Alleviation of insulitis of NOD mice by DPP-4 inhibitor through suppressing TLR4/NF-κB signaling path-way / 实用医学杂志

Objective To explore the effects of DPP-4 inhibitor sitagliptin on insulitis of NOD mice and the potential mechanism. Methods 223-month-old female NOD mice were randomly divided into Sitagliptin(Si-ta)group(n=11)gavaged with Sita(30 mg/Kg)daily for 12 weeks and control(Con)group with equal volume of normal saline(NS). The body weight,food-intake,water-intake and blood glucose were recorded weekly. Intraperi-toneal glucose tolerance test(IPGTT)was performed at the end of treatment and the blood sample was collected. Then mice were execute. The serum insulin level was measured by ELISA. Pancreas morphology and insulitis were evaluated by hematoxylin-eosin staining. The protein expression level of TLR4 ,MyD88 and NF-κB was analyzed by Western Blot. Results Compared with that of Con group ,the insulitis of Sita group was significantly alleviative(P < 0.05)and the serum insulin level was increased significantly(P < 0.05). The protein expression level of TLR4(P<0.05),MyD88(P<0.01)and NF-κB(P<0.05)in Sita group was significantly decreased. Conclusion Sitagliptin alleviates insulitis in NOD mice and increases the serum insulin level ,probably owing to the suppression of TLR4/MyD88/NF-κB signaling pathway.

Alleviation of insulitis of NOD mice by DPP-4 inhibitor through suppressing TLR4/NF-κB signaling path-way / 实用医学杂志

Objective To explore the effects of DPP-4 inhibitor sitagliptin on insulitis of NOD mice and the potential mechanism. Methods 223-month-old female NOD mice were randomly divided into Sitagliptin(Si-ta)group(n=11)gavaged with Sita(30 mg/Kg)daily for 12 weeks and control(Con)group with equal volume of normal saline(NS). The body weight,food-intake,water-intake and blood glucose were recorded weekly. Intraperi-toneal glucose tolerance test(IPGTT)was performed at the end of treatment and the blood sample was collected. Then mice were execute. The serum insulin level was measured by ELISA. Pancreas morphology and insulitis were evaluated by hematoxylin-eosin staining. The protein expression level of TLR4 ,MyD88 and NF-κB was analyzed by Western Blot. Results Compared with that of Con group ,the insulitis of Sita group was significantly alleviative(P < 0.05)and the serum insulin level was increased significantly(P < 0.05). The protein expression level of TLR4(P<0.05),MyD88(P<0.01)and NF-κB(P<0.05)in Sita group was significantly decreased. Conclusion Sitagliptin alleviates insulitis in NOD mice and increases the serum insulin level ,probably owing to the suppression of TLR4/MyD88/NF-κB signaling pathway.

Type 1 Diabetes Mellitus

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by selective autoimmune- mediated destruction of pancreatic islet beta- cells leading gradually to absolute insulin deficiency. T1D is under polygenic control. The HLA complex attributes 50% of the genetic risk for T1D while as many as 20 genes influence susceptibility to T1D. The autoimmune beta-cell destruction could be triggered by environmental factors. While the exact trigger of anti-islet autoimmunity remains elusive, it can lead to an imbalance between regulatory T cells and autoimmune effector T cells. During the initiation of insulitis, emerging evidences suggest that the infiltrating macrophages via toll-like receptor 2 (TLR2) activation lead to induction and amplification of insulitis. Following the priming of diabetogenic T-cells, autoreactive T effector cells destroy the beta cells by direct contact- dependent cytolysis or by soluble mediators secreted from macrophages or CD4 T effector cells. The hyperglycemia occurs late in its course after 80% of the beta cells have been destroyed. Although no current cure exists, refinement of genetic studies and islet autoantibodies has improved the ability to predict the risk of T1D and aid the establishment of rationally designed preventive therapies. Other strategies involve beta-cell replacement by islet transplantation. Extensive and long-term research on the efficacy of islet transplantation and preservation of beta-cell function is keenly needed.

Type 1 Diabetes Mellitus

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by selective autoimmune- mediated destruction of pancreatic islet beta- cells leading gradually to absolute insulin deficiency. T1D is under polygenic control. The HLA complex attributes 50% of the genetic risk for T1D while as many as 20 genes influence susceptibility to T1D. The autoimmune beta-cell destruction could be triggered by environmental factors. While the exact trigger of anti-islet autoimmunity remains elusive, it can lead to an imbalance between regulatory T cells and autoimmune effector T cells. During the initiation of insulitis, emerging evidences suggest that the infiltrating macrophages via toll-like receptor 2 (TLR2) activation lead to induction and amplification of insulitis. Following the priming of diabetogenic T-cells, autoreactive T effector cells destroy the beta cells by direct contact- dependent cytolysis or by soluble mediators secreted from macrophages or CD4 T effector cells. The hyperglycemia occurs late in its course after 80% of the beta cells have been destroyed. Although no current cure exists, refinement of genetic studies and islet autoantibodies has improved the ability to predict the risk of T1D and aid the establishment of rationally designed preventive therapies. Other strategies involve beta-cell replacement by islet transplantation. Extensive and long-term research on the efficacy of islet transplantation and preservation of beta-cell function is keenly needed.

Cyto-protective Effects of Aqueous Extract from the Gall of Rhus chinensis on Pancreatic Beta-cell / 대한해부학회지

We have previously reported that aqueous extract of gall from Rhus chinensis, known as "Obaeja", inhibited rat intestinal alpha-glucosidase and suppressed postprandial hyperglycemia by delaying digestion and absorption of intestinal carbohydrate (Shim et al., 2003). This led us to speculate that obaeja could be involved in ameliorating beta-cell injury by lowering glucotoxicity. In the present study, we thus examined the protective effect of obaeja on pancreatic beta-cell damage along with its anti-diabetic effect in streptozotocin-induced animal models. Streptozotocin was administered to rat pups (neonate/STZ model), or to adult rats with a lower dose using osmotic pump (osmotic pump/STZ model) for inducing beta cell death and diabetes. Obaeja was given to those rat pups after weaning in neonate/STZ model, or 2 weeks before subcutaneous implantation of osmotic pump to rats of the other latter model. In the diabetic control rats of the neonate/STZ model, which were not fed with obaeja, some pancreatic islets demonstrated a destruction of beta cell mass with insulitis 2 weeks after weaning, while some larger and irregular islets were formed by proliferation of alpha cells. In particular, we found some pancreatic lobules showing a severe inflammation and degeneration of islet and acinar tissues in this model. Islets in these inflammatory lobules were smaller in size with only few cells. In contrast, any inflammatory responses and insulitis were not observed in pancreas of the rats fed obaeja in this model. The islets in those rats maintained their normal profiles and islet cell population. Such anti-cytotoxic effect was also monitored in the diabetic rats of osmotic pump/STZ model. Especially, occurrence of hyperglycemia in the obaeja fed rats was delayed by 25~30 days than that of diabetic control rats in this model. Taken together, these results imply that regulation of postprandial blood glucose level by obaeja feeding may ameliorate a secondary injury caused by glucotoxicity.

Distribution of ~(125)Iodine-labeled Interleukin-2 and its relation to insulitis in NOD mice / 中国糖尿病杂志

Objective To evaluate the feasibility of ~ 125 Iodine -labeled IL-2 scintigraphic methods for the imaging of lymphocyte infiltration of the Langerhans′ islets. Methods ~ 125 I-IL2 was injected intravenously to pre-diabetic female NOD mice (aged 16-17 weeks)and female Balb/c mice as control. Animals were sacrificed at different time points and the radioactivity in different organs was measured.~ 131 I-IL-2 was injected iv to 3 pre-diabetic female NOD mice, and pancreas was imaged through SPECT after 30 minutes injection. Results The mean radio activities in the pancreas of NOD mice were significantly higher as compared to those of Balb/c mice at time points from 30 to 120 minutes (P

The Effect of Aminoguanidine and Insulin on the Development of Insulitis and the Expression of Inducible Nitric Oxide Synthase in Multiple Low Dose Streptozotocin-induced Diabetic Mice

In this study the effect of insulin and aminoguanidine on the expression of iNOS and the development of insulitis in the multiple low dose streptozotocin (SZ) induced diabetic (LDSD) mice was evaluated. Eighty mice (Charles-River CD-1 mice) were divided into four groups. Group I received SZ for five days. Group II received SZ for five days and was followed by insulin treatment. Group III received SZ for five days and was followed by aminoguanidine treatment. Group IV was normal control group. The blood glucose level and body weight were measured weekly. On the 35th day, pancreat ic sections were observed to evaluate the frequency and the severity of insulitis in addition to the immunohistochemical expression of iNOS in the pancreatic islets. Blood glucose levels of group IV were significantly lower than other experimental groups on the 21st, 28th, and 35th day. The difference in blood glucose levels was not statistically significant. Incidence of the insulitis was lower in group II than in groups I and III. The severity of insulitis correlated with the increase in blood glucose level only in group II. The expression of iNOS was more pronounced in group I than in groups II and III. Aminoguanidine did not inhibit development of the insulitis but decreased expression of iNOS in the pancreatic islets. Therefore it is speculated that iNOS production is one of the factors and other pathogenetic mechanisms might be involved in the development of insulitis.

The effect and morphology observation of oral administration insulin to NOD mice inducing immune tolerance / 中国糖尿病杂志

Objective To investigate the effect on prevention and treatment autoimmune diabetes mellitus in NOD mice by oral administration porcine insulin.Methods One hundred and twenty female NOD mice were divided randomly into insulin group(n=60) and control group(n=60).Beginning from 6 week old, NOD mice were fed porcine insulin 500ul or phosphate buffered saline(PBS) 500ul seperately till 40 week old. At 6 ?12 ?20 ?25 ?30 week old,serum insulin of healthy mice was measured and pancreas were used for histology.Results Oral administration of insulin can marked decreased incidence of diabetes ( P