Cannabidinoids are components of the Cannabis sativa (marijuana) plant that have been shown capable of suppressing inflammation and various aspects of cell-mediated immunity. Cannabidiol (CBD), a non-psychoactive cannabidinoid has been previously shown by us to suppress cell-mediated autoimmune joint destruction in an animal model of rheumatoid arthritis. We now report that CBD treatment significantly reduces the incidence of diabetes in NOD mice from an incidence of 86% in non-treated control mice to an incidence of 30% in CBD-treated mice. CBD treatment also resulted in the significant reduction of plasma levels of the pro-inflammatory cytokines, IFN-g and TNF-a. Th1-associated cytokine production of in vitro activated T-cells and peritoneal macrophages was also significantly reduced in CBD-treated mice, whereas production of the Th2-associated cytokines, IL-4 and IL-10, was increased when compared to untreated control mice. Histological examination of the pancreatic islets of CBD-treated mice revealed significantly reduced insulitis. Our results indicate that CBD can inhibit and delay destructive insulitis and inflammatory Th1-associated cytokine production in NOD mice resulting in a decreased incidence of diabetes possibly through an immunomodulatory mechanism shifting the immune response from Th1 to Th2 dominance.

Inflammatory destruction of insulin-producing ␤ cells in the pancreatic islets is the hallmark of insulin-dependent diabetes mellitus, a spontaneous autoimmune disease of non-obese diabetic mice resembling human juvenile (type I) diabetes. Histochemical analysis of diabetic pancreata revealed that mononuclear cells infiltrating the islets and causing autoimmune insulitis, as well as local islet cells, express the CD44 receptor; hyaluronic acid, the principal ligand of CD44, is detected in the islet periphery and islet endothelium. Injection of anti-CD44 mAb 1 hr before cell transfer of diabetogenic splenocytes and subsequently on alternate days for 4 weeks induced considerable resistance to diabetes in recipient mice, reflected by reduced insulitis. Contact sensitivity to oxazolone was not influenced by this treatment. A similar antidiabetic effect was observed even when the anti-CD44 mAb administration was initiated at the time of disease onset: i.e., 4 -7 weeks after cell transfer. Administration of the enzyme hyaluronidase also induced appreciable resistance to insulin-dependent diabetes mellitus, suggesting that the CD44 -hyaluronic acid interaction is involved in the development of the disease. These findings demonstrate that CD44-positive inflammatory cells may be a potential therapeutic target in insulin-dependent diabetes.T he inflammatory cascade in affected organs of autoimmune diseases is a complex process that involves triggering of the immunological response, release of chemokines, cytokines, and toxic agents (e.g., reactive oxygen) by the activated cells, stimulation of endothelial cells, up-regulation of cell surface adhesion molecules, transendothelial cell migration, and a shift in the Th1͞Th2 balance in favor of the Th1 cells (1). Hence, the destructive autoimmune inflammatory process depends substantially (but not exclusively) on cell migration and cell interaction with matrix components of target organs. The destruction of pancreatic islet ␤-cells in insulin-dependent diabetes mellitus (IDDM) by invading leukocytes and the consequent deterioration of the insulin-dependent glucose homeostasis is an excellent example of such an autoimmune process (2, 3), although neither the nature of the triggering self-antigen nor the molecules associated with its recognition and presentation have been unequivocally identified.Whereas the function of selectins and integrins in supporting inflammatory cell migration and lodgment has been well established (4), the role of cell surface CD44 has only recently attracted attention (5). Alternative splicing and͞or posttranslation modifications generate many CD44 isoforms. The large array of CD44 isoforms is mainly attributable to the insertion of amino acid sequences, encoded by different combinations of 10 variant exons, into a membrane proximal position of the extracellular domain. Transcripts in which these variant exons are spliced out encode the most common and widely expressed 85-kDa isoform, known as standard CD44. The expression of CD44 isoforms containing s...

Objective: Arabinoxylan (AX) consumption is associated with metabolic improvement during diabetes and with modulation of ghrelin, an orexigenic gut hormone. The effect of AX consumption on ghrelin secretion in disturbed metabolic states is unknown. Therefore, we investigated the postprandial responses to AX consumption of serum glucose, insulin and triglycerides and plasma total and acylated ghrelin in subjects with impaired glucose tolerance (IGT). Design: Randomized, single-blind, controlled, crossover intervention trial. Subjects: Seven female and four male adults with IGT, aged 55.5 years, and body mass index (BMI) 30.1 kg/m 2 . Intervention: Subjects received either placebo or 15 g AX supplement for 6 weeks with a 6-week washout period in-between. Main outcome measurements: Postprandial responses of serum glucose, insulin and triglycerides, and plasma total and acylated ghrelin after a liquid meal challenge test (LMCT) measured at the beginning and at the end of the dietary intervention at À20, À5, 0, 15, 30, 45, 60, 90, 120, 150, 180, 210 and 240 min. Results: After LMCT, AX consumption resulted in lower postprandial responses in serum glucose, insulin and triglycerides (Po0.05). Compared to placebo, total plasma ghrelin was also reduced by 4278 pg/ml (Po0.001) after AX consumption with no difference in plasma acylated ghrelin. Conclusion: AX consumption improved postprandial metabolic responses after an LMCT in subjects with IGT and reduced total ghrelin response. However, acylated ghrelin responses were unchanged, suggesting that the acylated ghrelin-mediated orexigenic regulation is not improved as only total plasma ghrelin decreased. Sponsorship: Federal Ministry of Education and Research Germany (PTJ-BIO/0313042C).