Type 2 Diabetes Mice Research Articles

The Accelerated Progression of Atherosclerosis Correlates with Decreased miR-33a and miR-21 and Increased miR-122 and miR-3064-5p in Circulation and the Liver of ApoE-/- Mice with Streptozocin (STZ)-Induced Type 2 Diabetes.

Atherosclerosis is a major risk factor for type 2 diabetes (T2D) mortality. We aim to investigate the changes in miR-21, miR-122, miR-33a and miR-3064-5p in circulation and the liver of ApoE-/- mice with streptozocin (STZ)-induced T2D. Twenty 5-week-old male ApoE-/- mice were randomly assigned to the control (n = 10) and T2D group (n = 10) and intraperitoneally injected with a citrate buffer and streptozotocin (STZ) (40 mg/kg BW) once a day for three consecutive days. The successfully STZ-induced T2D mice (n = 5) and control mice (n = 5) were then fed with a high-fat diet (HFD) for 34 weeks. Compared to the control mice, ApoE-/- mice with STZ-induced T2D had slower (p < 0.05) growth, increased (p < 0.05) total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), decreased (p < 0.05) high-density lipoprotein cholesterol (HDL-C) in serum, reduced (p < 0.05) TC and sterol regulatory element-binding protein-2 (Srebp-2), elevated (p < 0.05) ATP-binding-cassette-transporter-A1 (Abca1) in the liver, aggravated (p < 0.05) atherosclerotic lesions in the aorta, downregulated (p < 0.05) miR-21 and miR-33a, and upregulated (p < 0.05) miR-122 and miR-3064-5p in serum and the liver. In addition, the aortic lesions showed a positive correlation with miR-122 (r = 1.000, p = 0.001) and a negative correlation with miR-21 (r = −1.000, p = 0.001) in ApoE-/- mice with T2D. In conclusion, T2D-accelerated atherosclerosis correlates with a reduction in miR-21 and miR-33a and an elevation in miR-122 and miR-3064-5p in circulation and the liver of ApoE-/- mice.

Electroacupuncture reduces blood glucose by regulating intestinal flora in type 2 diabetic mice.

BackgroundThe development of diabetes is closely related to the gut microbiota in recent studies, which can be influenced by intestinal motility. A few studies report that electroacupuncture (EA) can lower blood glucose. EA can promote colonic motility and influence gut microbes. In this study, we explored the effect of the EA on blood glucose level in mice with type 2 diabetes (T2D) and its mechanism.MethodsThe T2D mice model, fecal microbiota transplantation mice model, and KitW/Wv mice model （Point mutation of mouse W locus encoding kit gene）were used to investigate the effect of EA on blood glucose as well as the mechanism; The blood glucose and insulin resistance level and the intestinal flora were evaluated. The level of intestinal junction protein, inflammatory cytokines in the serum, interstitial cells of Cajal content, and colonic motility were detected. Lastly, the IKKβ/NF‐κB‐JNK‐IRS‐1‐AKT pathway was explored.ResultsEA lowered the blood glucose level, altered the gut microbiota, and promoted colonic motility in T2D mice. EA‐altered microbiota decreased the blood glucose level and insulin resistance in the antibiotics‐treated diabetic mice. EA increased tight junction protein, lowered inflammatory factors, and regulated the IKKβ/NF‐κB‐JNK‐IRS‐1‐AKT pathway in the liver and muscles. EA could not reduce the blood glucose and regulated gut microbiota in the KitW/Wv mice model.ConclusionsEA promoted intestinal motility to regulate the intestinal flora, thereby reducing the level of systemic inflammation, and ultimately lowering the blood glucose by the IKKβ/NF‐κB‐JNK‐IRS‐1‐AKT signal pathway.

Sunlight-Controllable Biopharmaceutical Production for Remote Emergency Supply of Directly Injectable Therapeutic Proteins.

Biopharmaceutical manufacturing requires specialized facilities and a long-range cold supply chain for the delivery of the therapeutics to patients. In order to produce biopharmaceuticals in locations lacking such infrastructure, a production process is designed that utilizes the trigger-inducible release of large quantities of a stored therapeutic protein from engineered endocrine cells within minutes to generate a directly injectable saline solution of the protein. To illustrate the versatility of this approach, it is shown that not only insulin, but also glucagon-like peptide 1 (GLP-1), nanoluciferase (NLuc), and the model biopharmaceutical erythropoietin (EPO)can be trigger-inducibly released, even when using biologically inactive insulin as a carrier. The facilitating beta cells are engineered with a controllable TRPV1-mediated Ca2+ influx that induces the fusion of cytoplasmic storage vesicles with the membrane, leading to the release of the stored protein. When required, the growth medium is exchanged for saline solution, and the system is stimulated with the small molecule capsaicin, with a hand-warming pack, or simply by using sunlight. Injection of insulin saline solution obtained in this way into a type-1 diabetes mouse model results in the regulation of blood glucose levels. It is believed that this system will be readily adaptable to deliver various biopharmaceutical proteins at remote locations.

Magnolol effectively ameliorates diabetic peripheral neuropathy in mice

BackgroundDiabetic peripheral neuropathy (DPN) is a common complication of diabetes lacking efficient treatment. Magnolol (MG), a peroxisome proliferator-activated receptor γ (PPARγ) agonist, is a natural product derived from Magnolia officinalis and widely used to treat a variety of diseases as a traditional Chinese medicine and Japanese Kampo medicine. PurposeHere, we aimed to investigate the potential of MG in ameliorating DPN-like pathology in mice and decipher the mechanism of MG in treating DPN. Materials and methods12-week-old male streptozotocin (STZ)-induced type 1 diabetic (T1DM) mice and 15-week-old male BKS Cg-m+/+Lepr db/J (db/db) type 2 diabetic mice (T2DM) were used as DPN mice. MG was administrated (i.p) daily for 4 weeks. Peripheral nerve functions of mice were evaluated by measuring mechanical response latency, thermal response latency and motor nerve conduction velocity (MNCV). The mechanisms underlying the amelioration of MG on DPN-like pathology were examined by qRT-PCR, western blot and immunohistochemistry assays, and verified in the DPN mice with PPARγ-specific knockdown in dorsal root ganglia (DRG) neuron and sciatic nerve tissues by injecting adeno-associated virus (AAV)8-PPARγ-RNAi. ResultsMG promoted DRG neuronal neurite outgrowth and effectively ameliorated neurological dysfunctions in both T1DM and T2DM diabetic mice, including improvement of paw withdrawal threshold, thermal response latency and MNCV. Additionally, MG promoted neurite outgrowth of DRG neurons, protected sciatic nerve myelin sheath structure, and ameliorated foot skin intraepidermal nerve fiber (IENF) density in DPN mice by targeting PPARγ. Mechanism research results indicated that MG improved mitochondrial dysfunction involving PPARγ/MKP-7/JNK/SIRT1/LKB1/AMPK/PGC-1α pathway in DRG neurons, repressed inflammation via PPARγ/NF-κB signaling and inhibited apoptosis through regulation of PPARγ-mediated Bcl-2 family proteins in DRG neurons and sciatic nerves. ConclusionsOur work has detailed the mechanism underlying the amelioration of PPARγ agonist on DPN-like pathology in mice with MG as a probe, and highlighted the potential of MG in the treatment of DPN.

Xanthan gum oligosaccharides ameliorate glucose metabolism and related gut microbiota dysbiosis in type 2 diabetic mice

Xanthan gum oligosaccharides (XGOS) is a potentially commercial prebiotic. This study investigated the effects of XGOS on in vivo glucose metabolic parameters and gut microbiota structures in streptozotocin/high fat diet (STZ/HFD)-induced type 2 diabetic (T2D) mice and in vitro fecal fermentations using Hungate tubes and a Bionic Gastrointestinal Reactor (BGR). XGOS can efficiently ameliorate fasting hyperglycemia, glucose tolerance, insulin levels, pro-inflammatory cytokine interleukin-6 levels, and liver and pancreas pathological structures in T2D mice as compared with the model group. XGOS shaped the colonic microbiota structures by significantly reversing an increase in the Firmicutes to Bacteroidetes ratio and increasing Bacteroidales and Prevotella abundance in T2D mice and in vitro fecal fermentations. XGOS consumption increased by 83% of butyric acid in in vitro fecal fermentation using BGR, but not in T2D mice feces. Notably, XGOS degradation significantly stimulated expression of the short-chain fatty acid (SCFA) receptors, GPR41 and GPR43 in the liver. These findings indicated XGOS can ameliorate glucose metabolism in T2D mice, which was associated with the alteration of gut microbiota and the activation of SCFA receptors in the liver.

Daily Treatment of Mice with Type 2 Diabetes with Adropin for Four Weeks Improves Glucolipid Profile, Reduces Hepatic Lipid Content and Restores Elevated Hepatic Enzymes in Serum.

Adropin is a peptide hormone encoded by Energy Homeostasis Associated gene. Adropin modulates energy homeostasis and metabolism of lipids and carbohydrates. There is growing evidence demonstrating that adropin enhances insulin sensitivity and lowers hyperlipidemia in obese mice. The aim of this study was to investigate the effects of daily administration of adropin for four weeks in mice with experimentally induced type 2 diabetes (T2D). Adropin improved glucose control without modulating insulin sensitivity. Adropin reduced body weight, size of adipocytes, blood levels of triacylglycerol and cholesterol in T2D mice. T2D mice treated with adropin had lower liver mass, reduced hepatic content of triacylglycerol and cholesterol. Furthermore, adropin attenuated elevated blood levels of hepatic enzymes (ALT, AST, GGT and ALP) in T2D mice. In T2D mice, adropin increased the circulating adiponectin level. Adropin had no effects on circulating insulin and glucagon levels and did not alter pancreatic islets morphology. These results suggest that adropin improves glucose control, lipid metabolism and liver functions in T2D. In conjunction with reduced lipid content in hepatocytes, these results render adropin as an interesting candidate in therapy of T2D.

MLKL-mediated necroptosis is a target for cardiac protection in mouse models of type-1 diabetes

BackgroundCardiomyocyte death contributes to cardiac pathology of diabetes. Studies have shown that the RIPK3/MLKL necroptosis signaling is activated in diabetic hearts. Deletion of RIPK3 was reported to attenuate myocardial injury and heart dysfunction in streptozocin (STZ)-induced diabetic mice, suggesting a potential role of necroptosis in diabetic cardiomyopathy. This study characterized cardiomyocyte necroptosis in diabetic hearts and investigated whether MLKL-mediated necroptosis is a target for cardiac protection in diabetes.MethodsType 1 diabetes was induced in RIPK3 knockout, MLKL knockout and wild-type mice. Akita Type-1 diabetic mice were injected with shRNA for MLKL. Myocardial function was assessed by echocardiography. Immuno-histological analyses determined cardiomyocyte death and fibrosis in the heart. Cultured adult mouse cardiomyocytes were incubated with high glucose in the presence of various drugs. Cell death and phosphorylation of RIPK3 and MLKL were analysed.ResultsWe showed that the levels of phosphorylated RIPK3 and MLKL were higher in high glucose-stimulated cardiomyocytes and hearts of STZ-induced type-1 diabetic mice, akita mice and type-1 diabetic monkeys when compared to non-diabetic controls. Inhibition of RIPK3 by its pharmacological inhibitor or gene deletion, or MLKL deletion prevented high glucose-induced MLKL phosphorylation and attenuated necroptosis in cardiomyocytes. In STZ-induced type-1 diabetic mice, cardiomyocyte necroptosis was present along with elevated cardiac troponin I in serum and MLKL oligomerization, and co-localized with phosphorylated MLKL. Deletion of RIPK3 or MLKL prevented MLKL phosphorylation and cardiac necroptosis, attenuated serum cardiac troponin I levels, reduced myocardial collagen deposition and improved myocardial function in STZ-injected mice. Additionally, shRNA-mediated down-regulation of MLKL reduced cardiomyocyte necroptosis in akita mice. Interestingly, incubation with anti-diabetic drugs (empagliflozin and metformin) prevented phosphorylation of RIPK3 and MLKL, and reduced cell death in high glucose-induced cardiomyocytes.ConclusionsWe have provided evidence that cardiomyocyte necroptosis is present in diabetic hearts and that MLKL-mediated cardiomyocyte necroptosis contributes to diabetic cardiomyopathy. These findings highlight MLKL-mediated necroptosis as a target for cardiac protection in diabetes.

Genetic and Pharmacological Inhibition of GCN2 Ameliorates Hyperglycemia and Insulin Resistance in Type 2 Diabetic Mice.

It is well recognized that there is a strong and complex association between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). We previously demonstrated that genetic knockout or pharmacological inhibition of general control nondepressible kinase 2 (GCN2), a well-known amino acid sensor, alleviated hepatic steatosis and insulin resistance in obese mice. However, whether GCN2 affects the development of T2D remains unclear. After a high-fat diet (HFD) plus low-dose streptozotocin (STZ) treatments, Gcn2−/− mice developed less hyperglycemia, insulin resistance, hepatic steatosis, and oxidative stress than wild-type (WT) mice. Inhibition of GCN2 by intraperitoneal injection of 3 mg/kg GCN2iB (a specific inhibitor of GCN2) every other day for 6 weeks also ameliorated hyperglycemia, insulin resistance, hepatic steatosis, and oxidative stress in HFD/STZ- and leptin receptor deletion (db/db)-induced T2D mice. Moreover, depletion of hepatic GCN2 in db/db mice by tail vein injection of an AAV8-shGcn2 vector resulted in similar improvement in those metabolic disorders. The protective mechanism of GCN2 inhibition in T2D mice was associated with regulation of the glucose metabolic pathway, repression of lipogenesis genes, and activation of the Nrf2 pathway. Together, our data provide evidence that strategies to inhibit hepatic GCN2 activity may be novel approaches for T2D therapy.

Abstract P3017: Aldehyde Dehydrogenase 2 Augments Adiponectin Signaling In Coronary Angiogenesis In Hfpef Associated With Diabetes

4-hydroxy-2-nonenal (4HNE), a reactive aldehyde, is elevated in diabetes that decreases coronary angiogenesis and this was rescued by aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme that detoxifies 4HNE. Adiponectin (APN), a pleiotropic hormone, has pro-angiogenic properties which was shown to be critical in diabetes and its complications. However, the interaction between ALDH2 and APN signaling in coronary angiogenesis is unknown. Coronary endothelial cell (CEC) damage is the initiating step of diabetes-mediated heart failure with preserved ejection fraction (HFpEF) pathogenesis. Thus, we hypothesize that ALDH2 restores 4HNE-induced downregulation of APN signaling in CECs and subsequent coronary angiogenesis in diabetic HFpEF. First of all, APN significantly increased coronary angiogenesis. However, 4HNE treatment significantly decreased the levels of APN signaling molecules including adiponectin receptor (AdipoR)1, APPL1, phospho-AMPK, AMPK, phospho-AKT, and AKT in mouse CECs. Treatment with disulfiram (DSF), an ALDH2 inhibitor, exacerbated 4HNE-mediated decreases in APN-induced increased coronary angiogenesis and APN-signaling cascades, whereas pretreatment with alda1, an ALDH2 activator, rescued the effect of 4HNE. We employed control (db/m) mice, spontaneous type-2 diabetic (db/db) mice, ALDH2*2 knock-in mutant mice with intrinsic low ALDH2 activity (AL), and diabetic mice with intrinsic low ALDH2 activity (AF) that were created by crossing db/db and AL mice to test our hypothesis in vivo. AF mice exhibit severe HFpEF at 6 months compared to age-matched db/db mice as well as 3 months-old AF mice. At 6m, db/db, AL &amp; AF mice significantly decreased APN response to coronary angiogenesis along with increased serum APN levels and decreased cardiac tissue levels of AdipoR1, APPL1, P-AMPK, and P-AKT implicating occurrence of APN resistance which was higher in AF mice. Alda-1 treatment improved APN-mediated angiogenesis significantly in db/db and AF mice. In conclusion, 4HNE-induces APN resistance and subsequently decreases coronary angiogenesis in diabetic HFpEF which was rescued by ALDH2 activation.

Tirzepatide induces a thermogenic-like amino acid signature in brown adipose tissue

ObjectivesTirzepatide, a dual GIP and GLP-1 receptor agonist, delivered superior glycemic control and weight loss compared to selective GLP-1 receptor (GLP-1R) agonism in patients with type 2 diabetes (T2D). These results have fueled mechanistic studies focused on understanding how tirzepatide achieves its therapeutic efficacy. Recently, we found that treatment with tirzepatide improves insulin sensitivity in humans with T2D and obese mice in concert with a reduction in circulating levels of branched-chain amino (BCAAs) and keto (BCKAs) acids, metabolites associated with development of systemic insulin resistance (IR) and T2D. Importantly, these systemic effects were found to be coupled to increased expression of BCAA catabolic genes in thermogenic brown adipose tissue (BAT) in mice. These findings led us to hypothesize that tirzepatide may lower circulating BCAAs/BCKAs by promoting their catabolism in BAT. MethodsTo address this question, we utilized a murine model of diet-induced obesity and employed stable-isotope tracer studies in combination with metabolomic analyses in BAT and other tissues. ResultsTreatment with tirzepatide stimulated catabolism of BCAAs/BCKAs in BAT, as demonstrated by increased labeling of BCKA-derived metabolites, and increases in levels of byproducts of BCAA breakdown, including glutamate, alanine, and 3-hydroxyisobutyric acid (3-HIB). Further, chronic administration of tirzepatide increased levels of multiple amino acids in BAT that have previously been shown to be elevated in response to cold exposure. Finally, chronic treatment with tirzepatide led to a substantial increase in several TCA cycle intermediates (α-ketoglutarate, fumarate, and malate) in BAT. ConclusionsThese findings suggest that tirzepatide induces a thermogenic-like amino acid profile in BAT, an effect that may account for reduced systemic levels of BCAAs in obese IR mice.

Inhibition of GCN2 Alleviates Cardiomyopathy in Type 2 Diabetic Mice via Attenuating Lipotoxicity and Oxidative Stress.

Diabetic cardiomyopathy (DCM) is a kind of heart disease that affects diabetic patients and is one of the primary causes of death. We previously demonstrated that deletion of the general control nonderepressible 2 (GCN2) kinase ameliorates cardiac dysfunction in diabetic mice. The aim of this study was to investigate the protective effect of GCN2iB, a GCN2 inhibitor, in type 2 diabetic (T2D) mice induced by a high-fat diet (HFD) plus low-dose streptozotocin (STZ) treatments or deletion of the leptin receptor (db/db). GCN2iB (3 mg/kg/every other day) treatment for 6 weeks resulted in significant decreases in fasting blood glucose levels and body weight and increases in the left ventricular ejection fraction. GCN2iB treatment also attenuated myocardial fibrosis, lipid accumulation and oxidative stress in the hearts of T2D mice, which was associated with decreases in lipid metabolism-related genes and increases in antioxidative genes. Untargeted metabolomics and RNA sequencing analysis revealed that GCN2iB profoundly affected myocardial metabolomic profiles and gene expression profiles. In particular, GCN2iB increased myocardial phosphocreatine and taurine levels and upregulated genes involved in oxidative phosphorylation. In conclusion, the data provide evidence that GCN2iB effectively protects against cardiac dysfunction in T2D mice. Our findings suggest that GCN2iB might be a novel drug candidate for DCM therapy.

Inhibiting Fatty Acid Amide Hydrolase Ameliorates Enteropathy in Diabetic Mice: A Cannabinoid 1 Receptor Mediated Mechanism

Simple SummaryGastrointestinal (GI) disorder is a debilitating complication of diabetes that interferes with the quality of life of the patients and current medical treatments are not very effective. High blood glucose levels in diabetics and the duration of diabetes could lead to complications of the GI tract, such as enteropathy and gastroparesis. Enteropathy is a disorder of the GI tract and can manifest as diarrhea, abdominal pain, constipation, and fecal incontinence. About 20% of patients affected with long-standing diabetes are at risk of diarrhea or fecal incontinence. This study was focused on assessing specific GI symptoms as well as manifestations in Type 1 diabetic mice and evaluated the treatment options for this distressing condition.Gastrointestinal (GI) dysmotility in diabetics exhibits fecal incontinence or constipation which affects patients’ quality of life. In this study, we aimed to understand the pattern of GI transit in type 1 diabetic (T1D) mice and whether inhibiting endocannabinoid degradation would exhibit therapeutic effect. Whole gut-transit time and fecal-pellet output were measured at 16 week post-diabetes. T1D mice treated with fatty acid amide hydrolase (FAAH) inhibitor URB597 showed reduced fecal output as well as improved gut transit time. Cannabinoid 1 receptor antagonist, AM251 blocked the effects of URB597, which may demonstrate that FAAH inhibitor is a potential remedial strategy for GI dysmotility.

Aldehyde dehydrogenase 2 augments adiponectin signaling in coronary angiogenesis in HFpEF associated with diabetes

4-hydroxy-2-nonenal (4HNE), an oxidative stress byproduct, is elevated in diabetes which decreases coronary angiogenesis, and this was rescued by the 4HNE detoxifying enzyme, aldehyde dehydrogenase 2 (ALDH2). Adiponectin (APN), an adipocytokine, has pro-angiogenic properties and its loss of function is critical in diabetes and its complications. Coronary endothelial cell (CEC) damage is the initiating step of diabetes-mediated heart failure with preserved ejection fraction (HFpEF) pathogenesis. Thus, we hypothesize that ALDH2 restores 4HNE-induced downregulation of APN signaling in CECs and subsequent coronary angiogenesis in diabetic HFpEF. Treatment with disulfiram, an ALDH2 inhibitor, exacerbated 4HNE-mediated decreases in APN-induced increased coronary angiogenesis and APN-signaling cascades, whereas pretreatment with alda1, an ALDH2 activator, rescued the effect of 4HNE. We employed control mice (db/m), spontaneous type-2 diabetic mice (db/db), ALDH2*2 knock-in mutant mice with intrinsic low ALDH2 activity (AL), and diabetic mice with intrinsic low ALDH2 activity (AF) mice that were created by crossing db/db and AL mice to test our hypothesis in vivo. AF mice exhibited heart failure with preserved ejection fraction (HFpEF)/severe diastolic dysfunction at 6 months with a preserved systolic function compared with db/db mice as well as 3 months of their age. Decreased APN-mediated coronary angiogenesis, along with increased circulatory APN levels and decreased cardiac APN signaling (index of APN resistance) were higher in AF mice relative to db/db mice. Alda1 treatment improved APN-mediated angiogenesis in AF and db/db mice. In summary, 4HNE-induces APN resistance and a subsequent decrease in coronary angiogenesis in diabetic mouse heart which was rescued by ALDH2.

3,4-Dihydroxyphenylacetic acid ameliorates gut barrier dysfunction via regulation of MAPK-MLCK pathway in type 2 diabetes mice

AimsThis study aims to investigate whether 3,4-dihydroxyphenylacetic acid (DHAA) can improve gut barrier function by inhibiting the mitogen-activated protein kinase (MAPK) - myosin light-chain kinase (MLCK) signaling pathway in type 2 diabetes (T2D) mice. Main methodsT2D mice were induced by a high-fat diet combined with streptozotocin. T2D mice were intragastrically administered with DHAA at 75 and 150 mg kg/body weight per day for 4 weeks. Blood glucose, insulin level, oxidative stress and inflammatory cytokines were measured. TJ (tight junction) protein and MAPK-MLCK pathway-related proteins were analyzed by western blot. Key findingsDHAA alleviated hyperglycemia and decreased insulin resistance of T2D mice. It also decreased oxidative stress via increased glutathione (GSH) and total superoxide dismutase (T-SOD) activities and reduced containing malondialdehyde (MDA). DHAA exhibited a significant anti-inflammatory effect by decreasing the level of pro-inflammatory cytokines lipopolysaccharide (LPS) and interleukin (IL)-6 and increasing that of anti-inflammatory cytokine IL-10. More importantly, DHAA improved gut barrier function by enhancing tight junction protein expression and inhibiting the MAPK-MLCK signaling pathway. SignificanceDHAA could reduce oxidative stress, decrease inflammatory response, and improve intestinal function in T2D mice, which may help to relieve the symptoms of T2D.

Therapeutic Effects of Insulin-Producing Human Umbilical Cord-Derived Mesenchymal Stem Cells in a Type 1 Diabetes Mouse Model.

In patients with type 1 diabetes (T1D), compromised pancreatic β-cell functions are compensated through daily insulin injections or the transplantation of pancreatic tissue or islet cells. However, both approaches are associated with specific challenges. The transplantation of mesenchymal stem cells (MSCs) represents a potential alternative, as MSCs have tissue-forming capacity and can be isolated from various tissues. The human umbilical cord (hUC) is a good source of freely available MSCs, which can be collected through pain-free, non-invasive methods subject to minimal ethical concerns. We sought to develop a method for the in vitro generation of insulin-producing cells (IPCs) using MSCs. We examined the potential therapeutic uses and efficacy of IPCs generated from hUC-derived MSCs (hUC-IPCs) and human adipose tissue (hAD)-derived MSCs (hAD-IPCs) through in vitro experiments and streptozotocin (STZ)-induced C57BL/6 T1D mouse models. We discovered that compared to hAD-IPCs, hUC-IPCs exhibited a superior insulin secretion capacity. Therefore, hUC-IPCs were selected as candidates for T1D cell therapy in mice. Fasting glucose and intraperitoneal glucose tolerance test levels were lower in hUC-IPC-transplanted mice than in T1D control mice and hAD-IPC-transplanted mice. Our findings support the potential use of MSCs for the treatment of T1D.

Knockdown of IFNAR2 reduces the inflammatory response in mouse model of type 1 diabetes

Backgroundand Purpose: To investigate the biological role of interferon α/β receptor 2 (IFNAR2) in type 1 diabetes (T1D). MethodsFirst, IFNAR2 mRNA and protein expression levels in serum of T1D patients and healthy controls were detected by RT-qPCR and Western blot. For experimental studies, 80 male C57BL/6 mice were randomly divided into 4 groups with 20 mice in each group: the control group, the T1D group, the T1D + ad-con group and the T1D + ad-si-IFNAR2 group. The T1D mouse model was generated by multiple intraperitoneal injections of small doses of streptozotocin (STZ). Body weight and blood glucose levels were measured weekly until 6 weeks. After 6 weeks, all mice were sacrificed and the levels of insulin (Ins), tumor necrosis factor α (TNF-α), interleukin 4 (IL-4), IL-6, and type I interferon γ (IFN-γ), IFNAR2 protein expression, the number of dendritic cells (DCs), and changes in islet β cells were assessed. ResultsIFNAR2 mRNA and protein expression levels in serum of T1D patients were significantly higher than those in healthy controls (P < 0.05). Furthermore, IFNAR2 protein expression, number of DCs, and IFNAR2 mRNA, blood glucose, TNF-α, and IFN-γ levels were significantly upregulated in T1D mice compared with the control group (P < 0.05), while weight, and Ins, IL-6, and IL-4 levels were decreased (P < 0.05). However, knockdown of IFNAR2 reversed these trends. There was no significant difference in markers between the T1D + ad-con group and the T1D group (P > 0.05). ConclusionsKnockdown of IFNAR2 reduced the inflammatory response and improved islet function of T1D mice.

Pro-α-cell-derived β-cells contribute to β-cell neogenesis induced by antagonistic glucagon receptor antibody in type 2 diabetic mice

SummaryThe deficiency of pancreatic β-cells is the key pathogenesis of diabetes, while glucagon-secreting α-cells are another player in the development of diabetes. Here, we aimed to investigate the effects of glucagon receptor (GCGR) antagonism on β-cell neogenesis in type 2 diabetic (T2D) mice and explore the origins of the neogenic β-cells. We showed that GCGR monoclonal antibody (mAb) elevated plasma insulin level and increased β-cell mass in T2D mice. By using α-cell lineage-tracing (glucagon-cre-β-gal) mice and inducible Ngn3+ pancreatic endocrine progenitor lineage-tracing (Ngn3-CreERT2-tdTomato) mice, we found that GCGR mAb treatment promoted α-cell regression to progenitors, and induced Ngn3+ progenitor reactivation and differentiation toward β-cells. Besides, GCGR mAb upregulated the expression levels of β-cell regeneration-associated genes and promoted insulin secretion in primary mouse islets, indicative of a direct effect on β-cell identity. Our findings suggest that GCGR antagonism not only increases insulin secretion but also promotes pro-α-cell-derived β-cell neogenesis in T2D mice.

Whey protein and xylitol complex alleviate type 2 diabetes in C57BL/6 mice by regulating the intestinal microbiota

Type 2 diabetes (T2D) is a metabolic disorder that has become a major threat to public health. Epidemiological and experimental studies have suggested that whey protein isolate (WPI) and xylitol (XY) play an important role on T2D. This manuscript hypothesizes the supplementation of whey protein and xylitol complex (WXY) has the hypoglycemic and hyperlipidemia effect of T2D mice induced by the conjoint action of a high-fat diet and streptozotocin (STZ) by modulating of intestinal microbiota. The mice with diabetes displayed higher levels of fasting blood glucose (FBG), insulin, glycosylated hemoglobin, total triglycerides, total cholesterol, aspartate aminotransferase, alanine aminotransferase and other serum parameters than the normal mice. Treatment with WXY for 6 weeks significantly modulated the levels of FBG and insulin, improved insulin sensitivity, pancreas impairment and liver function in T2D mice, and the effect was better than that observed with WPI and XY groups. Moreover, supplementation with WXY significantly changed the diversity and composition of the intestinal microbiota in T2D mice and restored the intestinal bacteria associated with T2D (Firmicutes, Bacteroidetes, and Lactobacillus). This may be a potential mechanism for alleviating T2D symptoms. Spearman correlation analysis showed that the relative abundances of specific genera (Turicibacter, Lachnospiraceae_NK4A136_group, Lactobacillus, Candidatus_Saccharimonas, Faecalibaculum and Coriobacteriaceae_UCG-002) were correlated with the levels of blood glucose and serum parameters. Therefore, WXY may be considered a promising dietary supplement for T2D treatment in the future.

Methylsulfonylmethane and Sesame Seed Oil Improve Dyslipidemia and Modulate Polyunsaturated Fatty Acid Metabolism in Two Mouse Models of Diabetes.

The objective of this study was to identify alterations in lipids and polyunsaturated fatty acid (PUFA) metabolism in both the streptozotocin (STZ)-induced type 1 diabetic (T1D) mouse and the mutant db/db type 2 diabetic (T2D) mouse to establish a biological signature for the evaluation of natural products with purported lipid-altering activity. Eight-week-old male C57BL/6J mice were randomized to nondiabetic group or STZ-induced diabetic groups (n = 10/group). STZ-induced diabetic mice and 6-week-old male db/db mice (n = 10/group) were randomized to the following groups: (1) diabetic control, no treatment, (2) methylsulfonylmethane (MSM) treatment, (3) sesame seed oil (SSO) treatment, and (4) MSM+SSO combination treatment. Clinical parameters measured included weights, blood glucose, serum lipid panels, and liquid chromatography-tandem mass spectrometry (LC-MS/MS) detection of free fatty acids in serum, liver, brain, and eyes. Blood glucose significantly decreased after 4 weeks of MSM treatment in T1D mice. Serum PUFA levels were significantly reduced in T2D mice compared with control mice. In contrast, treatment with SSO reversed this effect in T2D mice, exhibiting serum PUFA levels comparable to control mice. Serum triglycerides were significantly increased in both diabetic models compared to nondiabetic control, mimicking diabetes in people. High-density lipoprotein (HDL) was significantly increased in T1D receiving MSM+SSO and all T2D treatment groups. A corresponding significant decrease in non-HDL cholesterol was seen in T2D mice in all treatment groups. MSM+SSO treatment's effects on HDL and non-HDL cholesterol and PUFA metabolism could lead to improved clinical outcomes in diabetics by improving the lipid profile.

Anti-Diabetic Potential of Chlorella Pyrenoidosa-Based Mixture and its Regulation of Gut Microbiota.

The aim of the present study was to investigate the anti-diabetic effect of CGSGCG and its beneficial effects on gut microbiota in type 2 diabetes (T2D) mice induced by streptozotocin and high sucrose and high fat diet. The results showed that treatment with CGSGCG reduced fasting blood glucose, improved oral glucose tolerance test, protected the liver from injury, and reduced inflammation in T2D mice. The contents of acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid and isovaleric acid in CGSGCG group were 2.49-, 1.74-, 3.31-, 1.93-, 1.36- and 1.30-fold than that of the model group. Moreover, administration of CGSGCG up-regulated the expression of INSR/IRS-1/PI3K/AKT/GLUT4 and mTOR but down-regulated the P38MAPK expression. Furthermore, the abundance of beneficial bacteria such as Verrucomicrobia, Proteobacteria, Osillibacter, Dubosiella and Lactococcus in intestinal tract increased, indicating that CGSCGG regulated and improved the bacterial community structure of T2D mice, which were closely related to glycometabolism.