Type 2 Diabetes Mellitus Animal Research Articles

Metabolic effects of Type 2 Diabetes mellitus might be mitigated by grape pomace flour

Type 2 diabetes mellitus (T2DM) is a multifaceted metabolic disorder characterized by insulin resistance and pancreatic β-cell dysfunction, leading to varying metabolic insults. Grape pomace, a byproduct of the winemaking industry, is under investigation as a potential therapy for T2DM due to its abundant content of bioactive polyphenols and dietary fiber. Within the current backdrop of environmental concerns, the conversion of grape pomace into a safe and applicable form, with the aim of promoting sustainable management of environmental waste, acts as a catalyst for the emergence of viable alternatives. Grape pomace flour (GPF) represents an economical and feasible solution. We hypothesized that dietary supplementation of GPF would improve the glycemic control and the associated risk factors in T2DM-induced animals. In this sense, the present study, approved by CEUA UFPel No 033578/2022-14, aimed to evaluate the effect of the GPF from ‘Arinto’ and ‘Touriga Nacional’ grape varieties on biochemical and histopathological parameters in an animal model of T2DM. To induce T2DM, rats were given a high-fat diet and a Streptozotocin (STZ) injection (35 mg/kg). The rats were divided into five groups: Control (CT), T2DM, T2DM+Metformin (Met) (250 mg/kg), T2DM+'Arinto' GPF 10% (WGPF), and T2DM+'Touriga Nacional' GPF 10% (RGPF). Results showed that Met, WGPF, and RGPF groups had significantly lower blood glucose ( p<0.05, P<0.001, and p<0.01, respectively) and triglyceride levels ( p<0.001) compared to the T2DM group. Also, we observed a significant increase in serum cholesterol levels in the T2DM when compared to the CT ( p<0.01), that was reversed in the treated groups. Additionally, the T2DM+RGPF group had higher levels of high-density lipoprotein (HDL) compared to the control group ( p<0.05). Histopathological analysis revealed structural changes in the pancreas in the T2DM animals, while tissue damage was not observed in the Met and GPF supplementation groups. In conclusion, both 'Arinto' and 'Touriga Nacional' GPF demonstrated protective effects against increased blood glucose, triglycerides, and cholesterol levels in a T2DM animal model. 'Touriga Nacional' GPF also increased HDL levels and showed protective effects on pancreatic cell structure. This suggests that GPF could be a promising dietary option for T2DM and its complications. FCT-Foundation for Science and Technology (UIDB/04567/2020 CBIOS, and UIDP/04567/2020 CBIOS), Pelotas Federal University (UFPel), and Brazil's Federal Government (CNPq). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Secretome hypoxia-mesenchymal stem cells decrease tumor necrosis factor-α and interleukin-18 in kidney of type 2 diabetes mellitus model rats

Background Type 2 diabetes mellitus (T2DM) is a chronic disease that affects millions of people worldwide and associated with an increased risk of kidney damage caused by prolonged inflammation. Secretome hypoxia- mesenchymal stem cells (SH-MSCs) have been investigated as a potential therapy for kidney inflammation in T2DM, due to their immunomodulatory properties and ability to promote tissue repair. In this study, we investigated the effects of SH-MSCs on tumor necrosis α (TNF-á) and interleukin-18 (IL-18) in the kidney of the T2DM model rats. MethodsA post-test-only control group involving 24 male Wistar rats. The rats were treated with a high-fat diet (HFD) for 4 weeks and streptozotocin-nicotinamide with sucrose solution for 5 days to induce T2DM animal models. Rats were randomly divided into four groups: healthy, control, and groups treated with SH-MSCs T1 and T2, with doses of 250 µL and 500 µL, respectively. TNF-α and IL-18 gene expression was measured by real time polymerase chain reaction (RT-PCR). One Way ANOVA and post-hoc LSD tests were used to determine the significant difference against all groups based on their quantitative measurement. ResultsAdministration of the SH-MSCs at a dose of 500µL (T2) was able to significantly reduce TNF-α and IL-18 gene expression when compared to control (T2DM rat without treatment) (p<0.05), but not significantly when compared to healthy and SH-MSC at a dose of 250µL (T1) group (p >0.05). ConclusionThis study demonstrated that the SH-MSCs decreased the levels of proinflammatory cytokines TNF-α and IL-18 gene expression in the kidney of T2DM model rats.

Combined untargeted and targeted lipidomics approaches reveal potential biomarkers in type 2 diabetes mellitus cynomolgus monkeys

AbstractBackgroundThe significantly increasing incidence of type 2 diabetes mellitus (T2DM) over the last few decades triggers the demands of T2DM animal models to explore the pathogenesis, prevention, and therapy of the disease. The altered lipid metabolism may play an important role in the pathogenesis and progression of T2DM. However, the characterization of molecular lipid species in fasting serum related to T2DM cynomolgus monkeys is still underrecognized.MethodsUntargeted and targeted LC–mass spectrometry (MS)/MS‐based lipidomics approaches were applied to characterize and compare the fasting serum lipidomic profiles of T2DM cynomolgus monkeys and the healthy controls.ResultsMultivariate analysis revealed that 196 and 64 lipid molecules differentially expressed in serum samples using untargeted and targeted lipidomics as the comparison between the disease group and healthy group, respectively. Furthermore, the comparative analysis of differential serum lipid metabolites obtained by untargeted and targeted lipidomics approaches, four common serum lipid species (phosphatidylcholine [18:0_22:4], lysophosphatidylcholine [14:0], phosphatidylethanolamine [PE] [16:1_18:2], and PE [18:0_22:4]) were identified as potential biomarkers and all of which were found to be downregulated. By analyzing the metabolic pathway, glycerophospholipid metabolism was associated with the pathogenesis of T2DM cynomolgus monkeys.ConclusionThe study found that four downregulated serum lipid species could serve as novel potential biomarkers of T2DM cynomolgus monkeys. Glycerophospholipid metabolism was filtered out as the potential therapeutic target pathway of T2DM progression. Our results showed that the identified biomarkers may offer a novel tool for tracking disease progression and response to therapeutic interventions.

Kaempferol attenuates nonalcoholic fatty liver disease in type 2 diabetic mice via the Sirt1/AMPK signaling pathway

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases with limited treatment options. Moreover, its prevalence is doubled in type 2 diabetes mellitus (T2DM). Kaempferol (KAP) is a flavonoid compound that has been suggested to have beneficial effects on NAFLD, but studies on the mechanism are lacking, especially in the diabetic state. Herein, we investigated the effect of KAP on NAFLD associated with T2DM and its underlying mechanism in vitro and in vivo. The results of in vitro studies indicated that KAP treatment (10−8–10−6 M) significantly reduced lipid accumulation in oleic acid-induced HepG2 cells. Moreover, in the T2DM animal model of db/db mice, we confirmed that KAP (50 mg/kg) significantly reduced lipid accumulation and improved liver injury. Mechanistic studies in vitro and in vivo showed that Sirtuin 1 (Sirt1)/AMP-activated protein kinase (AMPK) signal was involved in KAP regulation of hepatic lipid accumulation. KAP treatment activated Sirt1 and AMPK, upregulated the levels of fatty acid oxidation-related protein proliferator activated receptor gamma coactivator 1α (PGC1α); and downregulated lipid synthesis-related proteins, including acetyl-coA carboxylase (ACC), fatty acid synthase (FASN), and sterol regulatory element-binding protein 1 (SREBP1). Furthermore, the curative effect of KAP on lipid accumulation was abolished by siRNA-mediated knockdown of either Sirt1 or AMPK. Collectively, these findings suggest that KAP may be a potential therapeutic agent for NAFLD associated with T2DM by regulating hepatic lipid accumulation through activation of Sirt1/AMPK signaling.

Tat-CIAPIN1 Prevents Pancreatic β-Cell Death in hIAPP-Induced RINm5F Cells and T2DM Animal Model

It is well known that the cytokine-induced apoptosis inhibitor 1 (CIAPIN1) protein plays an important role in biological progresses as an anti-apoptotic protein. Human islet amyloid peptide (hIAPP), known as amylin, is caused to pancreatic β-cell death in type 2 diabetes mellitus (T2DM). However, the function of CIAPIN1 protein on T2DM is not yet well studied. Therefore, we investigated the effects of CIAPIN1 protein on a hIAPP-induced RINm5F cell and T2DM animal model induced by a high-fat diet (HFD) and streptozotocin (STZ). The Tat-CIAPIN1 protein reduced the activation of mitogen-activated protein kinase (MAPK) and regulated the apoptosis-related protein expression levels including COX-2, iNOS, Bcl-2, Bax, and Caspase-3 in hIAPP-induced RINm5F cells. In a T2DM mice model, the Tat-CIAPIN1 protein ameliorated the pathological changes of pancreatic β-cells and reduced the fasting blood glucose, body weight and hemoglobin Alc (HbAlc) levels. In conclusion, the Tat-CIAPIN1 protein showed protective effects against T2DM by protection of β-cells via inhibition of hIAPP toxicity and by regulation of a MAPK signal pathway, suggesting CIAPIN1 protein can be a therapeutic protein drug candidate by beneficial regulation of T2DM.

247-LB: Link between Hyperglycemia and Cognitive Deficits in T2DM Animal Model

The Goto-Kakizaki (GK) rat is a model of spontaneously developing non-obese type 2 diabetes mellitus (T2DM). With age, GK rats exhibit insulin resistance, decreased pancreatic function, and hyperglycemia. Studies have shown that GK rats experience cognitive impairment concurrent with hyperglycemia, but the mechanisms is unclear. In this study, we aimed to elucidate the potential link between hyperglycemia and cognitive impairment in this unique T2DM model. Longitudinal assessments of fasting blood glucose (FBG) were performed in male GK rats and age-matched Wistar rats. Our results showed that FBG in GK group was significantly higher than that in the Wistar group starting from 6 weeks of age, and there was progressive fasting hyperglycemia in GK group. In the spatial probe test of Morris water maze (MWM) at 33 weeks old, the GK rats spent less time in the target quadrant (12.16 ± 2.18s vs. 22.17 ± 1.21, P<0.001) and took more time to reach the location of the formerly hidden platform (36.78 ± 6.141 vs. 6.422 ± 0.8783s, P<0.001) than Wistar rats, suggesting that GK rats showed spatial memory deficits. In mechanistic studies, insulin receptors (IR) and synaptic proteins were down-regulated and impaired insulin signaling pathways in the hippocampus of GK rats (Figure), suggesting impaired neuroplasticity and neuropathological processes may lead to cognitive dysfunction. Disclosure L. Chen: Board Member; Hua Medicine. J. Ni: None. L. Feng: Employee; Hua Medicine. X. Zhang: None. Q. Wang: None. Y. Chen: Stock/Shareholder; Silaiputai (Shanghai) Biopharmaceutical Company. Funding Hua Medicine Co., Ltd.

Hyperpolarized [1-13C]pyruvate Magnetic Resonance Spectroscopy Shows That Agmatine Increased Lactate Production in the Brain of Type 2 Diabetic Mice.

Type 2 diabetes mellitus (T2DM) is associated with a 2-fold increased risk of developing Alzheimer's disease. In earlier research, agmatine has been demonstrated to alleviate diabetes symptoms and increase cognitive performance. However, it is unclear whether the improvement of cognitive function is attributable to the reduction of diabetic symptoms or its direct influence on brain metabolism. Using hyperpolarized (HP) [1-13C]pyruvate magnetic resonance spectroscopy (MRS), this study intends to evaluate the influence of agmatine on brain metabolism. ICR mice were fed a high-fat diet and injected with streptozotocin to develop a T2DM animal model. During a 2-week period, T2DM mice were treated with normal saline or 100 mg/kg of agmatine, and brain HP [1-13C]pyruvate MRS was performed. The effect of agmatine on lactate generation and NADH/NAD+ redox state was investigated using C6 and neuro-2a (N2a) cells. As a perfusion marker, the total 13C signals in the brain of T2DM mice (p=0.07) and agmatine-treated mice (p<0.05) were reduced. The conversion constant (Kpl) from [1-13C]pyruvate to [1-13C]lactate was not distinguishable in the brains of T2DM mice but was significantly increased in the brains of agmatine-treated T2DM mice. Treating C6 and N2a cells with agmatine increased NADH/NAD+ratio and lactate generation. Agmatine influences the NADH/NAD+ redox state in the brains of T2DM mice, which may be connected with enhanced cognitive performance and increased conversion of HP [1-13C]pyruvate to HP [1-13C]lactate.

Role of Reactive Oxygen Species in Glucose Metabolism Disorder in Diabetic Pancreatic β-Cells

The dysfunction of pancreatic β-cells plays a central role in the onset and progression of type 2 diabetes mellitus (T2DM). Insulin secretory defects in β-cells are characterized by a selective impairment of glucose stimulation, and a reduction in glucose-induced ATP production, which is essential for insulin secretion. High glucose metabolism for insulin secretion generates reactive oxygen species (ROS) in mitochondria. In addition, the expression of antioxidant enzymes is very low in β-cells. Therefore, β-cells are easily exposed to oxidative stress. In islet studies using a nonobese T2DM animal model that exhibits selective impairment of glucose-induced insulin secretion (GSIS), quenching ROS generated by glucose stimulation and accumulated under glucose toxicity can improve impaired GSIS. Acute ROS generation and toxicity cause glucose metabolism disorders through different molecular mechanisms. Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor, is a master regulator of antioxidant defense and a potential therapeutic target in oxidative stress-related diseases, suggesting the possible involvement of Nrf2 in β-cell dysfunction caused by ROS. In this review, we describe the mechanisms of insulin secretory defects induced by oxidative stress in diabetic β-cells.

Gut Microbiota: An Important Player in Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is one of the common metabolic diseases in the world. Due to the rise in morbidity and mortality, it has become a global health problem. To date, T2DM still cannot be cured, and its intervention measures mainly focus on glucose control as well as the prevention and treatment of related complications. Interestingly, the gut microbiota plays an important role in the development of metabolic diseases, especially T2DM. In this review, we introduce the characteristics of the gut microbiota in T2DM population, T2DM animal models, and diabetic complications. In addition, we describe the molecular mechanisms linking host and the gut microbiota in T2DM, including the host molecules that induce gut microbiota dysbiosis, immune and inflammatory responses, and gut microbial metabolites involved in pathogenesis. These findings suggest that we can treat T2DM and its complications by remodeling the gut microbiota through interventions such as drugs, probiotics, prebiotics, fecal microbiota transplantation (FMT) and diets.

Identification of Potential Biomarkers of Type 2 Diabetes Mellitus-Related Immune Infiltration Using Weighted Gene Coexpression Network Analysis.

Background Type 2 diabetes mellitus (T2DM) is characterized by chronic low-grade inflammation, showing an increasing trend. The infiltration of immune cells into adipose tissue has been shown to be an important pathogenic cause of T2DM. The purpose of this study is to use the relevant database to identify some abnormally expressed or dysfunctional genes related to diabetes from the perspective of immune infiltration. Methods Weighted gene coexpression network analysis (WGCNA) was employed to systematically identify the coexpressed gene modules and hub genes associated with T2DM development based on a microarray dataset (GSE23561) from the Gene Expression Omnibus (GEO) database. The key genes in modules highly related to clinical features were calculated and screened by using R software, and their participation in T2DM was determined by gene enrichment analysis. The mRNA levels of CSF1R, H2AFV, LCK, and TLR9 in pre-T2DM mice and normal wild-type mice were detected by WGCNA screening and real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Results We constructed 14 coexpressed gene modules, and the brown module was shown to be significantly related to T2DM. Through verification of the protein-protein interaction (PPI) network, four upregulated hub genes, CSF1R, H2AFV, LCK, and TLR9, were screened from the brown module and successfully distinguishedT2DM patients from healthy people. These hub genes may be used as biomarkers and important indicators for patient diagnosis. Enrichment analysis showed that these hub genes were highly associated with IL-6-related inflammatory metabolism, immune regulation, and immune cell infiltration. Finally, we verified the hub genes CSF1R, LCK, and TLR9 in a T2DM animal model and found that their mRNA levels were significantly higher in animals with T2DM than in control group mice (NC). Conclusions In summary, our results suggest that these hub genes (CSF1R, LCK, and TLR9) can serve as biomarkers and immunotherapeutic targets for T2DM.

Synthesis, Characterization and Screening of Some Novel 2-Methyl-N'- [(Z)-Substituted-Phenyl ethylidene] Imidazo [1, 2-a] Pyridine-3-Carbohy drazide Derivatives as DPP-IV Inhibitors for the Treatment of Type 2 Diabetes Mellitus

Background: One of the leading global metabolic diseases marked by insulin resistance and chronic hyperglycemia is type 2 diabetes mellitus (T2DM). Since the last decade, DPP-4 enzyme inhibition has proven to be a successful, safe, and well-established therapy for the treatment of T2DM. Objective: The present work reports the synthesis, characterization, and screening of some novel 2- methyl-N'-[(Z)-substituted-phenyl ethylidene] imidazo [1, 2-a] pyridine-3-carbohydrazide derivatives as DPP-IV inhibitors for the treatment of T2DM. Methods: The molecular docking was performed to study these derivatives' binding mode in the enzyme's allosteric site. All the synthesized compounds were subjected for DPP-IV enzyme assay and in vivo antihyperglycemic activity in STZ-induced diabetic rats. Results: The synthesized derivatives exhibited potent antidiabetic activity as compared to the standard drug Sitagliptin. Out of sixteen compounds, A1, A4, B4, C2, C3, and D4 have shown promising antidiabetic activity against the DPP-IV enzyme. The most promising compound, C2, showed a percentage inhibition of 72.02±0.27 at 50 μM concentration. On the 21st-day, compound C2 showed a significant reduction in serum blood glucose level, i.e., 156.16±4.87 mg/dL, then diabetic control, which was 280.00±13.29 mg/dL whereas, standard Sitagliptin showed 133.50±11.80 mg/dL. In the in vivo antihyperglycemic activity, the compounds have exhibited good hypoglycemic potential in fasting blood glucose in the T2DM animal model. All the docked molecules have exhibited perfect binding affinity towards the active pocket of the enzyme. The synthesized derivatives were screened through Lipinski's rule of five for better optimization, and fortunately, none of them violated the rule. Conclusion: The above results indicate that compound C2 is a relatively active and selective hit molecule that can be structurally modified to enhance the DPP-IV inhibitor's potency and overall pharmacological profile. From the present work, it has been concluded that substituted pyridine-3-carbohydrazide derivatives possess excellent DPP-IV inhibitory potential and can be better optimized further by generating more in vivo, in vitro models.

Isoliquiritigenin alleviates diabetic symptoms via activating AMPK and inhibiting mTORC1 signaling in diet-induced diabetic mice

PurposeTo determine the effects of isoliquiritigenin (ISL), a chalcone compound isolated from licorice, on type 2 diabetes mellitus (T2DM). Materials and methods8-week-old C7BL/6 mice were used to establish the T2DM animal model by feeding with high-fat-high-glucose diet (HFD) combined with intraperitoneal injection of streptozotocin. The animals were treated with ISL for 3 weeks. Blood glucose levels, oral glucose tolerance, and insulin tolerance were examined, serum parameters were determined, histologic sections were prepared, activities of enzymes related to glucolipid metabolism were analyzed, and the mitochondrial function was investigated to evaluate effects of ISL on metabolism. The underlying mechanisms of ISL alleviating insulin resistance and restoring metabolic homeostasis were analyzed in HepG2 and INS-1 cells. ResultsISL exhibits a potent activity in relieving hyperglycemia of type 2 diabetic mice. It alleviates insulin resistance and restores metabolic homeostasis without obvious adversary effects in HFD-induced diabetic mice. The metabolic benefits of ISL treatment include promoting hepatic glycogenesis, inhibiting hepatic lipogenesis, reducing hepatic steatosis, and sensitizing insulin signaling. Mechanistically, ISL activates adenosine monophosphate-activated protein kinase (AMPK) and inhibits mammalian target of rapamycin complex 1 (mTORC1). It also suppresses mitochondrial function and reduces ATP production. ConclusionOur findings demonstrate that ISL is able to significantly reduce blood glucose level and alleviate insulin resistance without obvious side effects in diabetic mice, hence uncovering a great potential of ISL as a novel drug candidate in prevention and treatment of T2DM.

Improvement of intestinal barrier function, gut microbiota, and metabolic endotoxemia in type 2 diabetes rats by curcumin

ABSTRACT Type 2 diabetes mellitus (T2DM) is known as a complex genetic disease characterized by genetic and environmental factors. The imbalanced intestinal flora and intestinal mucosal barrier are considered to be related to T2DM. Curcumin has been proved to affect the progression of T2DM. T2DM animal was established by low-dose streptozotocin intraperitoneal injection combined with high-fat diet (HFD) feeding. Hematoxylin and eosin (HE) staining and transfer electron microscopy (TEM) were used to observe morphological changes of intestinal tissues of T2DM rats. Insulin and glucose tolerance tests were performed to investigate the influence of curcumin on blood glucose. Curcumin significantly improved the intestinal integrity, hyperglycemia and insulin resistance in diabetic rats. The metabolic endotoxemia induced by HFD in diabetic rats was inhibited remarkably. Curcumin reversed gut microbiota dysbiosis in diabetic rats caused by HFD. We demonstrated that curcumin could protect intestinal mucosal barrier, improve insulin resistance and reduce blood glucose in diabetic rats. This study might provide experimental evidence for the prevention and treatment in T2DM.

Type 2 diabetes mellitus impaired nasal immunity and increased the risk of hyposmia in COVID-19 mild pneumonia patients

In patients with COVID-19,type 2 diabetes mellitus (T2DM) can impair the function of nasal-associated lymphoid tissue (NALT) and result in olfactory dysfunction. Exploring the causative alterations of T2DM within the nasal mucosa and NALT could provide insight into the pathogenic mechanisms and bridge the gap between innate immunity and adaptive immunity for virus clearance. Here, we designed a case-control study to compare the olfactory function (OF) among the groups of normal control (NC), COVID-19 mild pneumonia (MP), and MP patients with T2DM (MPT) after a 6–8 months’ recovery, in which MPT had a higher risk of hyposmia than MP and NC. No significant difference was found between the MP and NC. This elevated risk of hyposmia indicated that T2DM increased COVID-19 susceptibility in the nasal cavity with unknown causations. Therefore, we used the T2DM animal model (db/db mice) to evaluate how T2DM increased COVID-19 associated susceptibilities in the nasal mucosa and lymphoid tissues. Db/db mice demonstratedupregulated microvasculature ACE2 expression and significant alterations in lymphocytes component of NALT. Specifically, db/db mice NALT had increased immune-suppressive TCRγδ+ CD4−CD8− T and decreased immune-effective CD4+/CD8+ TCRβ+ T cells and decreased mucosa-protective CD19+ B cells. These results indicated that T2DM could dampen the first-line defense of nasal immunity, and further mechanic studies of metabolic damage and NALT restoration should be one of the highest importance for COVID-19 healing.

Adiponectin in onset and progression of T2DM with cardiac dysfunction in rats.

Cardiovascular disease and type 2 diabetes mellitus (T2DM) patients have low level of adiponectin, however, till now the role of adiponectin in progression of 'T2DM with cardiac dysfunction' in animal model has not been characterized. Therefore, the aim of the present study was to develop and characterize T2DM animal model with cardiac dysfunction and to study the role of cardiac adiponectin expression in cardiac dysfunction. For this, Wistar rats (M/F) were fed a high-fat diet for different time periods: 3, 4 and 5 weeks and given a single, low-dose streptozotocin (25mg/kg), intraperitoneal injection 1 week prior to the experiments. Rats in T2DM group (3 weeks) developed hyperglycaemia, hyperlipidaemia, oxidative stress with normoinsulinaemia and mild cardiac dysfunction suggesting onset of T2DM with cardiac dysfunction. Extended high-fat feeding, that is, 4 and 5 weeks induced insulin resistance accompanied with cardiac hypertrophy, cardiac dysfunction and reduced baroreflex sensitivity indicating development of T2DM with cardiac dysfunction. Cardiac adiponectin expression did not change in rats of T2DM group (3 weeks), however, it significantly decreased in rats of two T2DM groups (4 and 5 weeks) along with increased intracellular adhesion molecule-1 levels. Thus, the present study for the first time indicates that in the present T2DM animal model, as T2DM progresses cardiac adiponectin expression also decreases which might be the precipitating factor for cardiac hypertrophy and decrease in baroreflex sensitivity, which induces cardiac dysfunction.

Lactobacillus salivarius AP-32 and Lactobacillus reuteri GL-104 decrease glycemic levels and attenuate diabetes-mediated liver and kidney injury in db/db mice

ObjectivesPatients with type 2 diabetes mellitus (T2DM) exhibit strong insulin resistance or abnormal insulin production. Probiotics, which are beneficial live micro-organisms residing naturally in the intestinal tract, play indispensable roles...

Dynamic Phenotypes and Molecular Mechanisms to Understand the Pathogenesis of Diabetic Nephropathy in Two Widely Used Animal Models of Type 2 Diabetes Mellitus.

ObjectiveWe aimed to characterize the pathogenesis of diabetic nephropathy (DN) in two commonly used type 2 diabetes mellitus (T2DM) animal models and explore the preliminary molecular mechanisms underlying DN in two models.MethodsTo verify the effect of hyperglycemia on renal tissue, we observed the cell growth inhibition rate by adding different concentration of glucose to cell supernatant. After that, a chemically-induced T2DM model was established by administering streptozotocin (STZ) to Sprague Dawley (SD) rats in combination with high fat feeding. In addition, a spontaneous T2DM model was established by feeding 8 weeks old KK-Ay mice a high-fat diet during a period of over 20 weeks. Animal body weight, fasting blood glucose (FBG), insulin tolerance, lipid metabolism, renal function, and renal pathology were periodically measured (once every 2 or 4 weeks) over a duration of 20 weeks. At the 12th week, an Affymetrix gene chip assay was performed on the renal tissues extracted from the T2DM animal models and control animals. Through screening for the differentially expressed genes, some key genes were selected for PCR validation.ResultsHigh level of glucose could inhibit the growth of kidney cells. Besides, KK-Ay mice were found to have high FBG and abnormal insulin tolerance. Renal dysfunction and pathology were observed at the 4th week following the start of model creation, which increased in severity over the length of the experiment. The T2DM SD rats also showed high FBG, abnormal glucose tolerance and abnormal lipid metabolism, but the renal function and renal pathology changed only slightly within 20 weeks. Gene profiling in animal kidneys and subsequent analyses and validation revealed differentially expressed genes and enriched pathways in DN.ConclusionKK-Ay mice with both high fasting glucose and insulin resistance were more likely to develop diabetic nephropathy than STZ-induced diabetic SD rats with low fasting glucose or only insulin resistance. The KK-Ay mice model showed earlier onset of the typical pathological characteristics associated with T2DM and obvious renal lesions suggestive of kidney damage.

The insulin resistance is reversed by exogenous 3,5,3'triiodothyronine in type 2 diabetic Goto-Kakizaki rats by an inflammatory-independent pathway.

Diabetes mellitus (DM) has a multifactorial etiology that imparts a particular challenge to effective pharmacotherapy. Thyroid hormone actions have demonstrated beneficial effects in diabetic as well as obese rats. In both conditions, inflammation status plays a crucial role in the development of insulin resistance. Taking this into consideration, the present study aimed to demonstrate another possible pathway of thyroid hormone action on insulin sensitivity in a spontaneous type 2 diabetic rat model: the Goto-Kakizaki (GK) rats. GK animals present all typical hallmarks of type 2 DM (T2DM), except the usual peripheric inflammatory condition, observed in the other T2DM animal models. GK rats were treated or not with 3,5,3'triiodothyronine (T3). Insulin sensitivity, glucose tolerance, and proteins related to glucose uptake and utilization were evaluated in the skeletal muscle, white adipose tissue, and liver. GK rats T3-treated presented enhanced insulin sensitivity, increased GLUT-4 content in the white adipose tissue and skeletal muscle, and increased hexokinase and citrate synthase content in skeletal muscle. Both non-treated and T3-treated GK rats did not present alterations in cytokine content in white adipose tissue, skeletal muscle, liver, and serum. These results indicate that T3 improves insulin sensitivity in diabetic rats by a novel inflammatory-independent mechanism.

Dual-specificity tyrosine phosphorylation-regulated kinase 1A ameliorates insulin resistance in neurons by up-regulating IRS-1 expression

Insulin resistance in the brain is a pathological mechanism that is shared between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). Although aberrant expression and phosphorylation of insulin receptor substrate 1 (IRS-1) contribute to insulin resistance, the underlying mechanism remains elusive. In this study, we used several approaches, including adeno-associated virus-based protein overexpression, immunoblotting, immunoprecipitation, immunohistochemistry, and in situ proximal ligation assays, to investigate the function of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) in IRS-1 regulation and the downstream insulin signaling in neurons. We found that DYRK1A overexpression up-regulated IRS-1 expression by slowing turnover of the IRS-1 protein. We further observed that DYRK1A directly interacted with IRS-1 and phosphorylated IRS-1's multiple serine residues. Of note, DYRK1A and IRS-1 were coordinately up-regulated in the prefrontal cortex of db/db mice brain. Furthermore, DYRK1A overexpression ameliorated chronic high insulin-induced insulin resistance in SH-SY5Y cells as well as in primary rat neurons. These findings suggest that DYRK1A protects against insulin resistance in the brain by elevating IRS-1 expression.

Dapagliflozin Attenuates Hyperglycemia Related Osteoporosis in ZDF Rats by Alleviating Hypercalciuria.

Recent studies showed that in patients with type 2 diabetes mellitus (T2DM), Sodium-dependent glucose transporters 2 inhibitor (SGLT2I) may cause potential adverse effects on skeleton such as increasing the risk of fracture. This risk is possibly mediated by effects induced by all SGLT2I class drugs but whether Dapagliflozin aggravates osteoporosis in patients with T2DM remains controversial. Therefore, we designed this study to explore how Dapagliflozin affects the metabolism and the quality of bone in. T2DM animal models The effect of Dapagliflozin on skeleton was evaluated on male ZDF (Zucker Diabetic Fatty) rats—a rat model of diet induced spontaneous T2DM. Dapagliflozin was administrated via gavage at the dosage of 1.0 mg/kg/day. Bone tissue mineral density and the microarchitecture of tibiae were measured with micro-CT and biomechanics characteristic of the femora were tested using a three-point bending test. Serum bone biomarkers and other metabolic parameters were also tested via ELISA or other assays. Our results found that diabetic rats demonstrated symptoms of osteoporosis and Dapagliflozin could help to alleviate these defections caused by diabetes. Compared to the negative controls, the serum CT (calcitonin) level in ZDF rats as well as the uric calcium and phosphate levels were elevated, and these symptoms were alleviated by Dapagliflozin. Tibiae of Dapagliflozin treated rats demonstrated decreased cortical tissue mineral density while trabecular tissue mineral density and mean bone mineral density received a rise when compared to the matched controls. ZDF rats also showed defections in femora stiffness which could be relieved by Dapagliflozin administration. The mechanism of Dapagliflozin affecting bone quality is possibly connected to the suppression of serum calcitonin and excretion of calcium via urine rose by hyperglycemia. In conclusion, Dapagliflozin can prevent osteoporosis in ZDF rats by alleviating hypercalciuria.