An ADA diet consisting of 20% of calories as almonds over a 16-week period is effective in improving markers of insulin sensitivity and yields clinically significant improvements in LDL-C in adults with prediabetes.

The leukocyte 12-lipoxygenase (12-LO) gene is expressed in pancreatic β cells and macrophages. Products of the 12-LO enzyme are proinflammatory and may be involved in immune-mediated conditions, but formal proof of this hypothesis is lacking. Leukocyte 12-LO is preferentially expressed over 5-and 15-lipoxygenase in pancreatic β cells and may be involved in cytokine-mediated β-cell damage through generation of the lipid hydroperoxide 12-hydroperoxyeicosatetraenoic acid (12-HPETE) (1-7). Reduction of 12-HPETE to 12-hydroxyeicosatetraenoic acid (12-HETE) is facilitated by the enzyme glutathione peroxidase, and recent work has demonstrated that 12-LO inhibitors can prevent glutamate-induced neuronal cell death when intracellular glutathione stores are depleted (8). Both neuronal cell death and peroxide generation required 12-LO activity in this model and were prevented by treatment with a lipoxygenase inhibitor, baicalein (10 µM). Furthermore, the proinflammatory cytokine IL-1β was shown to increase 12-LO product formation in pancreatic islets (9, 10), whereas nordihydroguaiaretic, a lipoxygenase inhibitor, protected rat islet cells from cytokine-induced destruction (11). Given that 12-HPETE and/or other 12-LO products may damage pancreatic β cells through lipid peroxidation, it is possible that inhibition of the 12-LO pathway may protect pancreatic β cells from cytotoxic conditions.To test this hypothesis, we administered low-dose streptozotocin (STZ) to 12-LO knockout (12-LO KO) mice and genetic controls to evaluate the development of diabetes. In addition, we isolated pancreatic islets and tested them for sensitivity to cytokine-induced dysfunction. We also evaluated the capacity of macrophages to generate nitric oxide (NO) and superoxide when stimulated. We chose the low dose STZ-induced diabetic model because previous studies have demonstrated that β-cell destruction is mediated in part by generation of free radicals and lipid hydroperoxides as well as by immune activation (12, 13). 12-LO KO mice were generated by homologous recombination in embryonic stem cells, as described previously (14).In the present study, we found that 12-LO KO mice were significantly more resistant to STZ-induced diabetes than were C57BL/6 controls and that islets purified from 12-LO KO mice were protected from cytokine-induced dysfunction. Furthermore, macrophages from 12-LO KO mice generated ∼50% of the nitrate/nitrite compared with macrophages from control C57BL/6 mice. Leukocyte 12-lipoxygenase (12-LO) gene expression in pancreatic β cells is upregulated by cytotoxic cytokines like IL-1β. Recent studies have demonstrated that 12-LO inhibitors can prevent glutamateinduced neuronal cell death when intracellular glutathione stores are depleted. Therefore, 12-LO pathway inhibition may prevent β-cell cytotoxicity. To evaluate the role of 12-LO gene expression in immune-mediated islet destruction, we used 12-LO knockout (12-LO KO) mice. Male homozygous 12-LO KO mice and control C57BL/6 mice received 5 consecutive daily injections of low-...

In this review, we examine the evidence that intestinal helminths can control harmful inflammatory responses and promote homeostasis by triggering systemic immune responses. Induction of separable components of immunity by helminths, which includes type 2 and immune regulatory responses, can both contribute toward the reduction in harmful type 1 immune responses that drive certain inflammatory diseases. Despite inducing type 2 responses, intestinal helminths may also downregulate harmful type 2 immune responses including allergic responses. We consider the possibility that intestinal helminth infection may indirectly affect inflammation by influencing the composition of the intestinal microbiome. Taken together, the studies reviewed herein suggest that intestinal helminth-induced responses have potent systemic effects on the immune system, raising the possibility that whole parasites or specific molecules produced by these metazoans may be an important resource for the development of future immunotherapies to control inflammatory diseases.

Parasitic helminth infection has been shown to modulate pathological inflammatory responses in allergy and autoimmune disease. The aim of this study was to examine the effects of infection with a helminth parasite, Heligmosomoides polygyrus, on type 1 diabetes (T1D) in nonobese diabetic (NOD) mice and to elucidate the mechanisms involved in this protection. H. polygyrus inoculation at 5 weeks of age protected NOD mice from T1D until 40 weeks of age and also inhibited the more aggressive cyclophosphamide-induced T1D. Moreover, H. polygyrus inoculation as late as 12 weeks of age reduced the onset of T1D in NOD mice. Following H. polygyrus inoculation of NOD mice, pancreatic insulitis was markedly inhibited. Interleukin-4 (IL-4), IL-10, and IL-13 expression and the frequency of CD4 ؉ CD25 ؉ FoxP3 ؉ regulatory T cells were elevated in mesenteric and pancreatic lymph nodes. Depletion of CD4 ؉ CD25 ؉ T cells in vivo did not abrogate H. polygyrus-induced T1D protection, nor did anti-IL-10 receptor blocking antibody. These findings suggest that infection with H. polygyrus significantly inhibits T1D in NOD mice through CD25-and IL-10-independent mechanisms and also reduces the severity of T1D when administered late after the onset of insulitis.

Overnutrition and genetics both contribute separately to pancreatic β-cell dysfunction, but how these factors interact is unclear. This study was aimed at determining whether microRNAs (miRNAs) provide a link between these factors. In this study, miRNA-24 (miR-24) was highly expressed in pancreatic β-cells and further upregulated in islets from genetic fatty (db/db) or mice fed a high-fat diet, and islets subject to oxidative stress. Overexpression of miR-24 inhibited insulin secretion and β-cell proliferation, potentially involving 351 downregulated genes. By using bioinformatic analysis combined with luciferase-based promoter activity assays and quantitative real-time PCR assays, we identified two maturity-onset diabetes of the young (MODY) genes as direct targets of miR-24. Silencing either of these MODY genes (Hnf1a and Neurod1) mimicked the cellular phenotype caused by miR-24 overexpression, whereas restoring their expression rescued β-cell function. Our findings functionally link the miR-24/MODY gene regulatory pathway to the onset of type 2 diabetes and create a novel network between nutrient overload and genetic diabetes via miR-24.

Growing evidence indicates that adenosine receptors could be promising therapeutic targets in autoimmune diseases. Here we studied the role of adenosine receptors in controlling the course of type 1 diabetes. Diabetes in CD-1 mice was induced by multiple-low-dose-streptozotocin (MLDS) treatment and in nonobese diabetic (NOD) mice by cyclophosphamide injection. The nonselective adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA) prevented diabetes development in both MLDS-challenged mice and in cyclophosphamide-treated NOD mice. The effect of NECA was reversed by the selective A2B receptor antagonist N-(4-cyanophenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)phenoxy]acetamide (MRS 1754). The selective A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA) and A3 receptor agonist N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (IB-MECA) were less efficacious in ameliorating the course of diabetes. NECA inhibited diabetes in A2A receptor KO mice and the selective A2A receptor agonist 2-p-(2-carboxyethyl)phenethyl-amino-5'-N-ethyl-carboxamidoadenosine (CGS21680) had no effect in normal mice, indicating a lack of role of A2A receptors. NECA failed to prevent cytokine-induced beta-cell death in vitro, but NECA strongly suppressed expression of the proinflammatory cytokines TNF-alpha, MIP-1alpha, IL-12, and IFN-gamma in pancreata, endotoxin, or anti-CD3-stimulated splenic cells, and T helper 1 lymphocytes, indicating that the beneficial effect of NECA was due to immunomodulation. These results demonstrate that adenosine receptor ligands are potential candidates for the treatment of type 1 diabetes.

MMPs and tissue inhibitors of matrix metalloproteinases (TIMPs) are tightly regulated enzymes that coordinate matrix production and degradation. The obvious need for a dynamic process that regulates collagen turnover is evident in wound repair and remodeling (2,3). However, MMPs and TIMPs are involved in other significant but less obvious processes, such as tumor invasion and metastasis (4 -7), inflammatory responses (8), embryonic development (9,10), arthritic diseases (11,12), and multiple sclerosis (13,14).Recently, Herren et al. (15) discovered that certain metalloproteinases play a role in apoptosis. In particular, MMPs play a role in caspase activation by processing membrane-bound ␤-catenin to its active form via proteolysis. MMPs may also be involved in processing the transmembrane Fas ligand to the soluble Fas ligand (16). In addition, MMPs convert the membrane-bound form of protumor necrosis factor (TNF)-␣ to the mature active inflammatory cytokine through proteolytic cleavage of a critical alanine-valine bond at amino acids 76 and 77 (17,18).Alternatively, TIMP-1 overexpression prevented programmed cell death in a Burkitt's lymphoma cell line through both CD-95 (Fas)-dependent and -independent pathways. TIMP-1 overexpression upregulated Bcl-xL and decreased nuclear factor (NF)-B activity, and the protective effect was not related to metalloproteinase inhibition (19). Furthermore, TIMP-1 expression has been used to prevent apoptotic cell death induced by hydrogen peroxide, adriamycin, and X-ray irradiation in human breast epithelial cell lines (20).Pancreatic ␤-cells and islets are particularly sensitive to cytokine-mediated damage. Cytokine-treated rodent (and human) pancreatic islets demonstrate increased expression of the inducible nitric oxide synthase (iNOS) gene that in turn leads to nitric oxide (NO) production (21). NO inhibits glucose-stimulated insulin secretion (GSIS) and induces ␤-cell damage. Whereas inhibitors of iNOS, such as N-monomethyl-L arginine and L-N-arginine-methylester, can partially prevent cytokine-mediated ␤-cell damage through inhibition of NO production; NO-independent From the Leslie and Susan Gonda

Helminth infection can prevent type 1 diabetes (T1D); however, the regulatory mechanisms inhibiting disease remain largely undefined. In these studies, nonobese diabetic (NOD) IL-4(-/-) mice were infected with the strictly enteric nematode parasite, Heligmosomoides polygyrus. Short-term infection, 5-7 weeks of age, inhibited T1D onset, as late as 40 weeks of age. CD4(+) T-cell STAT6 phosphorylation was inhibited, while suppressed signal transducer and activator of transcription 1 phosphorylation was sustained, as were increases in FOXP3(-), CD4(+) T-cell interleukin (IL)-10 production. Blockade of IL-10 signaling in NOD-IL-4(-/-), but not in NOD, mice during this short interval abrogated protective effects resulting in pancreatic β-cell destruction and ultimately T1D. Transfer of CD4(+) T cells from H. polygyrus (Hp)-inoculated NOD IL-4(-/-) mice to NOD mice blocked the onset of T1D. These studies indicate that Hp infection induces non-T-regulatory cells to produce IL-10 independently of STAT6 signaling and that in this Th2-deficient environment IL-10 is essential for T1D inhibition.