ideas for developing natural antidiabetic drugs.

Effects of Auricularia auricula-judae (Bull.) Quél. polysaccharide acid hydrolysate on glucose metabolism in diabetic mice under oxidative stress

BackgroundOxidative stress can lead to uncontrolled glucose metabolism and, thus, diabetes. Auricularia auricula-judae (Bull.) Quél. polysaccharides possess biological activities, such as antioxidant and hypoglycemic effects, but their mechanism of their acid hydrolysates on oxidative stress-injured glucose metabolism disorders is unclear. PurposeUsing diabetic mice, we investigated the effect of the acid hydrolysate of polysaccharides from Auricularia auricula-judae (Bull.) Quél. on improving diabetes. Study design and MethodsThe structural information of sample polysaccharides was measured by high performance gel permeation chromatography, nuclear magnetic resolution, and high performance liquid chromatography. The diabetic model was established by intraperitoneal injection of streptozotocin. For eight consecutive weeks, the mice were orally administered sample polysaccharides (100, 200, and 300 mg/kg b.w. per day) for intervention. The improvement effect of the samples on diabetes was explored by detecting the changes in biochemical indicators in mice, and the underlying mechanism was studied by transcriptomic and metabolomic analysis. ResultsThe results showed that acid hydrolysate of Auricularia auricula-judae (Bull.) Quél. polysaccharides consisted mainly of mannose, xylose, glucuronic acid, and glucose; its weight-averaged molecular weight was 6.3842 × 104 Dalton, its number average molecular weight was 2.9594 × 104 Dalton; and the molecule contained α-Glc(1→4)-, β-Glc(1→3)-, and β-Man(1→4)-linked glycosidic bonds. A total of 100 mg/kg b.w. per day sample was the best intervention concentration. After eight weeks of intervention, the sample polysaccharides significantly reduced dynamic blood glucose and serum lipids, enhanced antioxidant enzyme activities, promoted glucagon like peptide-1 and insulin secretion, improved insulin sensitivity and alleviated insulin resistance in diabetic mice. Transcriptomic and metabolomic analyses showed that sample polysaccharides was able to ameliorate disorders of glucose metabolism by modulating gene expression such as glucokinase; and modulate the state of oxidative stress in mice in vivo by regulating the glutathione metabolism pathway. ConclusionAcid hydrolysate of Auricularia auricula-judae (Bull.) Quél. polysaccharides improved glucose metabolism disorders by slowing down the oxidative stress injury in mice, thereby alleviating diabetes. This study provided a basis for determining the underlying mechanism of the antidiabetic effect of Auricularia auricula-judae (Bull.) Quél. polysaccharides, which would significantly improve the deep development and application of these materials in diabetes control.

Tianhuang formula regulates adipocyte mitochondrial function by AMPK/MICU1 pathway in HFD/STZ-induced T2DM mice

BackgroundTianhuang formula (THF) is a Chinese medicine prescription that is patented and clinically approved, and has been shown to improve energy metabolism, but the underlying mechanism remains poorly understood. The purpose of this study is to clarify the potential mechanisms of THF in the treatment of type 2 diabetes mellitus (T2DM).MethodsA murine model of T2DM was induced by high-fat diet (HFD) feeding combined with low-dose streptozocin (STZ) injections, and the diabetic mice were treated with THF by gavaging for consecutive 10 weeks. Fasting blood glucose (FBG), serum insulin, blood lipid, mitochondrial Ca2+ (mCa2+) levels and mitochondrial membrane potential (MMP), as well as ATP production were analyzed. The target genes and proteins expression of visceral adipose tissue (Vat) was tested by RT-PCR and western blot, respectively. The underlying mechanism of the regulating energy metabolism effect of THF was further explored in the insulin resistance model of 3T3-L1 adipocytes cultured with dexamethasone (DXM).ResultsTHF restored impaired glucose tolerance and insulin resistance in diabetic mice. Serum levels of lipids were significantly decreased, as well as fasting blood glucose and insulin in THF-treated mice. THF regulated mCa2+ uptake, increased MMP and ATP content in VAT. THF increased the mRNA and protein expression of AMPK, phosphorylated AMPK (p-AMPK), MICU1, sirtuin1 (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). THF could increase the mCa2+ level of 3T3-L1 adipocytes and regulate mitochondrial function. The protein expression of AMPK, p-AMPK, mCa2+ uniporter (MCU) and MICU1 decreased upon adding AMPK inhibitor compound C to 3T3-L1 adipocytes and the protein expression of MCU and MICU1 decreased upon adding the MCU inhibitor ruthenium red.ConclusionsThese results demonstrated that THF ameliorated glucose and lipid metabolism disorders in T2DM mice through the improvement of AMPK/MICU1 pathway-dependent mitochondrial function in adipose tissue.

Abstract 443: BAFF Neutralization Impairs The Regression Of Insulin Resistance In Diabetic Mice By Modulating The Innate Immune Response

Adults with type 2 diabetes have a two-to-three-fold increased risk of cardiovascular diseases. B cell activating factor (BAFF), a tumor necrosis factor superfamily member, is implicated both in diabetes and cardiovascular diseases, and hence a therapeutic target of interest. High levels of BAFF are known to promote autoantibody synthesis and autoimmune diseases. We examined if BAFF neutralization with an anti-BAFF antibody improves glucose intolerance in a model of regression of insulin resistance in diabetic mice. Male C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks and segregated into two groups based on their glucose intolerance determined by a glucose tolerance test. Each group was simultaneously switched from HFD to a normal chow diet and received injections of anti-BAFF or an isotype control antibody every 2 nd week for a total of 6 weeks. As expected, body weights decreased in both groups parallel with the increase in insulin sensitivity. Unexpectedly, the BAFF-neutralized mice had impaired regression of insulin resistance compared to the control mice. Extensive cellular phenotyping of immune cells indicated systemic depletion of only the B2 cells and lower levels of circulating autoantibodies in the BAFF-neutralized mice. Gonadal white adipose tissue (gWAT) was the primary source of BAFF, and no differences in the M1 and M2 macrophages, eosinophils, natural killer cells, helper T cells, and cytotoxic T cell populations were found. RNA sequencing analysis of stromal vascular fraction from gWAT revealed impaired B cell receptor signaling, immunoglobulin production, complement activation, and phagocytosis pathways in the BAFF-neutralized mice. In this line, (i) an increased number of dead adipocytes, (ii) decreased levels of IgG2b and IgM, (iii) increased citrullinated histone H3, neutrophils, and DNA extracellular traps were found in the gWAT of BAFF-neutralized mice. These results suggest attenuated humoral response and a dominant and harmful role of innate response in the gWAT following BAFF neutralization in late-stage obesity. Since anti-BAFF biologics are approved for the treatment of lupus patients, our results highlight the need for further studies on the role of BAFF in late-stage obesity and diabetes.

PSTPIP2 alleviates obesity associated adipose tissue inflammation and insulin resistance in diabetes mice through promoting M2 macrophage polarization via activation of PPARγ

BackgroundProline-serine-threonine phosphatase-interacting protein 2 (PSTPIP2) plays a role in inflammatory disease. In diabetes, very little is known about PSTPIP2 until now. Hence, this study aimed to determine PSTPIP2 functional role in diabetes. MethodsDiabetes mouse model was constructed by feeding high fat diet (HFD). Intraperitoneal glucose tolerance test and intraperitoneal insulin tolerance test were examined the glucose and insulin tolerance. The expression of genes and proteins was detected by quantitative real time PCR, immunohistochemistry and western blotting. The pathological changes of epididymal adipose tissues were examined by hematoxylin-eosin staining. RAW264.7 macrophages were treated with GW9662 (PPARγ antagonist). Flow cytometry examined the proportion of M1/M2 macrophages. ResultsHFD enhanced the body weight, glucose and insulin tolerance, and inhibited PSTPIP2 expression in mice. PSTPIP2 overexpression alleviated glucose and insulin tolerance, reduced inflammation and macrophage accumulation in the epididymal adipose tissues of diabetic mice. The expression of iNOS and TNF-α was increased, the expression of IL-10 and Arg-1 was decreased in diabetic mice, which was abrogated by PSTPIP2 overexpression. In vitro, PSTPIP2 overexpression reduced the proportions of iNOS-positive cells and enhanced the proportions of CD206-positive cells in RAW264.7 cells. PPARγ and p-STAT6 were up-regulated, STAT6 was down-regulated in RAW264.7 cells. GW9662 impaired PSTPIP2 overexpression-mediated up-regulation of Arg-1, YM-1 and FIZZ1 in RAW264.7 cells. ConclusionPSTPIP2 alleviates obesity associated adipose tissue inflammation and insulin resistance in diabetic mice through promoting M2 macrophage polarization via activation of PPARγ, suggesting that PSTPIP2 is a prospective target for diabetes treatment.

Discovery of IHMT-MST1-39 as a novel MST1 kinase inhibitor and AMPK activator for the treatment of diabetes mellitus

Insulin-producing pancreatic β cell death is the fundamental cause of type 1 diabetes (T1D) and a contributing factor to type 2 diabetes (T2D). Moreover, metabolic disorder is another hallmark of T2D. Mammalian sterile 20-like kinase 1 (MST1) contributes to the progression of diabetes mellitus through apoptosis induction and acceleration of pancreatic β cell dysfunction. AMP-activated protein kinase (AMPK) is an energy sensing kinase and its activation has been suggested as a treatment option for metabolic diseases. Thus, pharmacological inhibition of MST1 and activation of AMPK simultaneously represents a promising approach for diabetes therapy. Here, we discovered a novel selective MST1 kinase inhibitor IHMT-MST1-39, which exhibits anti-apoptosis efficacy and improves the survival of pancreatic β cells under diabetogenic conditions, as well as primary pancreatic islets in an ex vivo disease model. Mechanistically, IHMT-MST1-39 activated AMPK signaling pathway in hepatocytes in vitro, combination of IHMT-MST1-39 and metformin synergistically prevented hyperglycemia and significantly ameliorated glucose tolerance and insulin resistance in diabetic mice. Taken together, IHMT-MST1-39 is a promising anti-diabetic candidate as a single agent or in combination therapy for both T1D and T2D.

Ginsenoside CK improves skeletal muscle insulin resistance by activating DRP1/PINK1-mediated mitophagy.

Skeletal muscle insulin resistance is the main cause of type 2 diabetes, and mitochondria play a key role. Ginsenoside CK is the main active compound of ginseng with a variety of therapeutic effects, but few studies have reported on its mechanism towards skeletal muscle insulin resistance. Here, we found that CK significantly increased skeletal muscle insulin sensitivity, thereby alleviating hyperglycemia and insulin resistance. Furthermore, the effects of CK on skeletal muscle were associated with an improved mitochondrial fusion/fission dynamics balance and fatty acid oxidation. In fatty acid (FA)-induced C2C12 cells, CK promoted the translocation of GLUT4 to the cell membrane to improve glucose uptake and glycogen synthesis and also enhanced the mitochondrial quality. CK ameliorated the damaged mitochondrial membrane potential (ΔΨm), which was based on mitophagy activation. After the knockdown of mitophagy-related receptors, we found that DRP1/PINK1 was the key pathway of CK-induced mitophagy. These findings indicated that ginsenoside CK is a promising lead compound against diabetes.

Fermented Psidium guajava leaves regulate the gut microbiota and improve metabolic alterations in diabetic mice

The phenolic extract from fermented Psidium guajava leaves (PFGL) helps to improve diabetes; however, its hypoglycemic and hypolipidemic mechanisms remain unclear. In this study, gut microbiota modulation and glucose-lipid metabolism was investigated. The results showed that dietary supplement of PFGL enriched in quercetin glucosides significantly improved serum glucose-lipid profiles as well as insulin resistance in diabetic mice. The gut microbiota of diabetic mice was modulated by PFGL (200 mg/kg), causing an abundance of Bacteroidetes, Prevotellaceae, and Alistipes and a reduced the presence of Firmicutes and Streptococcus. Increased levels of short-chain fatty acids (SCFA) activated G protein-coupled receptor signaling that induced peptide YY release to promote insulin secretion. Diabetes-induced serum metabolite disorders that are involved in glycerophospholipid metabolism and tryptophan metabolism were restored by PFGL. The protein expression of metabolic enzymes including phospho-adenosine 5’-monophosphate-activated protein kinase, fatty acid synthase, acyl-coenzyme A oxidase, and diacylglycerol aeyltransferase 2 were also regulated to promote glucose-lipid metabolism. In particular, gut microbiota enriched with Alistipes genera and SCFA metabolic regulation were closely correlated with diabetes-related indicators. These findings provide a theoretical support for the development and application of PFGL for the treatment of diabetes.

Characterization and anti-diabetic evaluation of sulfated polysaccharide from Spirulina platensis

In this study, the structure, composition, cytotoxicity, and in vitro hypoglycemic activity of a polysaccharide isolated from Spirulina platensis (PSP1) and its degradation fragments (PSP2, PSP3) were assessed. Structurally, PSP was identified as a sulfated α-pyranose. All three tested polysaccharides were found to inhibit α-glucosidase, with the small-molecule polysaccharide PSP3 exhibiting the best efficacy in this context. MTT assays indicated that none of the tested polysaccharides exhibited cytotoxic activity when used to treat 3T3-L1 preadipocytes, whereas all three were able to enhance the glucose uptake capacity of these cells in a model of insulin resistance and PSP3 exhibited the best in vitro hypoglycemic activity. In vivo hypoglycemic activity of PSP3 indicated that its oral administration alleviated glucose and lipid metabolism disorders in STZ-induced diabetic mice, PSP3 alleviating insulin resistance in diabetic mice while also improving liver function parameters and antioxidant system activity.

Hypoglycemic Effects of Lycium barbarum Polysaccharide in Type 2 Diabetes Mellitus Mice via Modulating Gut Microbiota.

This study aims to explore the molecular mechanisms of Lycium barbarum polysaccharide (LBP) in alleviating type 2 diabetes through intestinal flora modulation. A high-fat diet (HFD) combined with streptozotocin (STZ) was applied to create a diabetic model. The results indicated that LBP effectively alleviated the symptoms of hyperglycemia, hyperlipidemia, and insulin resistance in diabetic mice. A high dosage of LBP exerted better hypoglycemic effects than low and medium dosages. In diabetic mice, LBP significantly boosted the activities of CAT, SOD, and GSH-Px and reduced inflammation. The analysis of 16S rDNA disclosed that LBP notably improved the composition of intestinal flora, increasing the relative abundance of Bacteroides, Ruminococcaceae_UCG-014, Intestinimonas, Mucispirillum, Ruminococcaceae_UCG-009 and decreasing the relative abundance of Allobaculum, Dubosiella, Romboutsia. LBP significantly improved the production of short-chain fatty acids (SCFAs) in diabetic mice, which corresponded to the increase in the beneficial genus. According to Spearman’s correlation analysis, Cetobacterium, Streptococcus, Ralstonia. Cetobacterium, Ruminiclostridium, and Bifidobacterium correlated positively with insulin, whereas Cetobacterium, Millionella, Clostridium_sensu_stricto_1, Streptococcus, and Ruminococcaceae_UCG_009 correlated negatively with HOMA-IR, HDL-C, ALT, AST, TC, and lipopolysaccharide (LPS). These findings suggested that the mentioned genus may be beneficial to diabetic mice’s hypoglycemia and hypolipidemia. The up-regulation of peptide YY (PYY), glucagon-like peptide-1 (GLP-1), and insulin were remarkably reversed by LBP in diabetic mice. The real-time PCR (RT-PCR) analysis illustrated that LBP distinctly regulated the glucose metabolism of diabetic mice by activating the IRS/PI3K/Akt signal pathway. These results indicated that LBP effectively alleviated the hyperglycemia and hyperlipidemia of diabetic mice by modulating intestinal flora.

Effect of Danlou Tablets on alleviating hepatic adipogenesis, inflammatory response, and insulin resistance in db/db mice

This study explored the effect and potential mechanism of Danlou Tablets(DLT) on insulin resistance in db/db mice with type 2 diabetic mellitus(T2 DM). The db/db male mice were randomly assigned into model control(MC) group, metformin(MET, tablet, 100 mg·kg~(-1)) group, and DLT(1 g·kg~(-1)) group, and C57 BL/6 J mice were taken as normal control(NC) group. The mice in the MET group and DLT group were given corresponding drugs by gavage once a day for 16 weeks. The fasting blood glucose, glucose tolerance, and insulin tolerance were measured to evaluate the effect of DLT on blood glucose and insulin resistance in diabetic mice. The serum free fatty acid, triacylglycerol, and total cholesterol levels were determined to evaluate the effect of DLT on blood lipids in diabetic mice. The liver index and perirenal fat index were calculated to measure the effect of DLT on lipid accumulation in non-adipose tissue and adipose tissue. Western blot was performed to determine the protein levels of insulin receptor-β(IRβ), phospho-IRβ(p-IRβ), phosphatidylinositol 3-kinase(PI3 K), and insulin receptor substrate-1(IRS-1) involved in IRS-1/PI3 K/Akt signaling pathway in the livers of mice to reveal the mechanism of DLT in alleviating insulin resistance in diabetic mice. The protein levels of sterol regulatory element binding protein-1(SREBP-1) and the mRNA levels of sterol regulatory element binding protein-1 c(SREBP-1 c), fatty acid synthase(FAS), acetyl-CoA carboxylase(ACC), diacylglycerol acyltransferase-1(Dgat1), and diacylglycerol acyltransferase-2(Dgat2) involved in the SREBP-1/FAS signaling pathway were detected to evaluate the effect of DLT on lipid metabolism in diabetic mice. Real-time quantitative PCR was employed to determine the mRNA levels of galectin-3(Gal-3), interleukin-6(IL-6), and monocyte chemoattractant protein-1(MCP-1) in mouse liver to evaluate the effect of DLT on inflammatory response in diabetic mice. The results showed that DLT significantly reduced the blood glucose and lipid levels and alleviated the insulin resistance in diabetic mice. Compared with the MC group, DLT significantly up-regulated the protein levels of p-IRβ, PI3 K, and IRS-1(P<0.05 or P<0.01), and down-regulated the protein level of SREBP-1 in liver tissues of diabetic mice(P<0.05). DLT lowered the mRNA levels of SREBP-1 c, FAS, ACC, Dgat1, and Dgat2 related to lipid metabolism as well as those of Gal-3, IL-6, and MCP-1 associated with inflammation in the livers of diabetic mice(P<0.05 or P<0.01). The findings of this study suggest that DLT may alleviate insulin resistance in diabetic mice by regulating IRS-1/PI3 K/Akt signaling pathway and SREBP-1/FAS signaling pathway to reduce lipid production and inhibit inflammatory response.

Sarco/Endoplasmic Reticulum Ca2+ ATPase 2 Activator Ameliorates Endothelial Dysfunction; Insulin Resistance in Diabetic Mice.

Background: Sarco/endoplasmic reticulum Ca2+-ATPase2 (SERCA2) is impaired in various organs in animal models of diabetes. The purpose of this study was to test the effects of an allosteric SERCA2 activator (CDN1163) on glucose intolerance, hepatosteatosis, skeletal muscle function, and endothelial dysfunction in diabetic (db/db) mice. Methods: Either CDN1163 or vehicle was injected intraperitoneally into 16-week-old male control and db/db mice for 5 consecutive days. Results: SERCA2 protein expression was decreased in the aorta of db/db mice. In isometric tension measurements of aortic rings from db/db mice treated with CDN1163, acetylcholine (ACh)-induced relaxation was improved. In vivo intraperitoneal administrations of CDN 1163 also increased ACh-induced relaxation. Moreover, CDN1163 significantly decreased blood glucose in db/db mice at 60 and 120 min during a glucose tolerance test; it also decreased serum insulin levels, hepatosteatosis, and oxygen consumption in skeletal muscle during the early period of exercise in db/db mice. Conclusions: CDN1163 directly improved aortic endothelial dysfunction in db/db mice. Moreover, CDN1163 improved hepatosteatosis, skeletal muscle function, and insulin resistance in db/db mice. The activation of SERCA2 might be a strategy for the all the tissue expressed SERCA2a improvement of endothelial dysfunction and the target for the organs related to insulin resistance.

Potential probiotics Lactobacillus casei K11 combined with plant extracts reduce markers of type 2 diabetes mellitus in mice.

Probiotics and plant extracts have been used to prevent the development of type 2 diabetes mellitus (T2DM). The study aimed to explore the effect of the interaction between potential probiotics and bitter gourd extract (BGE) or mulberry leaf extract (MLE) on T2DM. Potential probiotics were tested for their gastrointestinal tract viability and growth situation combined with BGE and MLE in vitro. The diabetes model was constructed in C57BL/6 mice, and the potential effect and mechanism of regulating blood glucose were verified. Hematoxylin-eosin staining (HE), gas chromatography (GC), ELISA, and RT-PCR were also used for analysis. The results showed that Lactobacillus casei K11 had outstanding gastrointestinal tract viability and growth situation with plant extracts. Administration of L. casei K11 combined with BGE and MLE significantly reduced blood glucose levels and ameliorated insulin resistance in diabetic mice than the administration of Lactobacillus paracasei J5 combined with BGE and MLE. Moreover, in L. casei K11 combined with BGE and MLE groups, lipid metabolism, oxidative stress, and proinflammatory cytokine levels were regulated. Furthermore, the results indicated that L. casei K11 combined with BGE and MLE improved free fatty acid receptor 2 (FFAR2) upregulation, glucagon-like peptide-1 (GLP-1) secretion, and short-chain fatty acid (SCFA) levels. These findings showed that L. casei K11 combined with BGE and MLE modified the SCFA-FFAR2-GLP-1 pathway to improve T2DM. This study identified a new modality for evaluating interactions between potential probiotics and plant extracts. Our findings revealed that L. casei K11 combined with BGE and MLE significantly promoted the SCFA-FFAR2-GLP-1 pathway to inhibit T2DM.

Mesenchymal stem cell-conditioned medium improved mitochondrial function and alleviated inflammation and apoptosis in non-alcoholic fatty liver disease by regulating SIRT1

Non-alcoholic fatty liver disease (NAFLD), an emerging risk factor for diabetes, is now recognized as the most common liver disease worldwide. Mesenchymal stem cells (MSCs), a promising tool in regenerative medicine, release abundant molecules into the conditioned medium (CM). Increasing evidence showed that MSC-CM is beneficial for diabetes-associated NAFLD. However, the mechanism of how MSC-CM improves NAFLD remains uncertain. In this study, to determine the effects of MSC-CM on NAFLD, streptozotocin (STZ) and high-fat diet (HFD) induced T2DM mice model and palmitic acid (PA)-stimulated L-O2 cells were used and treated with MSC-CM. Our results demonstrated that MSC-CM improved insulin resistance in diabetic mice, amended the pathological structure of the liver, enhanced the liver’s total antioxidant capacity and mitochondrial function, reduced inflammation and cell apoptosis. We further verified that SIRT1 played a key role in mediating the protective effect of MSC-CM. These findings provide novel evidence that MSC-CM has the potential to treat T2DM patients with NAFLD clinically.

Protein Isolates from Raw and Cooked Foxtail Millet Attenuate Development of Type 2 Diabetes in Streptozotocin-Induced Diabetic Mice.

Millet protein has received much attention due to its beneficial role in alleviating metabolic disease symptoms. This study aims to investigate the role and molecular mechanism of foxtail millet protein isolates, including protein isolates from raw and cooked foxtail millet in alleviating diabetes, including gut microbiota and intracellular signal pathways. Protein isolates from raw and cooked foxtail millet are orally administered to streptozotocin (STZ)-induced diabetic mice for 5 weeks before hypoglycemic effect evaluation. The results show that foxtail millet protein isolates improve glucose intolerance and insulin resistance in diabetic mice. However, only the protein isolate from cooked foxtail millet reverse the weight loss trend and alleviate lipid disorders in diabetic mice. Besides, 16S rRNA sequencing show that both raw and cooked foxtail millet protein isolates altered diabetes-induced gut dysbiosis. In addition, western blotting analysis indicated that the protein isolate from cooked foxtail millet increases the expression levels of glucagon-like peptide-1 receptor (GLP-1R), phosphoinositide 3-kinase (PI3K), and phosphoinositide-protein kinase B (p-AKT)/AKT while the protein isolate from raw foxtail millet downregulates stearoyl-coenzyme A desaturase 1 (SCD1) level. Both raw and cooked foxtail millet protein isolates can exert hypoglycemic effects in diabetic mice through rewiring glucose homeostasis, mitigating diabetes-induced gut dysbiosis, and affecting the GLP-1R/PI3K/AKT pathway.

DNA aptamer raised against receptor for advanced glycation end products suppresses renal tubular damage and improves insulin resistance in diabetic mice.

Objective:Interaction of advanced glycation end products (AGEs) with the receptor RAGE plays a role in diabetic nephropathy. However, effects of RAGE-aptamer on tubular damage remain unknown. We examined whether RAGE-aptamer inhibited tubular damage in KKAy/Ta mice, obese type 2 diabetic mice with insulin resistance.Materials and Methods:Male 8-week-old KKAy/Ta mice received continuous intraperitoneal infusion of either control-aptamer or RAGE-aptamer for 8 weeks. Blood biochemistry and blood pressure, and urinary N-acetyl-β-D-glucosaminidase (NAG) activity and albumin excretion levels were monitored. Kidney and adipose tissue samples were obtained for immunohistochemical analyses.Results:Although RAGE-aptamer did not affect blood glucose, blood pressure, body weight, or serum creatinine values, it significantly inhibited the increase in urinary NAG activity and HOMA-IR in diabetic mice at 12 and 16 and at 16 weeks old, respectively. Furthermore, compared with control-aptamer-treated mice, renal carboxymethyllysine, RAGE, and NADPH oxidase-driven superoxide generation were significantly decreased in RAGE-aptamer-treated mice at 12 weeks old with subsequent amelioration of histological alterations in glomerular and interstitial area, while adipose tissue adiponectin expression was increased.Conclusion:Our present results suggest that RAGE-aptamer could inhibit tubular injury in obese type 2 diabetic mice partly by suppressing the AGE-RAGE-oxidative stress axis and improving insulin resistance.

Antidiabetic effect of a flavonoid-rich extract from Sophora alopecuroides L. in HFD- and STZ- induced diabetic mice through PKC/GLUT4 pathway and regulating PPARα and PPARγ expression

Headings ethnopharmacological relevanceSophora alopecuroides L. is a traditional ethnopharmacological plant, which is widely used in traditional Chinese medicine and Mongolian and Uighur medicine to ameliorate “thirst disease”. Aim of the studyThis study aimed to investigate the antidiabetic activities and mechanisms of a flavonoid-rich extract from Sophora alopecuroides L. (SA-FRE) both in vivo and vitro. Materials and methodsThe main six chemical constituents of SA-FRE were elucidated based on an off-line semi-preparative liquid chromatography nuclear magnetic resonance (LC-NMR) protocol. Myc-GLUT4-mOrange-L6 cell models and mouse model with diabetes induced by high-fat diet combined with STZ injection were respectively adopted to investigate the antidiabetic effects of SA-FRE both in vitro and vivo. ResultsIn vivo, 4-week treatment of SA-FRE ameliorated hyperglycemia, dyslipidemia, and insulin resistance in diabetic mice. Mechanically, SA-FRE regulated PPARα and PPARγ expression in white adipose tissue (WAT) and liver, thereby ameliorating dyslipidemia. Moreover, SA-FRE increased the phosphorylation of PKC and further stimulated the GLUT4 expression in WAT and skeletal muscle, thus increasing the glucose utilization in vivo. In vitro, 50 μg/mL SA-FRE increased GLUT4 translocation to about 1.91-fold and glucose uptake to 1.82-fold in L6-myotubes. SA-FRE treatment increased the GLUT4 expression at both gene and protein levels. Furthermore, only Gö6983, a PKC inhibitor, reversed the SA-FRE-induced GLUT4 translocation and expression at the gene and protein levels. ConclusionsGenerally, SA-FRE ameliorated hyperglycemia, dyslipidemia, and insulin resistance partly through activating PKC/GLUT4 pathway and regulating PPARα and PPARγ expression.

The effect of electric field, magnetic field, and infrared ray combination to reduce HOMA-IR index and GLUT 4 in diabetic model of Mus musculus

Diabetes mellitus (DM) is a metabolic disorder characterized by high blood glucose level (hyperglycemia). Type 2 diabetes mellitus is mainly featured by low cell sensitivity towards insulin stimulation, caused by ectopic fat storage. Insulin resistance can be quantified from high number of HOMA-IR index and observed from glucose transporter 4 (GLUT-4) translocation on membrane of skeletal muscle cells. Combined treatment of electric field, magnetic field, and infrared ray have potential to reduce insulin resistance due to improving blood circulation and increasing intracellular Ca2+ level. The aim of study was to determine the effect of electric field, magnetic field, and infrared ray combination to lower insulin resistance in the type II diabetic model of Mus musculus. This study used 30 adult male mice strain BALB/c. Diabetes was induced using high-fat diet/streptozotocin method until random blood glucose level reached > 200 mg/dL. Diabetic mice were then exposed to electrical field (static and dynamic), magnetic field (static and induce), and infrared ray (with or without infrared ray) combination therapy 15 min daily for 28 days. Fasting blood glucose level, plasma insulin level, HOMA-IR index, and membrane GLUT-4 density after treatment were analyzed statistically at α = 0.05. Result showed that exposure combination of electrical field, magnetic field, and infrared were found to be able to lower fasting blood glucose level and HOMA-IR index significantly, but plasma insulin level and GLUT-4 density were not found to be significantly different compared to diabetic control. Based on current study result, the best combination for reducing insulin resistance in diabetic mice is BsEsI (combination of static magnetic field (Bs), static electric field (Es), with infrared (I)), indicated by lowest HOMA-IR compared to other groups. Exposure to combination of magnetic field, electrical field, and infrared resulted in lowering fasting blood glucose level and HOMA-IR index in diabetic mice, indicating reduced insulin resistance.

Nuciferine ameliorates hepatic steatosis in high-fat diet/streptozocin-induced diabetic mice through a PPARα/PPARγ coactivator-1α pathway.

Nuciferine, an alkaloid found in Nelumbo nucifera leaves, alleviates dyslipidemia in vivo. However, whether it improves liver injury in diabetic conditions and the underlying mechanism is unclear. The present study aimed to investigate the effects of nuciferine on lipid and glucose metabolism in a murine model of Type 2 diabetes mellitus (T2DM) and to determine the underlying mechanisms of these effects. A murine model of T2DM was induced by high-fat diet (HFD) feeding combined with streptozocin (STZ) injections, and the diabetic mice were treated with nuciferine in their food. The underlying mechanism of the anti-steatotic effect of nuciferine was further explored in HepG2 hepatocytes cultured with palmitic acid. Major signalling profiles involved in fatty acid oxidation were then evaluated, using Western blot, RT-qPCR and si-RNA techniques, along with immunohistochemistry. Nuciferine restored impaired glucose tolerance and insulin resistance in diabetic mice. Hepatic levels of total cholesterol, triglycerides and LDL were decreased, as were the number of lipid droplets, by nuciferine treatment. Furthermore, nuciferine up-regulated β-oxidation related genes in livers of diabetic mice. Luciferase reporter cell assay showed that nuciferine directly reversed palmitic acid-induced inhibition of PPARα transcriptional activity. Silencing PPARγ coactivator-1α (PGC1α) expression in HepG2 cells abolished the effects of nuciferine in accelerating β-oxidation. Nuciferine improved lipid profile and attenuated hepatic steatosis in HFD/STZ-induced diabetic mice by activating the PPARα/PGC1α pathway. Nuciferine may be a potentially important candidate in improving hepatic steatosis and the management of T2DM.