Type 2 Diabetes Mellitus Rat Model Research Articles

Role of TLR4/MyD88/NF-κB signaling in heart and liver-related complications in a rat model of type 2 diabetes mellitus.

AimsTo analyze expression of members of the Toll-like receptor (TLR)4/myeloid differentiation primary response 88 (MyD88)/nuclear factor (NF)-κB signaling pathway in the heart and liver in a rat model of type 2 diabetes mellitus (T2DM). Our overall goal was to understand the underlying pathophysiological mechanisms.MethodsWe measured fasting blood glucose (FBG) and insulin (FINS) in a rat model of T2DM. Expression of members of the TLR4/MyD88/NF-κB signaling pathway as well as downstream cytokines was investigated. Levels of mRNA and protein were assessed using quantitative real-time polymerase chain reaction and western blotting, respectively. Protein content of tissue homogenates was assessed using enzyme-linked immunosorbent assays.ResultsDiabetic rats had lower body weights, higher FBG, higher FINS, and higher intraperitoneal glucose tolerance than normal rats. In addition, biochemical indicators related to heart and liver function were elevated in diabetic rats compared with normal rats. TLR4 and MyD88 were involved in the occurrence of T2DM as well as T2DM-related heart and liver complications. TLR4 caused T2DM-related heart and liver complications through activation of NF-κB.ConclusionsTLR4/MyD88/NF-κB signaling induces production of tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1, leading to the heart- and liver-related complications of T2DM.

Morus alba leaves ethanol extract protects pancreatic islet cells against dysfunction and death by inducing autophagy in type 2 diabetes

Protection of pancreatic islet cells against dysfunction or death by regulating autophagy is considered to be an effective method for treatment of type 2 diabetes mellitus (T2DM). Morus alba leaves (mulberry leaves), a popular herbal medicine, have been used for prevention of T2DM since ancient times. This study aimed to clarify whether Morus alba leaves ethanol extract (MLE) could protect islet cells in vivo and in vitro by regulating autophagy in T2DM, and explore the possible mechanism of action. The main chemical constituents in MLE were analyzed by HPLC. The T2DM rat model was induced via high-fat diet combined with peritoneal injection of low-dose streptozotocin, and MLE was administered by oral gavage. Fasting blood glucose (FBG) and plasma insulin were measured, and homeostatic model assessment of β cell function (HOMA-β) and insulin resistance (HOMA-IR) were determined. The histomorphology of pancreas islets was evaluated by haematoxylin and eosin staining. In palmitic acid (PA)-stressed INS-1 rat insulinoma cells, cell viability was assayed by an MTT method. Expression of the autophagy-related proteins LC3 I/II, p62, p-AMPK and p-mTOR in islet tissues and INS-1 cells was evaluated by western blotting or immunohistochemistry analysis. The four main chemical constituents in MLE were identified as chlorogenic acid, rutin, isoquercitrin and quercitrin. MLE ameliorated hyperglycemia, insulin resistance and dyslipidemia of T2DM rats with prominent therapeutic effect. Further study indicated that MLE observably improved islet function, alleviated islet injury of T2DM rats, and inhibited PA-induced INS-1 cell death. On the other hand, MLE significantly induced autophagy in islet cells both in vivo and in vitro, and autophagy inhibitors abolished its therapeutic effect on T2DM rats and protective effect on islet cells. Apart from this, MLE markedly activated the AMPK/mTOR pathway in INS-1 cells, and the AMPK inhibitor prevented the autophagy induction ability of MLE. Together, MLE could protect islet cells against dysfunction and death by inducing AMPK/mTOR-mediated autophagy in T2DM, and these findings provide a new perspective for understanding the treatment mechanism of Morus alba leaves against T2DM.

Amelioration of hyperglycaemia and hyperlipidaemia by adjusting the interplay between gut microbiota and bile acid metabolism: Radix Scutellariae as a case

BackgroundOur previous clinical research showed that the interaction between gut microbiota and bile acids (BAs) in patients with type 2 diabetes mellitus (T2DM) changed significantly. We hypothesized that T2DM could be improved by adjusting this interaction mediated by farnesoid X receptor (FXR). T2DM belongs to the category of “xiaoke” in traditional Chinese medicine. Radix scutellariae has the effects of clearing away heat and eliminating dampness, curing jaundice and quenching thirst and is widely used alone or in combination with other medicines for the treatment of T2DM in China and throughout Asia. Additionally, the interaction between Radix scutellariae and gut microbiota may influence its efficacy in the treatment of T2DM. PurposeThis study chose Radix scutellariae to validate that T2DM could improve by adjusting the interaction between gut microbiota and bile acid metabolism. Study design and methodsRadix scutellariae water extract (WESB) was administered to a T2DM rat model established by a high-fat diet combined with streptozotocin. The body weight and blood glucose and insulin levels were measured. The levels of serum lipids, creatinine, uric acid, albumin and total bile acid were also detected. Changes in the pathology and histology of the pancreas, liver and kidney were observed by haematoxylin-eosin staining. The 16S rRNAs of gut microbiota were sequenced, and the faecal and serum BAs were determined by liquid chromatography tandem mass spectrometry. The expression levels of BA metabolism-associated proteins in the liver and intestine were evaluated by immunoblot analysis. ResultsThe results showed that WESB improved hyperglycaemia, hyperlipaemia, and liver and kidney damage in T2DM rats. In addition, the abundances of key gut microbiota and the concentrations of certain secondary BAs in faeces and serum were restored. Moreover, there was a significant correlation between the restored gut microbiota and BAs, which might be related to the activation of liver cholesterol 7α-hydroxylase (CYP7A1) and the inhibition of FXR expression in the intestine rather than the liver. ConclusionsThis study provided new ideas for the prevention or treatment of clinical diabetes and its complications by adjusting the interaction between gut microbiota and bile acid metabolism.

Carob fruit extract-enriched meat, as preventive and curative treatments, improves gut microbiota and colonic barrier integrity in a late-stage T2DM model

Epidemiological and experimental studies have suggested that dietary fiber and proanthocyanidins play an important role on gut microbiota (GM), colonic integrity and body health. Type 2 Diabetes Mellitus (T2DM) is a prevalent disease in which the modifications in the GM and colonic markers stand out. This manuscript hypothesizes the consumption of functional meat enriched in carob fruit extract [CFE; CFE-restructured meat (RM)] ameliorates the dysbiosis and colonic barrier integrity loss in a late-stage T2DM rat model induced by the conjoint action of a high-saturated-fat/high-cholesterol diet (Chol-diet) and a low dose of streptozotocin (STZ) plus a nicotinamide (NAD) injection. Three groups of eight rats were used: (1) D group, a T2DM control group, fed the Chol-diet; (2) ED group, a T2DM preventive strategy group fed the CFE-Chol-diet since the beginning of the study; and (3) DE group, a T2DM curative treatment group, fed the CFE-Chol-diet once the diabetic state was confirmed. The study lasted 8 weeks. Amount and variety of GM, feces short-chain-fatty acids (SCFAs), colonic morphology [crypt depth and density, goblet cells, proliferating cell nuclear antigen (PCNA) and transferase dUTP nick end labelling (TUNEL) indexes] and tight junctions were evaluated. A global colonic index combining 17 markers (GCindex) was calculated. ED rats displayed higher levels of GM richness, SCFAs production, crypt depth, and goblet cells than the D group. DE group showed lower Enterobacteriaceae abundance and greater TUNEL index and occludin expression in the distal colon than D counterpart. GCindex differentiated the colonic health status of the experimental groups in the order (ED > DE > D; P < 0.001) as a 17–51 range-quotation, ED, DE, and D groups displayed the values 43, 32.5, and 27, respectively. Thus, CFE-RM used as a T2DM preventive therapy could induce higher GM richness, more adequate SCFAs production, and better colonic barrier integrity. Furthermore, CFE-RM used with curative purposes induced more modest changes and mainly at the distal colonic mucosa. Further studies are needed to confirm this study’s results, to ascertain the benefits of consuming proanthocyanidins-rich fiber during different T2DM stages.

Effect of Lupinus rotundiflorus gamma conglutin treatment on JNK1 gene expression and protein activation in a rat model of type 2 diabetes

Context Gamma conglutin (Cγ) from lupine species represents a potential complementary treatment for type 2 diabetes mellitus (T2DM) because of its hypoglycaemic effect. However, its underlying mechanism of action is not fully known. Objective To evaluate whether Cγ from Lupinus rotundiflorus M. E. Jones (Fabaceae) modulates c-Jun N-terminal kinase 1 (JNK1) expression and activation in a T2DM rat model. Materials and methods Gamma conglutin isolated from L. rotundiflorus seeds was characterized by SDS-PAGE. Fifteen Wistar rats with streptozotocin-induced T2DM (HG) were randomized into three groups (n = 5): vehicle administration (HG-Ctrl), oral treatment with Cγ (120 mg/kg/day) (HG-Lr) for one week, and treatment with metformin (300 mg/kg/day) (HG-Met); a healthy group (Ctrl, n = 5) was included as control. The levels of glucose and biomarkers of renal and hepatic function were measured pre- and post-treatment. Hepatic Jnk1 expression and phosphorylation of JNK1 were evaluated by qRT-PCR and western blot, respectively. Results Oral treatment with either Cγ or metformin reduced serum glucose level to 86.30 and 74.80 mg/dL, respectively (p ˂ 0.05), from the basal levels. Jnk1 expression was 0.65- and 0.54-fold lower (p ˂ 0.05) in the HG-Lr and HG-Met groups, respectively, than in HG-Ctrl. Treatment with Cγ decreased JNK1 phosphorylation. However, Cγ did not change the levels of kidney and liver biomarkers. Discussion and conclusions Treatment with Cγ from L. rotundiflorus inhibited Jnk1 expression, in vivo, suggesting JNK1 as a potential therapeutic target in diabetes and revealing one mechanism underlying the hypoglycaemic effect of lupine Cγ. Nevertheless, further studies are required.

ALDH2/SIRT1 Contributes to Type 1 and Type 2 Diabetes-Induced Retinopathy through Depressing Oxidative Stress.

Clinical observations found vision-threatening diabetic retinopathy (DR) occurs in both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) patients, but T1DM may perform more progressive retinal abnormalities at the same diabetic duration with or without clinical retinopathy. In the present study, T1DM and T2DM patients without manifestations of DR were included in our preliminary clinical retrospective observation study to investigate the differentiated retinal function at the preclinical stage. Then, T1DM and T2DM rat models with 12-week diabetic duration were constructed to explore the potential mechanism of the discrepancy in retinal disorders. Our data demonstrated T1DM patients presented a poor retinal function, a higher allele frequency for ALDH2GA/AA, and a depressed aldehyde dehydrogenase 2 (ALDH2) activity and silent information regulator 1 (SIRT1) level, compared to T2DM individuals. In line with this, higher amplitudes of neurovascular function-related waves of electroretinograms were found in T2DM rats. Furthermore, the retinal outer nuclear layers were reduced in T1DM rats. The levels of retinal oxidative stress biomarkers including total reactive oxygen species, NADPH oxidase 4 and mitochondrial DNA damage, and inflammatory indicators covering inducible/endothelial nitric acid synthase ratio, interleukin-1, and interleukin-6 were obviously elevated. Notably, the level of retinal ALDH2 and SIRT1 in T1DM rats was significantly diminished, while the expression of neovascularization factors was dramatically enhanced compared to T2DM. Together, our data indicated that the ALDH2/SIRT1 deficiency resulted in prominent oxidative stress and was in association with DR progression. Moreover, a differentiating ALDH2/SIRT1 expression may be responsible for the dissimilar severity of DR pathological processes in chronic inflammatory-related T1DM and T2DM.

SIRT3 alleviates neuropathic pain by deacetylating FoxO3a in the spinal dorsal horn of diabetic model rats

BackgroundThe underlying mechanisms of neuropathic pain remain unclear. This work aimed to investigate the role of Sirtuin3 (SIRT3), an nicotinamide adenosine dinucleotide+-dependent histone deacetylase, in the development of neuropathic pain...

Bioactive Agent Discovery from the Natural Compounds for the Treatment of Type 2 Diabetes Rat Model.

Diabetes mellitus is a well-known chronic metabolic disease that poses a long-term threat to human health and is characterized by a relative or absolute lack of insulin, resulting in hyperglycemia. Type 2 diabetes mellitus (T2DM) typically affects many metabolic pathways, resulting in β-cell dysfunction, insulin resistance, abnormal blood glucose levels, inflammatory processes, excessive oxidative reactions, and impaired lipid metabolism. It also leads to diabetes-related complications in many organ systems. Antidiabetic drugs have been approved for the treatment of hyperglycemia in T2DM; these are beneficial for glucose metabolism and promote weight loss, but have the risk of side effects, such as nausea or an upset stomach. A wide range of active components, derived from medicinal plants, such as alkaloids, flavonoids, polyphenol, quinones, and terpenoids may act as alternative sources of antidiabetic agents. They are usually attributed to improvements in pancreatic function by increasing insulin secretions or by reducing the intestinal absorption of glucose. Ease of availability, low cost, least undesirable side effects, and powerful pharmacological actions make plant-based preparations the key player of all available treatments. Based on the study of therapeutic reagents in the pathogenesis of humans, we use the appropriate animal models of T2DM to evaluate medicinal plant treatments. Many of the rat models have characteristics similar to those in humans and have the advantages of ease of genetic manipulation, a short breeding span, and access to physiological and invasive testing. In this review, we summarize the pathophysiological status of T2DM rat models and focus on several bioactive compounds from herbal medicine with different functional groups that exhibit therapeutic potential in the T2DM rat models, in turn, may guide future approach in treating diabetes with natural drugs.

Silkworm Extract Ameliorates Type 2 Diabetes Mellitus and Protects Pancreatic β-cell Functions in Rats

ObjectiveThe aim of the present study was to investigate the hypoglycemic effects of silkworm extract (SE) on experimental type 2 diabetes mellitus (T2DM) rats. MethodsSE was prepared by dissolving freeze-dried silkworm powder in 70% (v/v) aqueous ethanol. T2DM rats were induced by feeding them a high fat diet and an intraperitoneal injection of streptozotocin (STZ). The blood glucose, free fatty acid (FFA), malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α) and superoxide dismutase (SOD) levels were detected by enzyme-linked immunosorbent assay (ELISA). The quality of SE was controlled by high performance liquid chromatography (HPLC; Agilent 1260, Agilent, USA). Hematoxylin-eosin (HE) staining was performed for histological evaluation. Antibody expression was assessed via immunohistochemistry (IHC) staining. ResultsSE could improve insulin resistance and islet cell function by reducing FFA, MDA and TNF-α levels and increasing SOD level. In addition, pancreatic HE staining analysis revealed that SE has a protective effect on islet β-cells. ConclusionsThe present study indicates that SE has hypoglycemic as well as pancreatic protective effects in T2DM model rats.

Overexpression of microRNA-216a-3p Accelerates the Inflammatory Response in Cardiomyocytes in Type 2 Diabetes Mellitus by Targeting IFN-α2.

Background: Type 2 diabetes mellitus (T2DM) is a chronic, hyperglycemia-associated, metabolic disorder. Heart disease is a major complication of T2DM. The present study aimed to explore the effects of miR-216a-3p on cardiomyocyte proliferation, apoptosis, and inflammation in T2DM through the Toll-like receptor (TLR) pathway involving interferon-α2 (IFN-α2) mediation.Methods: T2DM was induced in rats by a high-fat diet, in combination with an intraperitoneal injection of low-dose streptozotocin. ELISAs were conducted to measure inflammatory-related factors in serum. Next, isolated cardiomyocytes were used in loss- and gain-of-function experiments, followed by MTT and flow cytometry assays, conducted to evaluate cell proliferation, cell cycle, and apoptosis.Results: Our results revealed an increase in the inflammatory response in T2DM rat models, accompanied by significantly increased expression of miR-216a-3p and TLR pathway-related genes. However, a decrease in the expression of IFN-α2 was observed. Moreover, the presence of an miR-216a-3p inhibitor and si-IFN-α2 increased the expression of TLR pathway-related genes and cell apoptosis, whereas cell proliferation was significantly decreased in the cardiomyocytes.Conclusion: We found that in T2DM, miR-216a-3p inhibited the proliferation and enhanced the apoptosis of cardiomyocytes and generated an inflammatory response through activation of the TLR pathway and targeting of IFN-α2.

Chitosan-stabilized selenium nanoparticles alleviate cardio-hepatic damage in type 2 diabetes mellitus model via regulation of caspase, Bax/Bcl-2, and Fas/FasL-pathway.

The present study was carried out to explore a novel strategy with the hypothesis that the combined treatment with standard antidiabetic drug metformin (MET) and chitosan stabilized nanoparticles (CTS-Se-NPs) may have a potential role on insulin level, hepatic damage and apoptosis, and cardiac injury markers of type 2 diabetes mellitus (T2DM) in rat model. T2DM was induced by a high fat diet (HFD) for 8weeks and a single injection of a low dose streptozotocin (STZ) (35mg/kg) in Sprague Dawley rats. A total number of one hundred rats were divided into five groups; the first served as a control (non-diabetic) group and the other four groups served as diabetic rats. The treatments were even mono or combined therapy by CTS-Se-NPs and/or MET for 8weeks. A group was given only MET (500mg/kg bw/day), another was administered only CTS-Se-NPs at a dose of 2mg se/kg/day, while the last group was given both of them (co-treated group). Biochemical, molecular and histopathological analyses were conducted to figure out the efficiency of the treatment by the monotherapeutic mode or combination therapy on the insulin level, oxidants/antioxidants status, inflammatory mediators, hepatic and cardiac injury biomarkers and apoptotic/anti-apoptotic gene expressions. Our results indicated that HFD/STZ-induced toxic effects on the serum, hepatic and cardiac tissues including a remarkable elevation of the oxidative and inflammatory mediators, and up-regulation of the apoptotic genes (Bax, Caspase-3, Fas, Fas-L) expression. Histologically, the heart tissue revealed various degenerative, vascular and inflammatory alterations characteristic to murine cardiomyopathy. Besides, livers from HFD-STZ-treated rats showed numerous cytotoxic, circulatory and inflammatory alterations. Combined therapy with MET and CTS-Se-NPs resulted in a better remarkable anti-diabetic effect demonstrated by substantial decreases in fasting blood glucose and insulin levels, and elevated with up-regulation of anti-apoptotic gene (BCL-2) and down-regulation of apoptotic genes after 8weeks of treatment than that revealed in the monotherapeutic strategy. In addition, it ameliorated the damage of cardiac and hepatic tissues and reduced lipid accumulation, and pro-inflammatory cytokines levels and restored the antioxidant capacity. It could be concluded that, the combined strategy applied in the current study have a potential role to limit the diabetic complications and restore insulin resistance to a higher extent than monotherapeutic strategy and could be considered a promising therapeutic alternative in T2DM rat model.

Epigallocatechin-3-gallate ameliorates glucolipid metabolism and oxidative stress in type 2 diabetic rats.

Aims:The objective of this study was to explore the effects of epigallocatechin-3-gallate (EGCG) on type 2 diabetes mellitus (T2DM).Main methods:Male Sprague–Dawley rats were allocated into six groups. The control group received a conventional diet. The diabetic group received a high-sucrose high-fat (HSHF) diet for 4 weeks and then was fasted and injected with streptozotocin (STZ); subsequently, the rats received a HSHF diet for another 4 weeks to develop diabetes. The four treatment groups were diabetic rats that received intragastric metformin (500 mg/kg/day) or EGCG (25, 50, and 100 mg/kg/day) for 10 weeks. All groups except the control group received a HSHF diet throughout the experiment. Several biochemical parameters such as fasting blood glucose (FBG), postprandial blood glucose (PBG), liver glycogen, muscle glycogen, fasting serum insulin (FSI), homeostasis model of insulin resistance (HOMA-IR), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), free fatty acids (FFA), superoxide dismutase (SOD), and malondialdehyde (MDA) were measured to assess the effects of EGCG on glycemic control, insulin resistance, lipid profile, and oxidative stress. Furthermore, oxidative stress in pancreatic islet β cells was detected by dihydroethidium staining.Key findings:A HSHF diet and STZ injection induced T2DM, as indicated by changed blood glucose and body weight, which was accompanied by insulin resistance, an altered lipid profile, and oxidative stress. Interestingly, EGCG treatment dose-dependently recovered these indexes.Significance:EGCG successfully ameliorated glycemic control and insulin sensitivity while reducing the lipid profile and oxidative stress in a T2DM rat model.

Research on sleeve gastrectomy for the treatment of rats with type 2 diabetes mellitus and the regulation of ghrelin and intestinal lesions.

To explore the effect of sleeve gastrectomy on type 2 diabetes mellitus (T2DM) in regulating ghrelin and intestinal lesions. Specific pathogen free (SPF) Wistar rats were injected with streptozotocin (STZ) after giving a high-sugar and high-fat diet, to establish a T2DM rat model. The rats were randomly divided into a sleeve gastric excision group, a non-surgical group and a fake surgical group, with 10 rats in each group. The weight, blood glucose, glucose tolerance and ghrelin hormone of rats were compared. The feces of rats in each group at the 8th week after surgery were collected, to extract the total bacterial deoxyribonucleic acid (DNA). The bacterial 16S universal primer was used to expand the 16SrRNA V46 conserved region. The total Polymerase ChainReaction (PCR) products were sequenced by PE101-bp to classify the gene and genera. The weight of the rats after sleeve gastrectomy significantly decreased (p <0.05). The area under the blood glucose curve and the area under the insulin curve were significantly smaller than those in the non-surgical group and the fake surgical group (p <0.05). Compared with the sleeve gastric excision group, the abundance of PhylumFirmicutes was higher, that of Bacteroidetes was lower. Compared with the sleeve gastric excision group, there were more genera in the fake surgical group and the non-surgical group. The genera with higher abundance in the three groups were Lactobacillus and Bacteroidetes. Compared with the sleeve gastric excision group, the fake surgical group and the non-surgical group had higher abundance of PhylumFirmicutes (p <0.05) and lower abundance of Bacteroidetes (p <0.05). To sum up, sleeve gastrectomy can reduce the weight of rats in T2DM rat model, lower blood glucose levels of rats in the model and improve insulin resistance levels. The related mechanism may be related to the upregulation of ghrelin and intestinal flora.

The Expression of Liver Metabolic Enzymes AMPKα1, AMPKα2, and PGC-1α due to Exercise in Type-2 Diabetes Mellitus Rat Model

BACKGROUND: AMP-activated protein kinase (AMPK) and PGC-1α were crucial metabolism enzymes not only in the skeletal muscles but also in the liver. Exercise can modify metabolic enzymes to improve insulin resistance.&#x0D; AIM: The aim of this study was to analyze the expression of mRNA liver metabolic enzymes gene, that is, AMPKα1, AMPKα2, and PGC-1α in different types and intensities of exercise.&#x0D; METHODS: Healthy male Wistar rats aged 8 weeks in 150–180 g body weight were given a combination of high fat diet for five weeks and low doses of streptozotocin (30 mg/kgbw and 45 mg/kgbw in 0.1 citrate buffer pH 4,5) to develop type 2 diabetes mellitus (T2DM) rat model. Animals then were divided into five groups: One group was sedentary, and four groups were forced to run on the treadmill 3 times/week, 30 min each season, for 8 weeks. mRNA gene expression of AMPKα1, AMPKα2, and PGC-1α was determined with real-time PCR.&#x0D; RESULTS: The results showed that expression of mRNA AMPKα1 in treatment groups was elevated than control and the much expression was showed in continuous types. The expression of mRNA AMPKα2 and PGC-1 α was declined in treatment group which little expression was showed in high intensity for AMPKα2 and moderate intensity for PGC-1 α. Base on type and exercise intensity, mRNA AMPKα1 gene expression much in moderate continuous, mRNA AMPKα2 gene expression higher in high intensity, both continuous and interval training, whereas mRNA PGC-1α gene expression higher in interval groups.&#x0D; CONCLUSION: Various types of aerobic exercises with moderate-vigorous intensities gave different impact to mRNA liver metabolic enzyme genes.

Type II diabetes accentuates diaphragm blood flow increases during submaximal exercise in the rat

We investigated the effect of type 2 diabetes mellitus (T2DM) on respiratory muscle blood flow (BF) during exercise. Using the Goto-Kakizaki (GK) rat model of T2DM, we hypothesized that diaphragm, intercostal and transverse abdominis BFs (radiolabeled microspheres) would be higher in male GK rats (n = 10) compared to healthy male Wistar controls (CON; n = 8) during submaximal exercise (20 m/min, 10 % grade). Blood glucose was significantly higher in GK (246 ± 29 mg/dL) compared to CON (103 ± 4 mg/dL; P < 0.01). Respiratory muscle BFs were not different at rest (P> 0.50). From rest to submaximal exercise, respiratory muscle BFs increased in both groups to all muscles (P < 0.01). During submaximal exercise GK rats had higher diaphragm BFs (GK: 189 ± 13; CON: 138 ± 14 mL/min/100 g, P < 0.01), and vascular conductance (GK: 1.4 ± 0.1; CON: 1.0 ± 0.1 mL/min/mmHg/100 g; P < 0.01) compared to CON. There were no differences in intercostal or transverse abdominis BF or VC during exercise (P> 0.15). These findings suggest that submaximal exercise requires a higher diaphragm BF and VC in T2DM compared to healthy counterparts.

Berberine ameliorates rats model of combined Alzheimer’s disease and type 2 diabetes mellitus via the suppression of endoplasmic reticulum stress

This study is aimed to investigate the protective effect against type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) of Berberine (BBR), and the underlying mechanism of action is explored. We established a rat model of combined AD and T2DM and used it to investigate the effect of BBR (150mg/kg) on the course of these pathologies. The Morris water maze, biochemical analysis, hematoxylin-eosin staining, immunohistochemical study, immunofluorescent staining, TUNEL assay, RT-qPCR and western blot were used to reveal the effect of BBR on blood glucose, lipid changes, hippocampal injuries and cognitive impairment. The results showed that BBR could alleviate memory deficits, restore the disordered arrangement of nerve cells, the damage of neurons, improve TUNEL-positive cells and decrease the elevated levels of fasting blood glucose, triglyceride, total cholesterol and glycosylated serum protein levels in Alzheimer diabetic rats. Moreover, BBR treatment reduces the transcription of mRNAs and expression of proteins related to endoplasmic reticulum (ER) stress. These findings conclude that BBR can protect neurons by inhibiting the pathway of ER stress and thereby play an essential role in the preventive and therapeutic of AD and T2DM.

RETRACTED: miR-363 Alleviates Detrusor Fibrosis via the TGF-β1/Smad Signaling Pathway by Targeting Col1a2 in Rat Models of STZ-Induced T2DM

Dysregulated expression of microRNAs (miRNAs or miRs) has been implicated in the pathophysiology of type 2 diabetes mellitus (T2DM). However, their underlying role in the complication of detrusor fibrosis remains poorly understood. Therefore, this study aimed to examine the potential functional relevance of miR-363 in detrusor fibrosis of rats with streptozotocin (STZ)-induced T2DM through the predicted target gene collagen type I alpha 2 (Col1a2). Immunohistochemical analysis found an increase in the positive expression of collagen type III alpha 1 (Col3a1) and Col1a2 in detrusor tissues, where miR-363 expression was decreased. Next, gain- and loss-of-function experiments were performed to clarify the effects of miR-363 and Col1a2 on the activities of bladder detrusor cells. Of note, binding affinity between miR-363 and Col1a2 was verified by a dual-luciferase reporter gene assay and RNA immunoprecipitation (RIP) assay. Upregulated miR-363 inhibited Col1a2 expression, which led to increased expression of B-cell lymphoma 2 (Bcl-2) and Smad7 and accelerated cell viability, along with decreases in cell apoptosis and Col3a1, Bcl-2-associated X protein (Bax), transforming growth factor (TGF)-β1, and Smad4 expressions. In conclusion, miR-363 upregulation reduces detrusor fibrosis in rats with STZ-induced T2DM through suppression of the TGF-β1/Smad signaling pathway by targeting Col1a2. Therefore, our study provided further insights for the development of new therapeutic targets for T2DM.

The difference between steroid diabetes mellitus and type 2 diabetes mellitus: a whole-body 18F-FDG PET/CT study

AimsSteroid diabetes mellitus (SDM) is a metabolic syndrome caused by an increase in glucocorticoids, and its pathogenesis is unclear. 18F-FDG PET/CT can reflect the glucose metabolism of tissues and organs under living conditions. Here, PET/CT imaging of SDM and type 2 diabetes mellitus (T2DM) rats was used to visualize changes in glucose metabolism in the main glucose metabolizing organs and investigate the pathogenesis of SDM.MethodsSDM and T2DM rat models were established. During this time, PET/CT imaging was used to measure the %ID/g value of skeletal muscle and liver to evaluate glucose uptake. The pancreatic, skeletal muscle and liver were analyzed by immunohistochemistry.ResultsSDM rats showed increased fasting blood glucose and insulin levels, hyperplasia of islet α and β cells, increased FDG uptake in skeletal muscle accompanied by an up-regulation of PI3Kp85α, IRS-1, and GLUT4, no significant changes in liver uptake, and that glycogen storage in the liver and skeletal muscle increased. T2DM rats showed atrophy of pancreatic islet β cells and decreased insulin levels, significantly reduced FDG uptake and glycogen storage in skeletal muscle and liver.ConclusionsThe pathogenesis of SDM is different from that of T2DM. The increased glucose metabolism of skeletal muscle may be related to the increased compensatory secretion of insulin. Glucocorticoids promote the proliferation of islet α cells and cause an increase in gluconeogenesis in the liver, which may cause increased blood glucose.

Moringa Isothiocyanate-rich Seed Extract Delays the Onset of Diabetes in UC Davis Type-2 Diabetes Mellitus Rats

Moringa seeds have been used traditionally in the management of type 2 diabetes mellitus (T2DM) and contain potent bioactive isothiocyanates. This study evaluated the efficacy of an isothiocyanate-rich moringa seed extract in delaying the onset of T2DM in UC Davis T2DM rats, a well validated model which closely mimics T2DM in humans. Rats were separated into three groups; control, moringa seed extract at 0.4%, and a weight matched group. Rats were fed respective diets for 8 months, during which energy intake, body weight, the onset of diabetes circulating hormones, metabolites and markers of inflammation and liver function, and were monitored. The MS group had a significantly slower rate of diabetes onset p = 0.027), lower plasma glucose (p = 0.043), and lower HbA1c (p = 0.008) compared with CON animals. There were no significant differences in food intake and body weight between all groups. This study demonstrated MS can delay the onset of diabetes in the UC Davis T2DM rat model to a greater extent than moderate caloric restriction (by comparison to the WM group). The results support its documented traditional uses and a bioactive role of moringa isothiocyanates and suggest the potential efficacy for moringa supplementation for diabetes management in populations at risk for T2DM.

Suppression of type 2 diabetes mellitus-induced aortic ultrastructural alterations in rats by insulin: an association of vascular injury biomarkers

ABSTRACT Diabetes represents a major public health problem and an estimated 70% of people with diabetes die of cardiovascular complications. The protective effect of insulin treatment against ultrastructural damage to the tunica intima and tunica media of the aorta induced by type 2 diabetes mellitus (T2DM) has not been investigated before using transmission electron microscopy (TEM). Therefore, we induced T2DM in rats using high fat diet and streptozotocin (50 mg/kg) and administered insulin daily by i.v injection for 8 weeks to the treatment group. Whereas, the T2DM control group were left untreated for the duration of the experiment. A comparison was also made between the effect of insulin on aortic tissue and the blood level of biomarkers of vascular injury, inflammation, and oxidative stress. T2DM induced profound ultrastructural damage to the aortic endothelium and vascular smooth muscle cells, which were substantially protected with insulin. Furthermore, insulin returned blood sugar to a control level and significantly (p < .05) inhibited diabetic up-regulation of endothelial and leukocyte intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein 1 (VCAM-1), endothelial cell adhesion molecules, P-selectin and E-selectin, tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), and malondialdehyde (MDA). Furthermore, insulin augmented the blood level of the anti-oxidant enzyme superoxide dismutase (SOD). We conclude that in a rat model of T2DM, insulin treatment substantially reduces aortic injury secondary to T2DM for a period of 8 weeks, possibly due to the inhibition of hyperglycemia, vascular activation, inflammation, and oxidative stress.