The potential antioxidant effect of N-acetylcysteine on X-ray ionizing radiation-induced pancreas islet cell toxicity.

PURPOSE: Previous research has highlighted the impact of X-ray irradiation-induced organ damage, on cancer patients after radiation therapy. The ionizing radiation-induced oxidative stress causes injury to the pancreatic islet cells of Langerhans. We used histopathological, immunohistochemical, and biochemical analyses to examine α- and ß-cells in the islets of Langerhans in rats undergoing whole-body x-ray ionizing radiation, a group of which was treated with NAC. MATERIAL AND METHODS: Twenty-four male rats were randomly divided into 3 groups, one control, and two experimental groups. Group I (Control) was administered only saline solution (0.09% NaCl) by oral gavage for 7 days. Group II (IR) was administrated whole body single dose 6 Gray ionizing radiation (IR) and saline solution (0.09% NaCl) by oral gavage for 7 days. Group III (IR + NAC) was administered 300 mg/kg NAC (N-acetylcysteine) by oral gavage for 7 days, 5 days before, and 2 days after 6 Gray IR application. RESULTS: In the X-ray irradiation group, we observed diffuse necrotic endocrine cells in the islets of Langerhans. In addition, we found that Caspase-3, malondialdehyde (MDA) levels increased, and insulin, glucagon, and glutathione (GSH) levels decreased in the IR group compared to the control group. In contrast, we observed a decrease in Caspase-3, and MDA levels in necrotic endocrine cells, and an increase in insulin, glucagon, and GSH levels in the IR + NAC group compared to the IR group. CONCLUSION: This study provides evidence for the beneficial effects of N-acetyl cysteine on islets of Langerhans cells with X-ray ionizing-radiation-induced damage in a rat model.

Okamoto model for necrosis and its expansions, CD38-cyclic ADP-ribose signal system for intracellular Ca2+ mobilization and Reg (Regenerating gene protein)-Reg receptor system for cell regeneration.

In pancreatic islet cell culture models and animal models, we studied the molecular mechanisms involved in the development of insulin-dependent diabetes. The diabetogenic agents, alloxan and streptozotocin, caused DNA strand breaks, which in turn activated poly(ADP-ribose) polymerase/synthetase (PARP) to deplete NAD+, thereby inhibiting islet ß-cell functions such as proinsulin synthesis and ultimately leading to ß-cell necrosis. Radical scavengers protected against the formation of DNA strand breaks and inhibition of proinsulin synthesis. Inhibitors of PARP prevented the NAD+ depletion, inhibition of proinsulin synthesis and ß-cell death. These findings led to the proposed unifying concept for ß-cell damage and its prevention (the Okamoto model). The model met one proof with PARP knockout animals and was further extended by the discovery of cyclic ADP-ribose as the second messenger for Ca2+ mobilization in glucose-induced insulin secretion and by the identification of Reg (Regenerating gene) for ß-cell regeneration. Physiological and pathological events found in pancreatic ß-cells have been observed in other cells and tissues.

Early ultra- and microstructural alterations in rat pancreas in alloxan-induced diabetes mellitus.

An adequate experimental model is important to understand pathophysiological processes ongoing in the pancreas with diabetes mellitus. Our study was aimed to describe early ultra- and microstructural changes in the rat pancreas in 12-48 h after alloxan administration in a dose of 180 mg/kg. A histopathological examination of the endocrine pancreas revealed the loss of borders between endocrine cells, granular dystrophy and degranulation, sings of necrosis in central cells of the Langerhans islets and apoptosis of their peripheral ones manifested as DNA fragmentation and an increased expression of apoptosis markers. There was a gradual increase of a Langerhans islet area, a decreased percentage of insulin+ cells and an increased one of glucagon+ cells, as well as the presence of proliferating islet cells were found. Structural changes of the exocrine pancreas included fatty degeneration, signs of exocrine cell mitochondrial damage, increased acini, which are located mainly around the Langerhans islets, as well as perivascular edema and leukocytic infiltration. Described ultra- and microstructural alterations suggest a significant contribution of apoptosis to death of endocrine cells exposed to alloxan. Coexisting damage of the exocrine pancreas with its stroma involvement is for the first time described.

Antidiabetic potential of salvianolic acid B in multiple low-dose streptozotocin-induced diabetes.

CONTEXT: Salvianolic acids are the most abundant water-soluble compounds extracted from the herb Salvia miltiorrhiza L. (Lamiaceae) with antioxidant and protective effects. OBJECTIVE: This study evaluates the antidiabetic effect of salvianolic acid B (Sal B) in multiple low-dose streptozotocin (MLDS)-induced diabetes in rat. MATERIALS AND METHODS: Rats were divided into control, Sal B40-treated control, diabetic, Sal B20-, and Sal B40-treated diabetic groups. Sal B was daily administered at doses of 20 or 40 mg/kg (i.p.), started on third day post-STZ injection for 3 weeks. Serum glucose and insulin level and some oxidative stress markers in pancreas were measured in addition to the oral glucose tolerance test (OGTT), histological assessment, and apoptosis determination. RESULTS: After 3 weeks, treatment of diabetic rats with Sal B20 and Sal B40 caused a significant decrease of the serum glucose (p < 0.05-0.01) and improvement of OGTT. Meanwhile, serum insulin was significantly higher in Sal B20- and Sal B40-treated diabetics (p < 0.01) and treatment of diabetics with Sal B40 significantly lowered malondialdehyde (MDA) (p < 0.05), raised glutathione (GSH) (p < 0.05), and activity of catalase (p < 0.01) with no significant change of nitrite. Furthermore, the number of pancreatic islets (p < 0.05) and their area (p < 0.01) was significantly higher and apoptosis reactivity was significantly lower (p < 0.05) in the Sal B40-treated diabetic group versus diabetics. DISCUSSION AND CONCLUSION: Three-week treatment of diabetic rats with Sal B exhibited antidiabetic activity which is partly exerted via attenuation of oxidative stress and apoptosis and augmentation of antioxidant system.

Clinacanthus nutans L Extracts Reduce the Serum Tumor Necrosis Factor-α, Malondialdehyde, and Interleukin-6 Levels and Improve the Langerhans Islet Area in Diabetic Rat Models.

Background: Diabetes mellitus-induced hyperglycemia increases oxidative stress and inflammatory cytokine production, which play a significant role in the damage and apoptosis of pancreatic ß cells. Therefore, the administration of medications that can reduce oxidative stress and inflammation plays an important role in diabetes treatment. Objective: To probe the Clinacanthus nutans leaf extract effect on oxidative stress and inflammatory markers and the Langerhans islet area in diabetic rat models. Design: An experimental laboratory in the animal model. Methods: Twenty-five diabetic rat models were randomly assigned into 5 clusters. Clusters 1, 2, and 3 were administered with C. nutans leaf extract in aqueous suspension with vehicle 1% Na-CMC at 75 mg/kg body weight (BW), 150 mg/kg BW, and 300 mg/kg BW, respectively. Cluster 4 was diabetic control rats administered with metformin at a 21 mg/rat dose. Cluster 5 was a control diabetic rat only administered with 1% Na-CMC suspension. Treatment was administered orally for 14 days. On the 15th day, the rats were sacrificed to obtain blood samples and pancreatic tissues. Serum interleukin (IL)-6, malondialdehyde (MDA), and tumor necrosis factor (TNF-α) were measured using the enzyme-linked immunosorbent assay (ELISA) method. Histopathological examination was performed by counting the Langerhans islet areas. Results: The average IL-6, MDA, and TNF-α levels declined in the cluster receiving C. nutans extract and were significantly different from the untreated cluster (P < .05). Histopathological examination revealed a significant upsurge in the Langerhans islets area in diabetic rats receiving C. nutans extract at doses of 75 and 150 mg/kg (P < .05). Conclusion: C. nutans leaf extract reduced the serum MDA, TNF-α, and IL-6 levels, and increased the Langerhans islets area in a diabetic rat model.

Patterns and Relevance of Langerhans Islet Invasion in Pancreatic Cancer.

Background: Pancreatic cancer-associated diabetes mellitus (PC-DM) is present in most patients with pancreatic cancer, but its pathogenesis remains poorly understood. Therefore, we aimed to characterize tumor infiltration in Langerhans islets in pancreatic cancer and determine its clinical relevance. METHODS: Langerhans islet invasion was systematically analyzed in 68 patientswith pancreatic ductal adenocarcinoma (PDAC) using histopathological examination and 3D in vitro migration assays were performed to assess chemoattraction of pancreatic cancer cells to isletcells. RESULTS: Langerhans islet invasion was present in all patients. We found four different patterns of islet invasion: (Type I) peri-insular invasion with tumor cells directly touching the boundary, but not penetrating the islet; (Type II) endo-insular invasion with tumor cells inside the round islet; (Type III) distorted islet structure with complete loss of the round islet morphology; and (Type IV)adjacent cancer and islet cells with solitary islet cells encountered adjacent to cancer cells. Pancreatic cancer cells did not exhibit any chemoattraction to islet cells in 3D assays in vitro. Further, there was no clinical correlation of islet invasion using the novel Islet Invasion Severity Score (IISS), which includes all invasion patterns with the occurrence of diabetes mellitus. However, Type IV islet invasion was related to worsened overall survival in our cohort. CONCLUSIONS: We systematically analyzed, for the first time, islet invasion in human pancreatic cancer. Four different main patterns of islet invasion were identified. Diabetes mellitus was not related to islet invasion. However, moreresearch on this prevailing feature of pancreatic cancer is needed to better understand underlying principles.

Relationship Between Insulin-Receptor Substrate 1 and Langerhans' Islet in a Rat Model of Type 2 Diabetes Mellitus.

BACKGROUND/AIM: In vivo studies on pathogenesis of type 2 diabetes mellitus (T2DM) have been reported, however, the relationship between insulin-receptor substrate 1 (IRS1) and the area of Langerhans' islets was unknown. Therefore, a correlation between both parameters was assessed. MATERIALS AND METHODS: Diabetic groups were fed with a high-fat diet (HFD) and injected with three different doses of streptozotocin, namely 25, 35 and 45 mg/kg, and compared to a control group after 9 weeks. RESULTS: Administration of HFD/streptozotocin increased the level of fasting blood glucose but reduced the level of IRS1 and the area of Langerhans' islets in diabetic groups. The coefficient of correlation between IRS1 and area of Langerhans' islets was 0.259 (p=0.232). In addition, the coefficient of correlation for fasting blood glucose with the area of Langerhans' islets and IRS1 was -0.520 (p=0.011) and -0.603 (p=0.002), respectively. CONCLUSION: The reduction of IRS1 was weakly correlated with the destruction of Langerhans' islets, suggesting there is an intermediate step between both parameters.

[Transplantation strategy in type 1 diabetic patients]. / Stratégie de transplantation chez les patients diabétiques de type 1.

Beta cell replacement by pancreas or Langerhans islets transplantation is the only way to restore glucose homeostasis in type 1 diabetic patients. The counterpart is the need for long-term immunosuppression. These transplantations are therefore mainly indicated for patients candidates for kidney transplantation and for patients with poor quality of life due to unstable diabetes with life-threatening hypoglycemic events. Both beta cell replacement techniques have different benefits and risks and should be adapted to each type 1 diabetic patient. The transplant strategy must be personalized according to parameters assessed in the pre-transplant period, validated by a multidisciplinary team and reassessed regularly until transplantation.

Synergistic effect of PEGylation and pentoxifylline addition on immunoprotection of pancreatic islets.

In this study, a method is proposed to reduce immunological response of immune system against Langerhans islets by PEGylation of islets combined with adjuvant therapy. For this purpose, the best composition for a mixture of succinimidyl valeric acid activated mPEG (mPEG-SVA) with different molecular weights (MWs) and for a mixture of succinimidyl carbonate activated mPEG (mPEG-SC) with different MWs was determined separately. Then, the effect of pentoxifylline (PTX) as an adjuvant drug on immunological response against PEGylated islets at best mPEG composition was studied. The extent of mPEGs reaction, the amount of interlukin-2 (IL-2) and perforin secretion, and the viability of lymphocytes and islets in homo and co-cultures in the presence of PTX at different concentrations were considered for the in vitro evaluation of the proposed method. It was found, that a mixture of mPEG-SVA with MWs of 10 and 5 kDa at a composition of 75 and 25%, respectively, was the best formulation. Also, the addition of PTX drug to co-culture medium increased the protection of PEGylated islets against immune system and a concentration of 75 µg mL-1 of PTX was suitable for islet protection with no adverse effect on immune cells.

The effects of aqueous extract of alfalfa on blood glucose and lipids in alloxan-induced diabetic rats.

Diabetes is a common metabolic disorder that is specified by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The use of nonpharmacological treatments (herbal agents) is a new approach in the management of diabetes. The aim of this study was to investigate the effect of aqueous extract of alfalfa on blood glucose and serum lipids in alloxan-induced diabetic rats. In this study, 32 female rats (210-250 g) were used which were divided randomly into 4 groups including intact control group, diabetic control group, and 2 diabetic groups which received 250 and 500 mg/kg doses of aqueous extract of alfalfa, respectively. In the diabetic groups, alloxan-monohydrate was injected peritoneally to create diabetic condition. The two last groups orally received aqueous extract of alfalfa for 21 days. At the end of experiment, sugar, cholesterol, triglycerides, high-density and low-density lipoprotein, and aspartate aminotransferase (ALT) and alanine aminotransferase (AST) levels were measured in the samples. Consumption of aqueous alfalfa extract significantly reduced glucose, cholesterol, triglycerides, and low-density lipoprotein (LDL) levels in the diabetic rats but enhanced high-density lipoprotein (HDL) levels. ALT and AST liver enzyme levels were also reduced in blood. Histological examination showed that the aqueous alfalfa extract caused reconstruction of damaged liver and enhanced Langerhans islets' diameter in pancreas. Therefore, all signs of diabetes were improved by oral administration of alfalfa in defined dose.

New technologies for diabetes presented at international congresses in 2006.

Diabetes is a medical specialty that is currently experiencing the rapid development of new technologies that can be applied to clinical management. At three international Diabetes Congresses held in 2006 (the annual meeting of European Association of Diabetes in Copenhagen, the World Congress of the International Diabetes Federation in Cape Town, and the Diabetes and Technology meeting in Atlanta), several new technologies and devices were demonstrated that are applicable to diabetes care. Out of various technological innovations, this article highlights three new interesting areas, which may represent the principal direction of future developments in science that may help improve the quality of life for the person with diabetes.