Low-dose Streptozotocin-induced Diabetes Research Articles

Discovery of novel hybrids of Morpholino-1,3,5-triazine-pyrimidine as an anti-diabetic agent in High-fat, Low-dose Streptozotocin-induced diabetes in Wistar rats: An in-vitro, in-silico and in-vivo study

Due to their favorable safety profile, DPP-4 inhibitors are the suggested option for Type 2 Diabetes Mellitus (T2DM) for therapeutic purposes. In light of this, in this paper, we report the discovery of several novel morpholino-1,3,5-triazine-pyrimidine hybrid compounds. These compounds were synthesized via an inexpensive and simple synthetic method in high yields. The target molecules' structures have been established using FT-IR, 1H NMR, 13C NMR, mass, and elemental analyses. These compounds inhibited DPP-4 more effectively and selectively than DPP-8 and DPP-9. Compound 8c has been identified as the most effective DPP-4 inhibitor with an inhibitory concentration (IC50) of 2.9 nM. In docking analysis, compound 8c demonstrated good glide energy, and various bonded and non-bonded interactions with key DPP-4 amino acid residues of the S1/S2 site, including Tyr666, Val656, Tyr547, Gly632, Asn710, etc. Furthermore, the effect of compound 8c was also studied on high-fat, low-dose streptozotocin (STZ)-induced diabetes in Wistar rats to determine its anti-diabetic performance. Compound 8c has been shown to considerably improve the insulin level, lipid profile, and anti-oxidant status of diabetic Wistar rats in a dose-dependent manner, with no toxicity. Our findings imply that new morpholino-pyrimidine 1,3,5-triazine hybrid compounds could serve as potential lead for anti-diabetic drug discovery.

Dose-dependent progression of multiple low dose streptozotocin-induced diabetes in mice.

This study investigated the effects of different multiple low doses of streptozotocin (STZ), namely 35 and 55 mg/kg, on the onset and progression of diabetes in mice. Both doses are commonly used in research, and while both induced a loss of beta cell mass, they had distinct effects on whole glucose tolerance, beta cell function and gene transcription. Mice treated with 55 mg/kg became rapidly glucose intolerant, whereas those treated with 35 mg/kg had a slower onset and remained glucose tolerant for up to a week before becoming equally glucose intolerant as the 55 mg/kg group. Beta cell mass loss was similar between the two groups, but the 35 mg/kg-treated mice had improved glucose-stimulated insulin secretion in gold-standard hyperglycemic clamp studies. Transcriptomic analysis revealed that the 55 mg/kg dose caused disruptions in nearly five times as many genes as the 35 mg/kg dose in isolated pancreatic islets. Pathways that were downregulated in both doses were more downregulated in the 55 mg/kg-treated mice, whereas pathways that were upregulated in both doses were more upregulated in the 35 mg/kg treated mice. Moreover, we observed a differential downregulation in the 55 mg/kg-treated islets of beta cell characteristic pathways, such as exocytosis or hormone secretion. On the other hand, apoptosis was differentially upregulated in 35 mg/kg-treated islets, suggesting different transcriptional mechanisms in the onset of STZ-induced damage in the islets. This study demonstrates that the two STZ doses induce distinctly mechanistic progressions for the loss of functional beta cell mass.

Nova1 or Bim Deficiency in Pancreatic β-Cells Does Not Alter Multiple Low-Dose Streptozotocin-Induced Diabetes and Diet-Induced Obesity in Mice.

The loss of functional pancreatic β-cell mass is an important hallmark of both type 1 and type 2 diabetes. The RNA-binding protein NOVA1 is expressed in human and rodent pancreatic β-cells. Previous in vitro studies indicated that NOVA1 is necessary for glucose-stimulated insulin secretion and its deficiency-enhanced cytokine-induced apoptosis. Moreover, Bim, a proapoptotic protein, is differentially spliced and potentiates apoptosis in NOVA1-deficient β-cells in culture. We generated two novel mouse models by Cre-Lox technology lacking Nova1 (βNova1−/−) or Bim (βBim−/−) in β-cells. To test the impact of Nova1 or Bim deletion on β-cell function, mice were subjected to multiple low-dose streptozotocin (MLD-STZ)-induced diabetes or high-fat diet-induced insulin resistance. β-cell-specific Nova1 or Bim deficiency failed to affect diabetes development in response to MLD-STZ-induced β-cell dysfunction and death evidenced by unaltered blood glucose levels and pancreatic insulin content. In addition, body composition, glucose and insulin tolerance test, and pancreatic insulin content were indistinguishable between control and βNova1−/− or βBim−/− mice on a high fat diet. Thus, Nova1 or Bim deletion in β-cells does not impact on glucose homeostasis or diabetes development in mice. Together, these data argue against an in vivo role for the Nova1-Bim axis in β-cells.

Enhancement of anti-inflammatory and immunomodulatory effects of adipose-derived human mesenchymal stem cells by making uniform spheroid on the new nano-patterned plates

Human mesenchymal stem cells (MSCs) are known to have anti-inflammatory and immunomodulatory functions; thus, several MSC products have been applied as cell therapy in clinical trials worldwide. Recent studies have demonstrated that MSC spheroids have superior anti-inflammatory and immunomodulatory functions to a single cell suspension. Current methods to prepare MSC spheroids include hanging drop, concave microwell aggregation, spinner flask, and gravity circulation. However, all these methods have limitations such as low scalability, easy cell clumping, low viability, and irregular size distribution. Here, we present a nano-patterned culture plasticware named PAMcell™ 3D plate to overcome these limitations. Nano-sized silica particles (700 nm) coated with RGD peptide were arrayed into fusiform onto the PLGA film. This uniform array enabled the seeded MSCs to grow only on the silica particles, forming uniform-sized semi-spheroids within 48 h. These MSC spheroids have been shown to have enhanced stemness, anti-inflammatory, and immunomodulatory functions, as revealed by the increased expression of stem cell markers (Oct4, Sox2, and Nanog), anti-inflammatory (IL-10, TSG6, and IDO), and immunomodulatory molecules (HGF, VEGF, CXCR4) both at mRNA and protein expression levels. Furthermore, these MSC spheroids demonstrated an increased palliative effect on glycemic control in a multiple low-dose streptozotocin-induced diabetes model compared with the same number of MSC single cell suspensions. Taken together, this study presents a new method to produce uniform-sized MSC spheroids with enhanced anti-inflammatory and immunomodulatory functions in vitro and in vivo.

Loss of ubiquitin-conjugating enzyme E2 (Ubc9) in macrophages exacerbates multiple low-dose streptozotocin-induced diabetes by attenuating M2 macrophage polarization

Type 1 diabetes (T1D) is characterized by the selective autoimmune destruction of the islet β cells, and macrophages play a significant role in this process. Small ubiquitin-like modification (SUMOylation) is an important posttranslational modification involved in T1D pathogenesis, but its function in macrophages remains unexplored. We presently developed and used macrophage-specific ubiquitin-conjugating enzyme E2 (Ubc9) knockout (LyzM-Cre-Ubc9fl/fl, KO) mice to address the impact of SUMOylation on macrophage function in a T1D model. We observed that blocking Ubc9 in macrophages exacerbated multiple-low dose streptozotocin (MLD-STZ)-induced diabetes. Specifically, after STZ treatment, blood glucose levels were consistently elevated in the KO mice. The KO mice exhibited a higher diabetes incidence than WT controls (85% vs. 55%, P < 0.01) along with a higher insulitis severity. The loss of Ubc9 impaired macrophage energy metabolism and attenuated macrophage M2 program, thereby enhancing T cell activation. Pancreas-resident macrophages, rather than migrant macrophages, played a predominant role in MLD-STZ-induced diabetes. Mechanistically, Ubc9-mediated SUMOylation of interferon regulator factor 4 (IRF4) enhanced its nuclear localization and stability, thereby transcribing IL-4 and arginase 1 (Arg1) to promote the macrophage M2 program. Ubc9-mediated SUMOylation modulates T1D risk at least in part by regulating macrophage function. Modulation of disturbed SUMOylation process in macrophages, either through cell adoptive transfer or targeted drug-delivery, could help to establish a tolerant pancreatic microenvironment and promote inflammation resolution in early insulitis stage, thus hindering T1D progression.

Metformin ameliorates diabetic nephropathy in a rat model of low-dose streptozotocin-induced diabetes.

The present study aimed to explore the renoprotective effect of metformin on diabetic nephropathy in type 2 diabetic rats. A rat model of type 2 diabetic nephropathy (T2DN) was successfully induced via a high-fat diet combined with a single low-dose of streptozotocin. Metformin was administered intragastrically for 13 weeks, and fasting blood glucose (FBG), total cholesterol (TC), triglycerides (TG), HDL-c, LDL-c, urinary and serum creatinine levels were subsequently examined at the end of administration. Renal function was determined after the treatment protocol. Expression levels of transforming growth factor (TGF)-β1 and connective tissue growth factor (CTGF) were assessed via immunohistochemical analysis. Superoxide dismutase activity, malondialdehyde content and glutathione peroxidase levels were assessed in kidney tissues using commercially available kits. The results of the present study demonstrated that metformin administration significantly decreased the levels of serum blood urea nitrogen, serum creatinine, creatinine clearance, urinary albumin excretion and fasting blood glucose in rats with T2DN. Furthermore, TG, TC and LDL-c levels were significantly decreased following metformin treatment, whereas HDL-c was increased. Metformin treatment significantly increased SOD activity and significantly decreased malondialdehyde levels, as compared with the model group. It was also demonstrated that metformin administration significantly decreased the expression levels of TGF-β1 and attenuated the morphological changes associated with T2DN in rats. These data clearly demonstrated the renoprotective effects of metformin against the development and progression of T2DN in rats. The underlying mechanism of this protective effect may be associated with glycemic control, lipid metabolism, and anti-oxidative and anti-inflammatory functions.

Comparison of the response using ICR mice derived from three different sources to multiple low-dose streptozotocin-induced diabetes mellitus

This study was conducted to compare the multiple low-dose streptozotocin (MLDS)-induced diabetic patterns of Korl:ICR, A:ICR, and B:ICR mice obtained from three different sources. Six-week-old male ICR mice were obtained from three difference sources. Korl:ICR mice were kindly provided by the National Institute of Food and Drug Safety Evaluation (NIFDS). The other two groups of ICR mice were purchased from different vendors located in the United States (A:ICR) and Japan (B:ICR). All ICR mice that received MLDS exhibited overt diabetic symptoms throughout the study, and the incidence and development of diabetes mellitus were similar among the three ICR groups. The diabetic mice exhibited hyperglycemia, loss of body weight gain, decreased plasma insulin levels, impaired glucose tolerance, decreased number of insulin-positive cells, and decreased size of β-cells in the pancreas. The diabetes symptoms increased as the blood glucose level increased in the three ICR groups. In particular, the level of blood glucose in the STZ-treated group was higher in Korl:ICR and A:ICR mice than in B:ICR mice. The plasma insulin levels, glucose tolerance, blood chemistry, and morphological appearance of the pancreas were very similar in the ICR groups obtained from the three different sources. In conclusion, our results suggest that Korl:ICR, A:ICR, and B:ICR mice from different sources had similar overall responses to multiple low-dose STZ to induce diabetes mellitus.

Effect of wild Korean ginseng (Panax ginseng) extract on blood glucose and serum lipid contents in rats with multiple low-dose streptozotocin-induced diabetes

Anti-diabetic effects of wild Korean ginseng extracts on multiple low-dose streptozotocin (STZ)-induced diabetic rats were investigated. Rats were administered extracts at rates of 100, 200, and 300 mg/kg of body weight for 8 weeks. Body weight was significantly (p 0.05) affected; however alanine aminotransaminase and alkaline phosphatase levels were reduced significantly (p<0.05) in higher ginseng dosage rat groups. Anti-diabetic effects were elicited by administration of wild Korean ginseng extracts in multiple low-dose STZ-induced diabetic rats.

N-3 Polyunsaturated fatty acids protect against pancreatic β-cell damage due to ER stress and prevent diabetes development.

In this study, we focus on the effects of n-3 polyunsaturated fatty acids (PUFAs) on tunicamycin-, streptozotocin-, or high fat diet (HFD)-induced β-cell damage and dysfunction. Pretreatment with n-3 PUFAs protected RINm5F cells and mouse islets against tunicamycin-induced β-cell damage through suppression of ER stress and apoptosis induction. This protective effect of n-3 PUFAs on β-cells was further demonstrated by the normalization of insulin secretion in response to glucose in tunicamycin-treated islets. In multiple low-dose streptozotocin-induced diabetes models, fat-1 mice, which endogenously synthesize n-3 PUFAs from n-6 PUFAs, were fully resistant to the development of diabetes, with normal islet morphology, high insulin immunoreactivity, and decreased apoptotic cells. In HFD-induced diabetes models, fat-1 mice also exhibited improved glucose tolerance and functional β-cell mass. In both diabetes models, we observed an attenuation of ER stress in fat-1 mice. Interestingly, n-3 PUFAs attenuated the nuclear translocation of lipogenic transcription factors sterol regulatory element-binding protein-1 (SREBP-1) and C/EBPβ, induced by tunicamycin or HFD, suggesting that n-3 PUFAs suppress ER stress via modulation of SREBP-1 and C/EBPβ. Together, these results suggest that n-3 PUFAs block ER stress, thus protecting β cells against diabetogenic insult; therefore, dietary supplementation of n-3 PUFAs has therapeutic potential for the preservation of functional β-cell mass.

Emodin isolated from Rheum palmatum prevents cytokine-induced β-cell damage and the development of type 1 diabetes

Emodin is an anthraquinone derivative from rhubarb and buckthorn, and is also produced by many species of fungi. Although its anti-diabetic effect in type 2 diabetes has been reported, the potential effects of emodin on type 1 diabetes remain unclear. Therefore, in this study, we isolated emodin from rhubarb (Rheum palmatum) and investigated its effects on cytokine- or streptozotocin-induced β-cell damage and dysfunction. Emodin protected RINm5F cells or mouse islets against cytokine-induced damage by suppressing inducible nitric oxide synthase expression and nitric oxide production. The cytoprotective potential of emodin was associated with the inhibition of NF-κB signaling by reducing IκB kinase activity. The protective effects of emodin were further demonstrated by normalizing insulin secretion of cytokine-treated islets in response to glucose. In multiple low-dose streptozotocin-induced diabetes model, emodin-pretreated mice were fully resistant to the development of diabetes with normal islet morphology and insulin secretion. Immunohistochemical analysis revealed that emodin significantly decreased the number of TUNEL-positive and nuclear p65-positive pancreatic islets. These results suggest that emodin blocks the NF-κB pathway, thus protecting β-cells against diabetogenic insults. Emodin may have therapeutic value in preventing the development of type 1 diabetes by delaying the process of insulitis and by protecting against β-cell damage.

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.

Increased levels of galectin-3 were associated with prediabetes and diabetes: new risk factor?

Galectin-3 (Gal-3) is a marker of cardiac fibrosis and predicts incident heart failure. Gal-3-deficient mice are resistant to multiple low-dose streptozotocin-induced diabetes. Recent experimental studies suggested an important role for Gal-3 in the regulation of adiposity, metaflammation and type 2 diabetes. This study aimed to examine the relationship between Gal-3 and newly diagnosed prediabetes and diabetes. Gal-3 concentrations were measured in 118 participants and 56 age- and sex-matched healthy controls. All subjects underwent a 75-g oral glucose tolerance test and were stratified into normal, prediabetic, and diabetes mellitus subgroups. DM was defined as a plasma glucose level ≥126 mg/dL in the fasting state or ≥200 mg/dL in the second hour after glucose loading. Impaired fasting glucose was defined as an FPG level of 100-125 mg/dL, and impaired glucose tolerance was defined as a 2-h plasma glucose level of 140-199 mg/dL. Sixty-one patients had prediabetes (Group 1), 57 had diabetes (Group 2), and 56 had neither diabetes nor prediabetes (Group 3). Gal-3 levels correlated with FPG (r = 0.787, P < 0.01), 2hPG (r = 0.833, P < 0.01), CRP (r = 0.501, P < 0.01), and HOMA-IR (r = 0.518, P < 0.01). Gal-3 levels were higher in Group 2 than in Groups 1 and 3 [1,053.9 (358.1) and 744.1 (119.3) vs. 481.7 (175.4) pg/mL; P < 0.001]. Gal-3 is an independent predictor of diabetes in multivariate logistic analysis. In ROC analysis, a Gal-3 cutoff value of 803.55 pg/mL diagnoses diabetes with a sensitivity of 80.7 % and a specificity of 85.5 % (AUC = 0.912). Gal-3 is a promising biomarker for detecting prediabetes and diabetes.

Enhanced Anti-Diabetogenic Effect of Intravenous Immune Globulin Modified by Ferrous Ion Exposure

The aim of this study was to investigate the immunomodulatory capacity of native and Fe(II)-exposed intravenous immune globulin (IVIg) in multiple low dose streptozotocin-induced diabetes and to delineate the mechanisms of their influence on immune cell functions. Optimal doses (200–600mg/kg) of IVIg prevented the development of hyperglycemia, glycosuria and attenuated mononuclear cell infiltration in pancreatic islets. Fe(II) exposure of IVIg decreased their optimal therapeutic dose to 100mg/kg which significantly decreased the serum levels of proinflammatory cytokines compared to the same dose of native IVIg. This was accompanied by lower numbers of TNF-α, IFN-γ and IL-17 producing CD4+ T cells and increased frequencies of CD4+IL-10+ and CD4+IL-4+ T cells in the pancreatic lymph nodes and islets on day 16 after diabetes induction. Ferrous ion-exposed IVIg enhanced the bias towards Th2 response while the regulatory Foxp3+ T cells were not affected.

Detection of Islet β-Cell Death in Vivo by Multiplex PCR Analysis of Differentially Methylated DNA

Noninvasive detection of early β-cell death in type 1 diabetes might identify individuals in whom therapeutic interventions would preserve β-cell mass and prevent hyperglycemia. Recent studies in mice have shown that β-cell death produces a corresponding increase in unmethylated preproinsulin (PPI) DNA in serum. Here, we report the development of a novel assay using dual fluorescent-probe multiplex PCR (TaqMan) to detect differential methylation of circulating PPI DNA. Key assay features include low background signals, linear assay output across a large range of values, and simultaneous detection of methylated and unmethylated PPI DNA in a single reaction. We defined the "unmethylation index" as a summary parameter that reflects the relative amounts of unmethylated vs methylated PPI DNA. To validate this assay's ability to detect β-cell death in vivo, we measured the unmethylation index in the serum of diabetic mouse models, including high- and multiple low-dose streptozotocin-induced diabetes, and the nonobese diabetic mouse model of type 1 diabetes. Our data show a significantly increased unmethylation index concordant with the known timeline of β-cell death that precedes the onset of hyperglycemia. Subsequently, we observed a decrease in the unmethylation index following diabetes development, likely reflecting the absence of further β-cell death in the pancreas. We conclude that simultaneous measurement of methylated and unmethylated PPI DNA using the multiplex PCR method described here is a readily available and sensitive indicator of dying β-cells that may be useful to track diabetes progression and response to therapeutic intervention.

Thalidomide attenuates multiple low-dose streptozotocin-induced diabetes in mice by inhibition of proinflammatory cytokines

Thalidomide is an immunomodulatory and anti-inflammatory agent and is used in autoimmune disorders. It has been shown that thalidomide inhibits proinflammatory cytokines production. The purpose of this study was to investigate the effect of thalidomide on the prevention of autoimmune diabetes in mice. Diabetes was induced by multiple low-dose of streptozotocin (MLDS) injection. Mice were treated with thalidomide (300mg/kg/day orally) for 21days. Plasma levels of glucose, insulin and nitrate/nitrite as well as pancreatic cytokine levels were measured. Pathological examinations of the pancreas revealed that thalidomide reduced the islet inflammation (insulitis) and destruction of beta cells. Thalidomide treatment prevented hyperglycemia and preserved pancreatic insulin secretion in the diabetic mice. Thalidomide treatment also significantly decreased plasma levels of nitric oxide and pancreatic proinflammatory cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-12, IL-17 and interferon (IFN)-γ)] while increased anti-inflammatory cytokine IL-10. In conclusion, these findings indicate that thalidomide may have a protective effect against the autoimmune destruction of the pancreatic beta-cells during the development of MLDS-induced type 1 diabetes in mice.

The roles of Galectin-3 in autoimmunity and tumor progression

Galectin-3, a unique chimera-type member of the β-galactoside-binding soluble lectin family, is widely expressed in numerous cells. Here, we discuss the role of Galectin-3 in T-cell-mediated inflammatory (auto) immunity and tumor rejection by using Galectin-3-deficient mice and four disease models of human pathology: experimental autoimmune encephalomyelitis (EAE), Con-A-induced hepatitis, multiple low-dose streptozotocin-induced diabetes (MLD-STZ diabetes) and metastatic melanoma. We present evidence which suggest that Galectin-3 plays an important pro-inflammatory role in Con-A-induced hepatitis by promoting the activation of T lymphocytes, NKT cells and DCs, cytokine secretion, prevention of M2 macrophage polarization and apoptosis of mononuclear cells, and it leads to severe liver injury. In addition, experiments in Galectin-3-"knock-out" mice indicate that Galectin-3 is also involved in immune-mediated β-cell damage and is required for diabetogenesis in MLD-STZ model by promoting the expression of IFN-gamma, TNF-alpha, IL-17 and iNOS in immune and accessory effector cells. Next, our data demonstrated that Galectin-3 plays an important disease-exacerbating role in EAE through its multifunctional roles in preventing cell apoptosis and increasing IL-17 and IFN-gamma synthesis, but decreasing IL-10 production. Finally, based on our findings, we postulated that expression of Galectin-3 in the host may also facilitate melanoma metastasis by affecting tumor cell adhesion and modulating anti-melanoma immune response, in particular innate antitumor immunity. Taken together, we discuss the evidence of pro-inflammatory and antitumor activities of Galectin-3 and suggest that Galectin-3 may be an important therapeutic target.

Ranolazine Increases β-Cell Survival and Improves Glucose Homeostasis in Low-Dose Streptozotocin-Induced Diabetes in Mice

In addition to its anti-ischemic and antianginal effects, ranolazine has been shown to lower hemoglobin A(1c) (HbA(1c)) in patients with coronary artery disease and diabetes. The present study was undertaken to test the hypothesis that ranolazine lowers HbA(1c) because of improved glucose homeostasis in an animal model. Diabetes in mice was induced by giving multiple low doses of streptozotocin. Ranolazine was given twice daily via an oral gavage (20 mg/kg) for 8 weeks. Fasting plasma glucose levels were significantly lower in the ranolazine-treated group (187 ± 19 mg/dl) compared with the vehicle group (273 ± 23 mg/dl) at 8 weeks. HbA(1c) was 5.8 ± 0.4% in the vehicle group and 4.5 ± 0.2% in the ranolazine-treated group (p < 0.05). Glucose disposal during the oral glucose tolerance test (OGTT) and insulin tolerance test were not different between the two groups; however, during OGTT, peak insulin levels were significantly (p < 0.05) higher in ranolazine-treated mice. Mice treated with ranolazine had healthier islet morphology and significantly (p < 0.01) higher β-cell mass (69 ± 2% per islet) than the vehicle group (50 ± 5% per islet) as determined from hematoxylin and eosin staining. The number of apoptotic cells was significantly (p < 0.05) less in the pancreas of the ranolazine-treated group (14 ± 2% per islet) compared with the vehicle group (24 ± 4% per islet). In addition, ranolazine increased glucose-stimulated insulin secretion in rat and human islets in a glucose-dependent manner. These data suggest that ranolazine may be a novel antidiabetic agent that causes β-cell preservation and enhances insulin secretion in a glucose-dependent manner in diabetic mice.

NFκB1 (p50)-deficient mice are not susceptible to multiple low-dose streptozotocin-induced diabetes

NFκB1 (p50)-deficient mice are not susceptible to multiple low-dose streptozotocin-induced diabetes

Immune Cell–Derived C3 Is Required for Autoimmune Diabetes Induced by Multiple Low Doses of Streptozotocin

OBJECTIVEThe complement system contributes to autoimmune injury, but its involvement in promoting the development of autoimmune diabetes is unknown. In this study, our goal was to ascertain the role of complement C3 in autoimmune diabetes.RESEARCH DESIGN AND METHODSSusceptibility to diabetes development after multiple low-dose streptozotocin treatment in wild-type (WT) and C3-deficient mice was analyzed. Bone marrow chimeras, luminex, and quantitative reverse transcription PCR assays were performed to evaluate the phenotypic and immunologic impact of C3 in the development of this diabetes model.RESULTSCoincident with the induced elevations in blood glucose levels, we documented alternative pathway complement component gene expression within the islets of the diabetic WT mice. When we repeated the experiments with C3-deficient mice, we observed complete resistance to disease, as assessed by the absence of histologic insulitis and the absence of T-cell reactivity to islet antigens. Studies of WT chimeras bearing C3-deficient bone marrow cells showed that bone marrow cell–derived C3, and not serum C3, is involved in the induction of diabetes in this model.CONCLUSIONSThe data reveal a key role for immune cell–derived C3 in the pathogenesis of murine multiple low-dose streptozotocin-induced diabetes and support the concept that immune cell mediated diabetes is in part complement-dependent.

Taenia crassicepsInfection Attenuates Multiple Low-Dose Streptozotocin-Induced Diabetes

Taenia crassiceps, like other helminths, can exert regulatory effects on the immune system of its host. This study investigates the effect of chronic T. crassiceps infection on the outcome of Multiple Low Dose Streptozotocin-Induced Diabetes (MLDS). Healthy or previously T. crassiceps-infected mice received MLDS and type 1 diabetes (T1D) symptoms were evaluated for 6 weeks following the induction of MLDS. T. crassiceps-infected mice displayed lower blood glucose levels throughout the study. A significantly lower percentage of T. crassiceps-infected mice (40%) developed T1D compared to the uninfected group (100%). Insulitis was remarkably absent in T. crassiceps-infected mice, which had normal pancreatic insulin content, whereas uninfected mice showed a dramatic reduction in pancreatic insulin. Infected mice that received MLDS did not show an increase in their regulatory T cell population, however, they had a greater number of alternatively activated macrophages, higher levels of the cytokine IL-4, and lower levels of TNF-α. Therefore, infection with T. crassiceps causes an immunomodulation that modifies the incidence and development of MLDS-induced autoimmune diabetes.