Pancreas Of Diabetic Mice Research Articles

Antidiabetic Activity and Pancreatic Histopathology Analysis of Averrhoa bilimbi L. Leaves Extract on Alloxan-Induced Diabetes on Wistar Mice

Background: Diabetes mellitus is a multi-etiological metabolic disorder characterized by chronic hyperglycemia, total or relative insulin deficiency, and further complications by metabolic disorders. Drug therapy for diabetes mellitus is costly and fraught with potential side effects. The aim of this research is to investigate antidiabetic and histopathological analysis of ethanolic A. bilimbi leaves extract in alloxan induced diabetic mice.Methods: Wuluh starfruit leaves is one of Indonesia's plants that can be used to treat diabetes mellitus. Thirty male Wistar mice were divided into five groups as follows: Negative control group that didn't receive any treatment, Diabetes control group that received alloxan 150 mg/kg, Positive control group that received glibenclamide 600 μg/kg, and lastly the two test groups that received A. bilimbi leaves extract 150 and 300 mg/kg orally for 14 days. After extract administration, blood glucose and histopathological alterations in the pancreas of diabetic mice were observed.Results: Alloxan to the diabetes control group significantly raised blood glucose levels compared to the negative control group. Administration of wuluh starfruit leaves extract and glibenclamide could significantly lower blood sugar levels compared to the diabetic control group. Administration of wuluh starfruit leaves extract treatment and glibenclamide also showed favorable effect on the histopathological changes of the pancreas in alloxan induced diabetes.Conclusion: The study concludes the administration of wuluh starfruit leaves extract (150 and 300 mg/kg) and glibenclamide could reduce blood glucose levels and can help with cell regeneration and protecting pancreatic cells from damage caused by alloxan.Keywords: A. bilimbi leaves extract; Alloxan; Diabetes; Pancreatic histopathology

HISTOPATHOLOGICAL PICTURE OF THE PANCREAS OF MICE (MUS MUSCULUS) DIABETES INDUCED BY STREPTOZOTOCIN-SUKROSA BY GIVING PEPAYA SEED EXTRACT (CARICA PAPAYA L.)

This study aimed to investigate the potential of papaya seed extract as an antihyperglycemic agent and to determine the histopathological features of the pancreas of female mice induced by streptozotocin-sucrose. The study used female DDY mice and divided them into five groups, including a negative control group, a positive control group, and three test groups given different doses of papaya seed methanol extract. The parameters measured were the decrease in fasting blood glucose levels, the number, diameter, and area of the islets of Langerhans in each group. The data was analyzed using the one-way ANOVA method with a confidence level of 95% followed by a comparison test using the Least Significant Difference method. The results showed that the methanol extract of papaya seeds has the potential to reduce blood glucose levels and improve the histological structure of the pancreas of diabetic mice induced by streptozotocin-sucrose at an optimum dose of 100 mg/kgBW. There was a significant difference in reducing blood glucose levels between the negative control group and the test group given 100 mg/kgBW papaya seed methanol extract after seven days of treatment. After fourteen days, there was a significant difference between the negative control group and test groups I, II, and III. Although no significant differences were found in the number, diameter, and area of the islets of Langerhans through morphometric photo testing, microscopic photo testing showed that test group I had the best histopathological picture with no vacuolization and necrosis found.

Anti-Hyperglycemic Effect of the Brown Slime Cap Mushroom Chroogomphus rutilus (Agaricomycetes) Crude Polysaccharide In Vitro and In Vivo.

The prevalence of diabetes is increasing worldwide, and it is very important to study new hypoglycemic active substances. In this study, we investigated the hypoglycemic effect of Chroogomphus rutilus crude polysaccharide (CRCP) in HepG2 cells and streptozotocin-induced diabetic mice. A glucose consumption experiment conducted in HepG2 cells demonstrated the in vitro hypoglycemic activity of CRCP. Furthermore, CRCP exhibited significant hypoglycemic effects and effectively ameliorated insulin resistance in insulin resistant HepG2 cells. In high-fat diet and streptozotocin-induced diabetic mice, after 4 weeks of CRCP administration, fasting blood glucose, fasting serum insulin, triglyceride, total cholesterol, low-density lipoprotein cholesterol, glutamate transaminase, alanine transaminase, and insulin resistance index significantly decreased, while high-density lipoprotein cholesterol and insulin sensitivity index (ISI) were markedly increased. Moreover, hematoxylin-eosin (HE) staining and immunofluorescence labeling of tissue sections indicated that CRCP attenuated the pathological damage of liver and pancreas in diabetic mice. These results indicate that CRCP is a potential hypoglycemic agent.

Prophylactic and Curative Effect of Boswellia Serrata on Blood Glucose Level and Architecture of Pancreas in Diabetic Mice Induced by Alloxan

Background and objectives. Herbal medicines have gained significant attention from the scientific community for treating and managing diabetes in both developing and developed countries. Boswellia serrata, known for its anti-inflammatory and antioxidant properties, has been historically used to treat various diseases. This study aimed to determine the effect of Boswellia serrata on body weight, blood glucose level, and pancreas architecture in alloxan-induced diabetes in albino mice. Methods. Forty albino male mice, aged 10 to 12 weeks and weighing between 24 and 34 grams, were divided into four groups of ten each. The first group was the negative control group, and the second group was the diabetic positive control group that received 120 mg/kg alloxan intraperitoneally. The third group received a single injection of alloxan at a dose of 120 mg/kg bw and was treated with Boswellia serrata macerated at a dose of 150 mg/kg bw for four weeks. The fourth group received orally Boswellia serrata extract at a dose of 150 mg/kg for two weeks, followed by a single injection of alloxan at a dose of 120 mg/kg, and were left for two weeks. Results. This study found that Boswellia serrata has antidiabetic properties in diabetic mice, as it significantly reduced blood sugar levels compared to the diabetic group. Additionally, histological analyses of the groups treated with B. serrata showed a significant improvement in the harmful effects of alloxan on pancreatic islet cells. Conclusion. Boswellia serrata has shown a notable improvement in the detrimental effect of alloxan on pancreatic islet cells, and its curative effect has been proven to be better than its prophylactic effect. This is supported by the improved blood glucose levels and the histological changes that were more pronounced.

Pancreas patch grafting to treat type 1 diabetes

Stem/progenitor cell therapy is a promising treatment option for patients with type 1 diabetes (T1D) a disease characterized by autoimmune destruction of pancreatic β cells. Actively injecting cells into an organ is one option for cell delivery, but in the pancreas, this contributes to acute inflammation and pancreatitis. We employed a patch grafting approach to transplant biliary tree stem cells/progenitor cells (BTSC) onto the surface of the pancreas in diabetic mice. The cells engraft and differentiate into β-like cells reversing hyperglycemia during a four-month period of observation. In addition, C-peptide and insulin gradually increase in blood circulation without detectable adverse effects during this period. Moreover, the patch graft transplant promoted the proliferation and differentiation of pancreatic β-like cells with co-expression of the β cell biomarker. ConclusionBTSC transplantation can effectively attenuate T1D over a four-month period that is vital important for clinical applications.

Metal-polyphenol microgels for oral delivery of puerarin to alleviate the onset of diabetes.

Puerarin (Pue) is a naturally bioactive compound with many potential functions in regulating blood glucose and lipid metabolism. However, the low bioavailability and rapid elimination in vivo limit the application of Pue in diabetic treatment. Here, we developed a metal-polyphenol-functionalized microgel to effectively deliver Pue in vivo and eventually alleviate the onset of diabetes. Pue was initially encapsulated in alginate beads through electrospray technology, and further immersed in Fe3+ and tannic acid solution from tannic acid (TA)-iron (Fe) coatings (TF). These constructed Pue@SA-TF microgels exhibited uniform spheres with an average size of 367.89 ± 18.74µm and high encapsulation efficiency of Pue with 61.16 ± 1.39%. In vivo experiments proved that compared with free Pue and microgels without TF coatings, the biological distribution of Pue@SA-TF microgels specifically accumulated in the small intestine, prolonged the retention time of Pue, and achieved a high effectiveness in vivo. Anti-diabetic experimental results showed that Pue@SA-TF microgels significantly improved the levels of blood glucose, blood lipid, and oxidative stress in diabetic mice. Meanwhile, histopathological observations indicated that Pue@SA-TF microgels could significantly alleviate the damage to the liver, kidney, and pancreas in diabetic mice. Our study provided an effective strategy for oral delivery of Pue and achieved high anti-diabetic efficacy.

Histological Detection and Anti-oxidant Effect of Bee Venom on the Pancreas of Diabetic Mice

Bee venom BV draws attention in the medical field to manage several diseases, including type 2 diabetes mellitus (T2DM). Due to limited research on this field in Iraq, the study aimed to detect BV's histological and anti-oxidant impact in diabetic mice. Fifteen male mice were randomly assigned into three groups. The first group is control (C), the second is diabetic, and the last group is BV. At the end of 30 days, the obtained serum was used to measure the level of glucose, insulin, superoxide dismutase (SOD), and malondialdehyde (MDA). Furthermore, the pancreas was histologically assessed using the Gomori stain. Alloxan showed significant elevation and reduction in the level of glucose and insulin compared to the control. These alterations were positively enhanced by BV. BV promoted significant elevation in the activity of SOD and suppressed MDA compared to diabetic mice. Histologically, diabetic mice pancreas displayed a reduction of capsular tissue, islets and beta cells vacuolization, beta cells initial degeneration, reduction in the shape and size of the islets and beta cells, and vascular hemorrhage. These changes were remarkably enhanced nearly to normal by BV. Therefore, BV could control the diabetic condition, which may be considered a potential anti-diabetic agent. Keywords: Diabetes mellitus, SOD, MDA, pancreas, mice, BV

Metformin and Bee Venom: a Comparative Detection of Histological Alteration of the Pancreas and Systemic Inflammatory Markers in Diabetic Mice.

Metformin is the approved medication for managing global health issues concerning type 2 diabetes mellitus (T2DM). Using natural bioactive compounds as an alternative therapy is crucial to managing several metabolic diseases. Therefore, due to recent limited studies that detected the role of bee venom (BV) in improving diabetic conditions in Iraq, the current study was designed to identify the potential therapeutic role of BV and metformin in diabetic mice. Twenty male mice (Balb/c) aged about 60 days with an average weight of 26.55±2.70 g were randomly divided into four groups (n=5). The animals were placed in plastic cages for acclimatization for one week of access to food and water ad libitum. Overnight fasting was applied to 15 mice which were then injected with 95 mg/kg body weight of prepared alloxan. The mice were supplemented with glucose fluid for 3 days. On day 4, the blood was collected from the tail to measure the circulating glucose level. When blood glucose levels exceed 200 mg/dl, the animals are considered diabetic. After induction of diabetes, the animals were divided as follows: Control group: included five mice that were not subjected to diabetes induction; the animals in this group: did not receive any medications. Diabetic group: including five mice confirmed with diabetes without receiving any treatments. Metformin group: including five diabetic mice exposed to a single oral dose of 150 mg/kg of metformin for 30 days. Bee Venom group: including five diabetic mice exposed to a single intraperitoneal dose of 1 mg/kg Bee Venom for 30 days. After 30 days of treatment, blood was drained, and serum was obtained to detect the levels of glucose, insulin, TNFα, IL6, and IL10 by using precise enzyme-linked immunosorbent assay (ELIZA) kits. Also, the pancreas was collected from all mice for histopathological investigation. The result displayed significantly elevated glucose concentration in diabetic mice, while metformin and BV significantly reversed these increases. A significant decline in insulin concentration was seen in diabetic mice, whereas metformin and BV significantly enhanced this reduction in insulin concentration. Furthermore, mice treated with alloxan exhibited remarkable increases in TNFα and IL6 compared to control mice, while supplemented metformin and BV significantly reduced these high concentrations. Moreover, the level of IL10 markedly declined in diabetic mice, which was reversed significantly in response to metformin and BV. Histological detection of the pancreas in diabetic mice showed significant changes in the shape and size of islets associated with the arrangement and number of beta cells with a reduction of islets covering connective tissue. Metformin slightly restored these alterations; however, significant and remarkable restoring of histological changing was promoted by BV. Thus, BV could be a potential agent for managing metabolic disorders including diabetes.

Effect of Eight Weeks of Endurance Training in Light and Dark Phases of Circadian Rhythm on the Oxidative Stress Index in Pancreas of Diabetic Mice

Introduction: Chronic hyperglycemia is associated with an increase in cellular damage due to oxidative stress in pancreatic tissue. The effect of exercise in different phases of the circadian cycle on protecting pancreatic tissue from oxidative stress in diabetic patients is unknown. The aim of this study was to investigate the effect of eight weeks of endurance training in light and dark phases of circadian rhythm on the oxidative stress index in pancreas of diabetic mice.
 Methods: In this study, 18 mice from the Naval Medical Research Institute (26.3±3.22 gr) were selected and after inducing diabetes through high-fat food and Streptozotocin injection (20 mg/kg), randomly divided into 6 groups: light phase healthy control, dark phase healthy control, light phase diabetic control, dark phase diabetic control, light phase diabetic training and dark phase diabetic training. The endurance training protocol (50-60 %Vmax) was performed 5 d/w for 8 weeks. After anesthesia, blood samples and pancreatic tissues were removed. Insulin resistance markers, oxidative stress index and expression of Brain and Muscle ARNT-Like1 protein expression were measured in pancreas of diabetic rats. Data were analyzed by one way analysis of variance at the significance level of p <0.05.
 Results: The eight weeks of endurance training significantly decreased insulin resistance markers (p= 0.005), oxidative stress index (p ˂0.05) and significantly increased the Bmal1 protein expression (p = 0.009). The mean values of all variables showed significant differences between light and dark phases.
 Conclusion: Endurance training may improve insulin sensitivity and oxidant damage in diabetic conditions by increasing the function of the antioxidant system and the expression of Circadian regulation proteins. Activity in the dark phase causes further increases the metabolism of cells. As a result, performing these types of exercises in the dark phase is recommended to these patients as a new treatment strategy.

MiR-190 ameliorates glucotoxicity-induced dysfunction and apoptosis of pancreatic β-cells by inhibiting NOX2-mediated reactive oxygen species production.

Glucotoxicity-induced pancreatic β-cell failure contributes to the development of type 2 diabetes mellitus (T2DM). Accumulating evidence reveals that miRNAs play a critical role in regulating pancreatic β-cell function and survival. In this study, we employed a self-assembled cell microarray (SAMcell)-based functional screening assay to identify miRNAs that are capable of regulating the dysfunction of β-cells induced by glucotoxicity. Among 62 conserved miRNAs we tested, miR-190 was identified as a candidate regulator that could effectively restore insulin expression in NIT-1 cells under high-glucose (HG) stimulation. Further analyses demonstrated that miR-190 was significantly down-regulated in HG-treated NIT-1 cells, as well as in the pancreas of diabetic mice. Mechanistic studies showed that Cybb is the direct target gene of miR-190, which encodes the gp91phox protein, a subunit of the NOX2 complex. Furthermore, both miR-190 overexpression and Cybb knockdown inhibited apoptosis and improved glucose-stimulated insulin secretion (GSIS) in HG-stimulated NIT-1 cells by attenuating the excessive production of reactive oxygen species (ROS). More importantly, a targeted delivery of mPEG-PCL-g-PDMAEMA nanoparticles/miR-190 complexes (PECgD NPs/miR-190) to the pancreas significantly ameliorated hyperglycemia, decreased fasting serum insulin levels, and improved glucose tolerance in diabetic mice. Taken together, our findings suggest that the miR-190/Cybb axis plays an important role in glucotoxicity-induced pancreatic β-cell failure. Restoring miR-190 expression levels may be a possible therapeutic strategy to protect β-cells in T2DM.

SYZYGIUM CUMINI DEPARTS THE NEGATIVES OF THE ALLOXAN INDUCED DIABETES IN SWISS ALBINO MICE

Background: Because of the unfavorable side effects and higher cost of synthetic anti-diabetic medicines, an alternative approach to manage diabetes mellitus from an herbal source would be safe and within the affordability of the common people. Hence we investigated the hypoglycemic and pancreatic islets restoration effect of Syzygium cumini seed extract using glibenclamide as positive control.
 Methods: Six (06) normal control mice and eighteen (18) alloxan induced diabetic mice grouped as diabetic control, Syzygium cumini and standard drug, were used for this experiment. In comparison to a reference drug-glibenclamide (@600μg/kg body weight), Syzygium cumini seed ethanolic extract (@500mg/kg body weight) was given orally once daily for thirty days to counteract alloxan induced alteration in blood glucose level and pancreatic cells morphology. Fasting blood glucose (FBG) level was evaluated at 15 days intervals, whereas mice were ethically sacrificed to collect pancreas at the completion of the experiment and processed for histological examination.
 Results: Research results revealed that in both the Syzygium cumini and standard drug treated groups, FBG level were significantly lower than the diabetic control group (P < 0.05). Histologically, smaller islets and necrosis, present in the pancreas of diabetic mice were returned to normal following treatment with Syzygium cumini seed extract and standard anti-diabetic drug.
 Conclusion: Syzygium cumini seed extract could be recommended as anti-diabetic for humans and animals especially in developing and under developed countries where this plant is readily available and affordable.

Urolithin A suppresses glucolipotoxicity-induced ER stress and TXNIP/NLRP3/IL-1β inflammation signal in pancreatic β cells by regulating AMPK and autophagy

BackgroundPancreatic inflammation plays a key role in diabetes pathogenesis and progression. Urolithin A (UA), an intestinal flora metabolite of pomegranate, has anti-diabetic, anti-inflammatory and kidney protection effects among others. However, its effects on pancreatic inflammation and the potential mechanisms have not been clearly established. PurposeThis study aimed at investigating the molecular mechanisms of UA anti-pancreatic inflammation under a diabetic environment. MethodsDiabetes induction in male C57BL/6 mice was achieved by a high fat diet and intraperitoneal streptozotocin injections. Then, diabetic mice were orally administered with UA for 8 weeks. In vitro, endoplasmic reticulum stress and MIN6 pancreatic β cell inflammation were induced using 25 mM glucose and 0.5 mM palmitic acid. The effects of UA were evaluated by immunohistochemistry, Western blot, and enzyme linked immunosorbent assays. Finally, the underlying mechanisms were elucidated using an autophagy inhibitor (chloroquine, CQ) and an AMPK inhibitor (dorsomorphin dihydrochloride). ResultsUA significantly inhibited IL-1β secretion and TXNIP/NLRP3 expression in the pancreas of diabetic mice and in MIN6 pancreatic cells. UA downregulated the ER stress protein, p-PERK, and promoted AMPK phosphorylation. UA activated autophagy to inhibit TXNIP/NLRP3 IL-1β inflammatory signal, an effect that was reversed by CQ. Dorsomorphin 2HCL, reversed the autophagy-activation and anti-inflammatory effects of UA. Verapamil, clinically applied as an antiarrhythmic drug, is a TXNIP inhibitor for prevention of beta cell loss and diabetes development, but limited by its cardiac toxicity. In this study, verapamil (as positive control) inhibited NLRP3 /IL-1β signaling in MIN6 cells. Inhibitory effects of UA on TXNIP and IL-1β were weaker than those of verapamil (both at 50 μM, p < 0.05, p < 0.01). Conversely, inhibitory effects of UA on p62 were stronger, relative to those of verapamil (p < 0.05), and there were no differences in AMPK activation and LC3 enhancement effects between UA and verapamil. ConclusionUA is a potential anti-pancreatic inflammation agent that activates AMPK and autophagy to inhibit endoplasmic reticulum stress associated TXNIP/NLRP3/IL-1β signal pathway.

Nanocurcumin Modulates Ultramicroscopic Changes in the β-Cells of Pancreas in Diabetic Mice

Nanocurcumin Modulates Ultramicroscopic Changes in the β-Cells of Pancreas in Diabetic Mice

The Effect of Antlion (Myrmeleon sp.) Extract Towards Histopathology Image of Pancreas in Diabetic Mice

Introduction: Some studies indicated that antlions (Myrmeleon sp.) is traditionally used by many people in Indonesia as a diabetes treatmenter. However. reseach has not been done to find the effect of antlion extract in pancreas, an important organ in diabetes mellitus pathophysiology. Objective: To prove the effect of antlion extract towards histopathological feature of pancreas in diabetic mice.Methods: In the post test only control group design, 25 Swiss mice were divided into five groups. Normal group (Nor-G), Negative control group (Neg-G), and the other 3 groups were intraperitoneally injected with Streptozotocine 200 mg/kg to induce diabetic state. In Neg-G had no antlion treatment, whereas in At-14, At-28, and At-56 were treated with antlion extract at the dose of 14, 28, and 56 mg/kg BW respectively for 24 days. Pancreas then collected and prepared to be examined under microscope with 400x magnification. The score of pancreatic islet injury was determined by assessing structural damage and inflammatory cells infiltration. Kruskal-Wallis and Mann-Whitney were adopted as statistical analysis.Results: Mann-Whitney analysis indicated that the score of pancreatic islets injury in At-56 was significant lower compared to that of Neg-G, p&lt;0.05. The score of pancreatic islets injury in At-56 also significant lower compared to that of At-14 and At-28, p&lt;0.05. In contrary, when compared to that of Nor-G, the pancreatic islets injury in At-56 was not signicantly lower, p&gt;0.05.Conclusion: Antlion extract treatment at the dose of 56 mg/kg BW was capable of reducing pancreatic islet injury in diabetic mice induced by streptozotocine.

Hypoglycemic Activity of Total Flavonoids from Slippery Jack Mushroom, Suillus luteus (Agaricomycetes), In Vitro and In Vivo.

The hypoglycemic effects of total flavonoids from Suillus luteus (SLFLA) were investigated in vitro and in vivo. The glucose consumption experiment in HepG2 cells showed that SLFLA had hypoglycemic activity in vitro. Moreover, SLFLA could improve insulin resistance and exhibited good hypoglycemic activity in the insulin resistance model. In streptozotocin-induced diabetic mice, SLFLA could effectively reduce blood sugar, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, triglyceride, alanine aminotransferase, and aspartate aminotransferase levels. Damage to the liver, kidney, and pancreas in diabetic mice was mitigated after intragastric administration of SLFLA. These results suggested that SLFLA might be a promising functional food or medicine for T2DM treatment.

Long-term treatment of polysaccharides-based hydrogel microparticles as oral insulin delivery in streptozotocin-induced type 2 diabetic mice

To develop a more effective and safer drug for the treatment of type 2 diabetes mellitus (T2DM), polysaccharides-based hydrogel microparticles as oral insulin delivery was prepared and explored. This study was aimed to evaluate the antidiabetic effects and hypoglycemic mechanism with long-term administration(four weeks) of oral insulin hydrogel microparticles in type 2 diabetic mice on a model of diabetes using a high fat diet combined with streptozotocin. The results revealed that the long-term treatment of oral insulin polysaccharides-based hydrogel microparticles could significantly alleviate the symptoms of polyphagia, polydipsia, polyuria and weight loss in diabetic mice. Also, oral administration of insulin hydrogel microparticles could significantly reduce fasting blood glucose levels, ameliorate insulin resistance and increase insulin sensitivity in the mice with T2DM. The concentration of plasma TG, TC, LDL-C, FFA, BUN, CRE significantly decreased and the levels of HDL-C increased showed that insulin polysaccharides-based hydrogel microparticles were effective in regulating lipid metabolism and prevent diabetic nephropathy complication in diabetic mice. In addition, the supplementation of insulin hydrogel microparticles could significant improve the antioxidant capacity by increasing the level of SOD, CAT and decreasing the level of MDA, GPT, NO, TNF-α, and reverse histological deterioration of kidney and pancreas in diabetic mice. The above outcome concluded that insulin polysaccharides-based hydrogel microparticles may exhibit promising anti-diabetic activity and the potential to be a drug candidate for T2DM.

Pancreas protective effects of Urolithin A on type 2 diabetic mice induced by high fat and streptozotocin via regulating autophagy and AKT/mTOR signaling pathway.

Urolithin A (UroA), the main intestinal microflora metabolite of ellagic acid of berries, pomegranate,and some other traditional chinese herbals such as emblica officinalis,etc,has been reported to exhibit anti-inflammatory, anti-oxidative, anti-tumor and pro-autophagy effects. This study evaluated the anti-diabetic and pancreas-protective effects of UroA using a mice model of type 2 diabetes and preliminarily explored its effect on autophagy as well as the mechanism involved. Type 2 diabetes model was induced by high-fat diet (HFD; 60% energy as fat) and low-dose streptozotocin (85mg/kg) injection. Mice were administered with UroA (50mg/kg/d) alone or UroA-chloroquine (autophagy inhibitor) combination for 8 weeks. UroA improved symptoms of diabetic mice such as high water intake volume, high urine volume, significantly decreased fasting blood glucose (FBG), after-glucose-loading glucose, glycated hemoglobin (GHb) levels, plasma C-peptide, malondialdehyde (MDA) and interleukin-1 β level, increased reduced glutathione (GSH), interleukin-10 content, and glucose tolerance. UroA also improved pancreatic function indexes such as HOMA-β as evidenced by improved pathological and ultrastructural features of the pancreas assessed by light microscopy and transmission electron microscopy (TEM). Accordingly, UroA decreased mitochondrial swelling and myelin-like cytoplasmic inclusions. UroA significantly upregulated the protein levels of microtubule-associated protein 1 light chain 3-II (LC3II) and beclin1, downregulated sequestosome 1 (p62) accompanied by decreased expression of apoptotic protein cleaved caspase3 in pancreas of diabetic mice. In addition, it increased the phosphorylation level of protein kinase B (p-Akt) and mammalian target of rapamycin (p-mTOR). Most of these effects of UroA were reversed by treatment with autophagy inhibitor chloroquine. Our findings reveal that the pancreas protective effects of UroA against diabetes were partially mediated by its regulation of autophagy and AKT/mTOR signal pathway.

Dracorhodin perchlorate protects pancreatic β-cells against glucotoxicity- or lipotoxicity-induced dysfunction and apoptosis invitro and invivo.

Glucotoxicity or lipotoxicityleads to hyperglycemia and insulin secretion deficiency, which are important causes for the onset of type 2 diabetes mellitus (T2DM). Thus, the restoration of β-cell function is a long-sought goal in diabetes research. Previous studies have implicated pancreatic and duodenal homeobox 1 gene (Pdx1) in β-cell function and insulin secretion. In this study, we established a Pdx1 promoter-dependent luciferase system and identified the natural compound dracorhodin perchlorate (DP) as an effective promotor of Pdx1 expression. We further demonstrated that DP could significantly inhibit β-cell apoptosis induced by 33mm glucose or 200 μm palmitate by interfering with endoplasmic reticulum stress and mitochondrial pathways and enhance insulin secretion as well. These effects were associated with enhanced activities of Erk1/2, which in turn promoted Pdx1 expression and increased the ratio of Bcl2/Bax, since inhibition of the Erk1/2 pathway abolished the DP-induced expression of Pdx1 and suppression of apoptosis. In addition, our invivo results in diabetic mice indicated that DP treatment lowered blood glucose, raised insulin levels, enhanced Pdx1 expression and increased islet size and number in the pancreas of diabetic mice. Our findings suggest that Pdx1 is a potential target molecule of DP in the treatment of T2DM via the inhibition ofglucotoxicity- or lipotoxicity- induced β-cell apoptosis and the attenuation of insulin secretion dysfunction.

Endoplasmic reticulum stress contributes to NMDA-induced pancreatic β-cell dysfunction in a CHOP-dependent manner

AimsAccumulating evidence suggest that endoplasmic reticulum (ER) stress is an important mechanism underlying the development of diabetes. We have reported that sustained treatment with N-methyl-d-aspartate (NMDA) results in apoptotic β-cell death and impairs insulin secretion. However, the molecular mechanism responsible for NMDA-induced β-cell dysfunction remains largely obscure. Thus, this study aimed to determine whether sustained activation of NMDA receptors (NMDARs) causes β-cell dysfunction through ER stress. Main methodsPrimary mouse islets and MIN6 mouse pancreatic β-cells were treated with NMDA for 24 h or high-glucose for 72 h. After the treatment, glucose-stimulated insulin secretion (GSIS) and the expression of ER stress markers were measured, respectively. In vivo, the expression of ER stress markers was measured in the pancreas of diabetic mice treated with or without NMDARs inhibitor Memantine. Key findingsNMDA treatment caused an increase in the expression of ER stress markers (ATF4, CHOP, GRP78, and Xbp1s) in primary islets. While, tauroursodeoxycholic acid (TUDCA), an inhibitor of ER stress, significantly attenuated NMDA-induced β-cell dysfunction, including the loss of glucose-stimulated insulin secretion and reduction of pancreas duodenum homeobox factor-1 (Pdx-1) mRNA expression, a transcription factor regulating insulin synthesis. Besides, NMDA-induced ER stress strongly promoted pro-inflammatory cytokines synthesis (IL-1β and TNF-α) in β cells. Interestingly, knockdown of CHOP attenuated β-cell dysfunction evoked by NMDA. Furthermore, we demonstrated that blockade of NMDARs ameliorated high-glucose-induced ER stress in vitro and in vivo. SignificanceThis study confirms that ER stress is actively involved in the activation of NMDARs-related β-cell dysfunction.

Beneficial Effects of Hydroalcoholic Extract of Saffron in Alleviating Experimental Autoimmune Diabetes in C57bl/6 Mice

Streptozocin (STZ) is a strong alkalizing agent which is capable of destroying the beta cells of the pancreatic islets. Multiple low doses (40 mg/kg, intraperitoneally for 5 consecutive days) prescription of STZ to mice can lead to the T cell-dependent immune response and induction of autoimmune diabetes (AD) with complete similarity to the human type 1 diabetes (T1D). This study has evaluated the effects of hydroalcoholic extract of saffron on the clinical and immunological profile of experimental autoimmune diabetes in C57BL/6 mice. After the establishment of the AD, mice were treated orally with hydroalcoholic extract of saffron (500 mg/kg) for 3 weeks. The results with p<0.05 were considered significant. Obtained data showed that treatment with the hydroalcoholic extract of saffron significantly reduced the incidence of hypoglycemia and restored insulin secretion and histopathological changes in pancreas sections. In addition, treatment with saffron reduced lymphocyte proliferation index in the cells isolated from the pancreas of diabetic mice. Also, the extract of saffron markedly decreased the production of pro-inflammatory interleukin-17 (IL-17) increased anti-inflammatory IL-10 and transforming growth factor-β in the pancreatic cell population. Moreover, the production of proinflammatory nitric oxide and reactive oxygen substances were down-regulated by the saffron extract. It seems that the hydroalcoholic extract of saffron can be considered as a useful strategy in the treatment of type 1 diabetes.