Vitamin D supplementation induces CatG-mediated CD4+ T cell inactivation and restores pancreatic ß-cell function in mice with type 1 diabetes.

Type 1 diabetes (T1D) is a chronic autoimmune disease accompanied by the immune-mediated destruction of pancreatic ß-cells. In this study, we aimed to explore the regulatory effects of vitamin D (VD) supplementation on pancreatic ß-cell function by altering the expression of bioinformatically identified cathepsin G (CatG) in T1D mice. A T1D mouse model was established in nonobese diabetic (NOD) mice, and their islets were isolated and purified. Pancreatic mononuclear cells (MNCs) were collected, from which CD4+ T cells were isolated. The levels of interleukin (IL)-2, IL-10, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) in the supernatant of mouse pancreatic tissue homogenate were assessed using ELISA. Immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelin (TUNEL) staining were conducted to evaluate the effects of VD supplementation on pancreatic tissues of T1D mice. The pancreatic ß-cell line MIN6 was used for in vitro substantiation of findings in vivo. VD supplementation reduced glucose levels and improved glucose tolerance in T1D mice. Furthermore, VD supplementation improved pancreatic ß-cell function and suppressed immunological and inflammatory reactions in the T1D mice. We documented overexpression of CatG in diabetes tissue samples, and then showed that VD supplementation normalized the islet immune microenvironment through downregulating CatG expression in T1D mice. Experiments in vitro subsequently demonstrated that VD supplementation impeded CD4+ T activation by downregulating CatG expression and thereby enhanced pancreatic ß-cell function. Results of the present study elucidated that VD supplementation can downregulate the expression of CatG and inhibit CD4+ T cell activation, thereby improving ß-cell function in T1D.NEW & NOTEWORTHY We report that vitamin D (VD) supplementation downregulates CatG expression and inhibits CD4+ T cell activation, thereby improving ß-cell function in type 1 diabetes (T1D). This study deepens our understanding of the pathogenesis of T1D and clarifies molecular events underlying the alleviatory effect of VD for immunotherapy against T1D.

Influence of Vitamin D on Islet Autoimmunity and Beta-Cell Function in Type 1 Diabetes.

Type 1 diabetes (T1D) is a chronic autoimmune disease leading to immune-mediated destruction of pancreatic beta cells, resulting in the need for insulin therapy. The incidence of T1D is increasing worldwide, thus prompting researchers to investigate novel immunomodulatory strategies to halt autoimmunity and modify disease progression. T1D is considered as a multifactorial disease, in which genetic predisposition and environmental factors interact to promote the triggering of autoimmune responses against beta cells. Over the last decades, it has become clear that vitamin D exerts anti-inflammatory and immunomodulatory effects, apart from its well-established role in the regulation of calcium homeostasis and bone metabolism. Importantly, the global incidence of vitamin D deficiency is also dramatically increasing and epidemiologic evidence suggests an involvement of vitamin D deficiency in T1D pathogenesis. Polymorphisms in genes critical for vitamin D metabolism have also been shown to modulate the risk of T1D. Moreover, several studies have investigated the role of vitamin D (in different doses and formulations) as a potential adjuvant immunomodulatory therapy in patients with new-onset and established T1D. This review aims to present the current knowledge on the immunomodulatory effects of vitamin D and summarize the clinical interventional studies investigating its use for prevention or treatment of T1D.

Artesunate prevents type 1 diabetes in NOD mice mainly by inducing protective IL-4-producing T cells and regulatory T cells.

Type 1 diabetes (T1D) is an autoimmune disease characterized by the immune-mediated destruction of insulin-producing ß cells. Recent studies showed that in addition to malaria, artemisinin and its derivative, artesunate (AS), could alleviate several autoimmune diseases. However, whether AS has a role in the prevention or treatment of T1D is still unknown. Therefore, in this study we administrated AS or DMSO in the drinking water of nonobese diabetic (NOD) mice, a mouse model of T1D. We found that AS administration significantly prevented the incidence of T1D. The frequency of IL-4-producing CD4+ single-positive T cells and CD8+ T cells was significantly elevated, and IFN-γ-producing T cells were reduced in the spleen and pancreatic lymph nodes. In the pancreas, the skewing to IL-4-producing T cells was also observed. In addition, more regulatory T cells were found in the pancreas. mRNA levels of proinflammatory cytokines, including TNF-α and IL-6, were decreased. In addition, AS administration promoted the functional maturity of ß cells in vitro. Our findings demonstrate that AS administration can prevent T1D in NOD mice mainly by reducing autoimmune T cells and increasing protective T cells. Our data constitute the first functional study of AS in T1D, which may provide a new rationale for future translational studies.-Li, Z., Shi, X., Liu, J., Shao, F., Huang, G., Zhou, Z., Zheng, P. Artesunate prevents type 1 diabetes in NOD mice mainly by inducing protective IL-4-producing T cells and regulatory T cells.

The Effect of Aronia Berry on Type 1 Diabetes In Vivo and In Vitro.

The number of diabetic patients worldwide is increasing, and complications such as stroke and cardiovascular disease are becoming a serious cause of death. Diabetes mellitus is classified into two types according to the etiopathogenic mechanism and insulin dependence. Type 1 diabetes (T1D), an insulin-dependent diabetes mellitus, is caused by damage and destruction of pancreatic ß cells that produce insulin. It is a disease that is characterized by hyperglycemia and hypoinsulinemia. Aronia berry has been used as a medicinal food in Europe. Aronia contains a variety of ingredients such as polyphenols, anthocyanins, flavonoids, and tannins. Especially, anthocyanin content in aronia berry is known to be much higher than in other plants and berries. It is known for exerting antioxidant, anti-inflammation, and anti-aging effects. Therefore, this study was conducted to investigate the effects of aronia berry extract intake in multiple low-dose streptozotocin (STZ)-induced T1D and to confirm the functional properties of aronia berry. ICR mice (6-week male) were divided into four groups: control (normal control group), STZ (100 mg/kg of STZ-induced T1D group), AR 10 (STZ with oral administration of aronia 10 mg/kg), and AR 100 (STZ with oral administration of aronia 100 mg/kg). Afterward, STZ was injected in a single dose to induce T1D, and the extract was orally administered daily. Dietary intake and body weight were measured twice a week. We confirmed that aronia berry has the effect of decreasing the increase of blood glucose level and also has the protection effect of pancreas ß cell (RINm5F cell). This study confirms the anti-diabetic activity of aronia berry, and it can be expected to increase the utilization according to the results.

Protective effects of carbonyl iron against multiple low-dose streptozotocin-induced diabetes in rodents.

Particulate adjuvants have shown increasing promise as effective, safe, and durable agents for the stimulation of immunity, or alternatively, the suppression of autoimmunity. Here we examined the potential of the adjuvant carbonyl iron (CI) for the modulation of organ-specific autoimmune disease-type 1 diabetes (T1D). T1D was induced by multiple low doses of streptozotocin (MLDS) that initiates beta cell death and triggers immune cell infiltration into the pancreatic islets. The results of this study indicate that the single in vivo application of CI to MLDS-treated DA rats, CBA/H mice, or C57BL/6 mice successfully counteracted the development of insulitis and hyperglycemia. The protective action was obtained either when CI was applied 7 days before, simultaneously with the first dose of streptozotocin, or 1 day after MLDS treatment. Ex vivo cell analysis of C57BL/6 mice showed that CI treatment reduced the proportion of proinflammatory F4/80+ CD40+ M1 macrophages and activated T lymphocytes in the spleen. Moreover, the treatment down-regulated the number of inflammatory CD4+ IFN-γ+ cells in pancreatic lymph nodes, Peyer's patches, and pancreas-infiltrating mononuclear cells, while simultaneously potentiating proportion of CD4+ IL17+ cells. The regulatory arm of the immune system represented by CD3+ NK1.1+ (NKT) and CD4+ CD25+ FoxP3+ regulatory T cells was potentiated after CI treatment. In vitro analysis showed that CI down-regulated CD40 and CD80 expression on dendritic cells thus probably interfering with their antigen-presenting ability. In conclusion, particulate adjuvant CI seems to suppress the activation of the innate immune response, which further affects the adaptive immune response directed toward pancreatic beta cells.

Regulatory T cell therapy for type 1 diabetes: May the force be with you.

Type 1 diabetes mellitus (T1DM) results from autoimmune destruction of insulin producing beta cells. Regulatory T cells (Tregs) have been shown to be defective in this setting. Immuno-therapies targeting T cells, and resetting the balance between T effectors and Tregs, have had some initial success in preserving beta cell function. With a goal to use Tregs themselves as a novel therapeutic, we developed a technique to isolate and expand Tregs from patients with T1DM. These ex vivo expanded CD4(+)CD127(lo/-)CD25(+) cells exhibit improved function and retain their T cell receptor diversity. These cells have subsequently been used in phase I clinical trials in patients with recent onset T1DM. The infusions were well tolerated, with no safety concerns. The studies are too small to assess efficacy definitively, although some individuals exhibit stable beta cell function over intervals as long as 2 years. These efforts set the stage for a larger phase II effort in new onset T1DM, and combination studies with other drugs, as well as efforts in other autoimmune diseases.

Iron Regulation of Pancreatic Beta-Cell Functions and Oxidative Stress.

Dietary advice is the cornerstone in first-line treatment of metabolic diseases. Nutritional interventions directed at these clinical conditions mainly aim to (a) improve insulin resistance by reducing energy-dense macronutrient intake to obtain weight loss and (b) reduce fluctuations in insulin secretion through avoidance of rapidly absorbable carbohydrates. However, even in the majority of motivated patients selected for clinical trials, massive efforts using this approach have failed to achieve lasting efficacy. Less attention has been given to the role of micronutrients in metabolic diseases. Here, we review the evidence that highlights (a) the importance of iron in pancreatic beta-cell function and dysfunction in diabetes and (b) the integrative pathophysiological effects of tissue iron levels in the interactions among the beta cell, gut microbiome, hypothalamus, innate and adaptive immune systems, and insulin-sensitive tissues. We propose that clinical trials are warranted to clarify the impact of dietary or pharmacological iron reduction on the development of metabolic disorders.

Evaluating the toxic and beneficial effects of lichen extracts in normal and diabetic rats.

Lichens can be used as a novel bioresource for natural antioxidants. However, there is need for further investigations to validate the lichens used in medicinal remedies. In this study, the effects of Cetraria islandica and Pseudevernia furfuracae lichen species in streptozotocin (STZ)-induced diabetes were evaluated. Diabetic rats were treated with aqueous lichen extracts (250 and 500 mg/kg/day) for 2 weeks starting at 72 h after STZ injection. On the 14th day, animals were anesthetized, and then metabolic and biochemical parameters were evaluated between control and treatment groups. Pancreatic histology and ß-cell mass were examined by hematoxylin and eosin and insulin immunohistochemistry stainings. Our findings revealed that these lichen species could be used safely in this dose range. In addition, C. islandica extracts showed prominent results compared to the doses of P. furfuracae extract for antioxidant capacity. However, the protectivity of C. islandica extract was inadequate against diabetes-induced pancreatic damages via forming oxidative stress. In conclusion, the usage of C. islandica might serve for early intervening in the risk reduction of type 1 diabetes.

Interaction of dendritic cells and T lymphocytes for the therapeutic effect of Dangguiliuhuang decoction to autoimmune diabetes.

In traditional Chinese medicine (TCM), Dangguiliuhuang decoction (DGLHD) is an effective treatment of autoimmune diabetes. Here, we studied potential anti-diabetic mechanisms of DGLHD in a non-obese diabetic (NOD) mouse model. In vitro, DGLHD and individual active ingredients enhanced glucose uptake in HepG2 cells, inhibited T lymphocyte proliferation, and suppressed dendritic cells (DCs) function. In vivo, DGLHD significantly inhibited insulitis, delayed the onset and development of diabetes, promoted insulin secretion and sensitivity, and balanced partially normalized Th1 and Th2 cytokines in NOD mice. In addition, DGLHD increased α1-antitrypsin (AAT-1), Bcl-2, and CyclinD1, and decreased Bax levels in pancreas, spleen, thymus, DCs, and a NIT-1 cell line, all consistent with protecting and repairing islet ß cell. More detailed studies indicated that DGLHD regulated the maturation and function of DCs, decreased the percentage of merocytic dendritic cells (mcDCs) subset, and increased programmed death ligand-1 (PD-L1) expression in DCs. DGLHD also impeded T lymphocyte proliferation and promoted regulatory T cells (T(regs)) differentiation in vivo. A JAK2-STAT3-dependent pathway was involved in the suppression by DGLHD of interactions between DCs and T lymphocyte. The experiments implicated five active ingredients in specific anti-diabetic actions of DGLHD. The results demonstrated the reasonable composition of the formula.

Fetuin A promotes lipotoxicity in ß cells through the TLR4 signaling pathway and the role of pioglitazone in anti-lipotoxicity.

OBJECTIVE: Fetuin A (FetA), a secreted glycoprotein, is known to affect inflammation and insulin resistance (IR) in obese humans and animals. Lipotoxicity from chronic hyperlipidemia damages pancreatic ß cells, hastening the onset of diabetes. We sought to determine whether FetA promotes lipotoxicity through modulation of the toll-like receptor 4 (TLR4) inflammatory signaling pathway as well as the protective effect of pioglitazone(PIO) on lipotoxicity. METHODS: ßTC6, a glucose-sensitive mouse pancreatic ß cell line, and Sprague-Dawley rats with diet-induced obesity, were used to investigate FetA-mediated lipotoxicity. Protein expression/activation were measured by Western blotting. Small interfering (si)RNAs for TLR4 were used. Cell apoptosis was quantified by TUNEL analysis or flow cytometry, respectively. Insulin release was assessed with an insulin ELISA. RESULTS: FetA dose-dependently aggravated palmitic acid (PA)-induced ßTC6 cell apoptosis, insulin secretion impairment, and inhibition of the expression of G-protein-coupled receptor 40 (GPR40) and pancreatic duodenal homeobox-1(PDX-1). Combined FetA + PA induced TLR4 expression, and subsequent inhibition of TLR4 signaling or expression was shown to prevent the strengthening effect of FetA on PA-induced lipotoxicity in ßTC6 cells. FetA + PA induced p-JNK and nuclear factor-κB (NF-κB) subunit P65 expression, and inhibition of this activity reduced PA+ FetA lipotoxicity in ßTC6 cells. PIO could ameliorate PA+ FetA-induced damage to ßTC6 cells. Similarly, PIO improved insulin secretion disorder, reduced apoptosis, decreased FetA, TLR4, p-JNK, NF-κB subunit P65 and cleaved caspase 3 expression, and increased GPR40 and PDX-1 expression in islet ß cells of diet-induced obese rats. The correlative bivariate analysis showed that increases in Fetuin A were directly proportional to the development of ß cell injury. CONCLUSIONS: FetA can promote lipotoxicity in ß cells through the TLR4-JNK-NF-κB signaling pathway. The protective effects of PIO on lipotoxicity in ß cells may involve the inhibition of the activation of the FetA and TLR4 signaling pathway.

A Targeted Multiple Antigenic Peptide Vaccine Augments the Immune Response to Self TGF-ß1 and Suppresses Ongoing Hepatic Fibrosis.

Transforming growth factor (TGF)-ß1 expression is induced upon liver injury, and plays a critical role in hepatic fibrosis. Antibodies against TGF-ß1 represent a novel approach in the treatment of hepatic fibrosis. However, TGF-ß1 is not a suitable antigen due to immunological tolerance. In the current study, we synthesized a multiple antigenic peptide (MAP) vaccine against the dominant B-cell epitope of TGF-ß1. The immunogenicity and potential therapeutic effects of this vaccine were examined using a rat model of hepatic fibrosis. Dominant B-cell epitopes of TGF-ß1 were identified using bioinformatic program. An MAP vaccine corresponding to the 90-98 amino acid domain of TGF-ß1 and containing four dendritic arms was synthesized using a 9-fluorenylmethoxycarbonyl solid phase method. Hepatic fibrosis which was induced in male Sprague-Dawley rats received a high-fat diet and ethanol (1.8 g/kg). Starting from the third week, rats were exposed to 40 % carbon tetrachloride (CCl4; 150 µl/100 g body weight twice weekly, initially 200 µl/100 g) treatment for a duration of 8 weeks. Rats received the MAP vaccine (100 µg) or Freund's adjuvant at weeks 1, 3, 5. A group of rats receiving the fibrosis-inducing regimen alone and a group of healthy rats (receiving an olive oil vehicle alone) were included as controls. At the conclusion of the experiment, serum titre of TGF-ß1 antibody was measured using ELISA and a standard liver functional test panel was examined. The extent of hepatic fibrosis was determined by measuring hydroxyproline content in the liver as well as hematoxylin-eosin (HE) and van Gieson (VG) staining. The expression of TGF-ß1 and alpha-smooth muscle actin (α-SMA) was examined using immunohistochemistry, and presented as positive staining cells. The MAP purity was >90 % upon reverse phase high-performance liquid chromatography, with apparent molecular weight at 4.77 kDa. Serum TGF-ß1 antibody titre was 1:256. The fibrosis-inducing treatment produced significant liver damage, as reflected by increases in liver functional test, HE and VG staining. The MAP vaccine attenuated such damage, as reflected by decreased alanine aminotransferase, aspartate aminotransferase, total bilirubin, and hepatic hydroxyproline (116.78 ± 23.76 vs. 282.71 ± 136.94 IU/L; 319.78 ± 82.48 vs. 495.29 ± 137.13 IU/L; 2.02 ± 0.27 vs. 4.01 ± 0.52 µmol/L; 263.67 ± 41.18 vs. 439.14 ± 43.29 µg/g vs. in model rats, respectively; p < 0.01), as well as fibrosis extent by HE and VG staining. The MAP vaccine reduced TGF-ß1 and α-SMA expression in rats (0.325 ± 0.059 vs. 0.507 ± 0.044 IOD/area; 0.318 ± 0.058 vs. 0.489 ± 0.029 IOD/area vs. model rats, respectively; p < 0.05). The TGF-ß1 MAP vaccine could generate sufficient antibody that suppresses the development of hepatic fibrosis.

Effects of 12 weeks high dose vitamin D3 treatment on insulin sensitivity, beta cell function, and metabolic markers in patients with type 2 diabetes and vitamin D insufficiency - a double-blind, randomized, placebo-controlled trial.

OBJECTIVES: Vitamin D insufficiency is common in subjects with type 2 diabetes. Observational studies suggest that vitamin D plays a role in the pathogenesis of type 2 diabetes. However, results of intervention studies have been inconsistent. We investigated the effects of improving vitamin D status on insulin sensitivity, insulin secretion, and inflammatory markers in patients with type 2 diabetes. MATERIALS/METHODS: A double blind, randomized, placebo controlled trial was conducted. Sixteen patients with type 2 diabetes and hypovitaminosis D were recruited. Eight patients received colecalciferol and (280 µg daily for 2 weeks, 140 µg daily for 10 weeks) and 8 patients received identical placebo tablets for 12 weeks. Before and after intervention, patients underwent IVGTT, hyperinsulinemic euglycemic clamp, assessment of baseline high-frequency insulin pulsatility, glucose-entrained insulin pulsatility, DXA scans, 24-hour-ambulatory blood pressure monitorings, and fasting blood samples. RESULTS: Serum-25(OH) vitamin D and serum-1,25(OH)2 vitamin D increased significantly after 12 weeks in the intervention group (p=0.01, p=0.004). Serum-25(OH) vitamin D was also significantly higher in the vitamin D group compared to the placebo group (p=0.02) after intervention. Although no significant changes in insulin sensitivity, inflammation, blood pressure, lipid profile, or HbA1c were found, we observed borderline (p between 0.05 and 0.10) improvements of insulin secretion, in terms of c-peptide levels, first phase incremental AUC insulin and insulin secretory burst mass. CONCLUSIONS: Improvement in vitamin D status does not improve insulin resistance, blood pressure, inflammation or HbA1c, but might increase insulin secretion in patients with established type 2 diabetes.

Vitamin D and diabetes mellitus.

The vitamin D endocrine system in now recognized as subserving a wide range of fundamental biological functions in cell differentiation, inhibition of cell growth as well as immunomodulation. Both forms of immunity, namely adaptive and innate, are regulated by 1,25(OH)2D3. The immune-modulatory properties of vitamin D suggest that it could play a potential therapeutic role in prevention of type 1 diabetes mellitus (T1DM). It is postulated that large doses of vitamin D supplementation may influence the pattern of immune regulation and subsequent progression to T1DM in a genetically susceptible individual. More studies are required to substantiate the relation between T1DM and vitamin D/vitamin D analogues in the pattern of immune regulations in susceptible individuals. In type 2 diabetes mellitus (T2DM), vitamin D may influence both insulin secretion and sensitivity. An inverse relationship between T2DM and vitamin D is postulated from cross-sectional and prospective studies, though conclusive proof is as yet lacking. Available studies differ in their design and in the recommended daily allowances (RDA) of vitamin D in non-skeletal diseases and ß-cell function. Large, well designed, controlled, randomized interventional studies on the potential role of vitamin D and calcium in prevention and management of T2DM are required to clarify the relationship between vitamin D and glucose homeostasis in T2DM.

Type 2 diabetes, PUFAs, and vitamin D: their relation to inflammation.

Chronic diseases have become one of the most important public health problems, due to their high costs for treatment and prevention. Until now, researchers have considered that the etiology of Type 2 diabetes mellitus (T2DM) is multifactorial. Recently, the study of the innate immune system has offered an explanation model of the pathogenesis of T2DM. On the other hand, there is evidence about the beneficial effect of polyunsaturated fatty acids (PUFA) n-3 and n-6 in patients with chronic inflammatory diseases including diabetes. Furthermore, high vitamin D plasmatic concentrations have been associated with the best performance of pancreatic ß cells and the improving of this disease. In conclusion, certain fatty acids in the adequate proportion as well as 25-hydroxivitamin D can modulate the inflammatory response in diabetic people, modifying the evolution of this disease.

Treating diabetes with islet transplantation: lessons from the past decade in Lille.

Type 1 diabetes (T1D) is due to the loss of both beta-cell insulin secretion and glucose sensing, leading to glucose variability and a lack of predictability, a daily issue for patients. Guidelines for the treatment of T1D have become stricter as results from the Diabetes Control and Complications Trial (DCCT) demonstrated the close relationship between microangiopathy and HbA1c levels. In this regard, glucometers, ambulatory continuous glucose monitoring, and subcutaneous and intraperitoneal pumps have been major developments in the management of glucose imbalance. Besides this technological approach, islet transplantation (IT) has emerged as an acceptable safe procedure with results that continue to improve. Research in the last decade of the 20th century focused on the feasibility of islet isolation and transplantation and, since 2000, the success and reproducibility of the Edmonton protocol have been proven, and the mid-term (5-year) benefit-risk ratio evaluated. Currently, a 5-year 50% rate of insulin independence can be expected, with stabilization of microangiopathy and macroangiopathy, but the possible side-effects of immunosuppressants, limited availability of islets and still limited duration of insulin independence restrict the procedure to cases of brittle diabetes in patients who are not overweight or have no associated insulin resistance. However, various prognostic factors have been identified that may extend islet graft survival and reduce the number of islet injections required; these include graft quality, autoimmunity, immunosuppressant regimen and non-specific inflammatory reactions. Finally, alternative injection sites and unlimited sources of islets are likely to make IT a routine procedure in the future.

Transdisciplinary approach to restore pancreatic islet function.

The focus of our research is on islet immunobiology. We are exploring novel strategies that could be of assistance in the treatment and prevention of type 1 diabetes, as well as in the restoration of metabolic control via transplantation of insulin producing cells (i.e., islet cells). The multiple facets of diabetes and ß-cell replacement encompass different complementary disciplines, such as immunology, cell biology, pharmacology, and bioengineering, among others. Through their interaction and integration, a transdisciplinary dimension is needed in order to address and overcome all aspects of the complex puzzle toward a successful clinical translation of a biological cure for diabetes.

Maternal taurine supplementation in rats partially prevents the adverse effects of early-life protein deprivation on ß-cell function and insulin sensitivity.

Dietary protein restriction during pregnancy and lactation in rats impairs ß-cell function and mass in neonates and leads to glucose intolerance in adult offspring. Maternal taurine (Tau) supplementation during pregnancy in rats restores ß-cell function and mass in neonates, but its long-term effects are unclear. The prevention of postnatal catch-up growth has been suggested to improve glucose tolerance in adult offspring of low-protein (LP)-fed mothers. The objective of this study was to examine the relative contribution of ß-cell dysfunction and insulin resistance to impaired glucose tolerance in 130-day-old rat offspring of LP-fed mothers and the effects of maternal Tau supplementation on ß-cell function and insulin resistance in these offspring. Pregnant rats were fed i) control, ii) LP, and iii) LP+Tau diets during gestation and lactation. Offspring were given a control diet following weaning. A fourth group consisting of offspring of LP-fed mothers, maintained on a LP diet following weaning, was also studied (LP-all life). Insulin sensitivity in the offspring of LP-fed mothers was reduced in females but not in males. In both genders, LP exposure decreased ß-cell function. Tau supplementation improved insulin sensitivity in females and ß-cell function in males. The LP-all life diet improved ß-cell function in males. We conclude that i) maternal Tau supplementation has persistent effects on improving glucose metabolism (ß-cell function and insulin sensitivity) in adult rat offspring of LP-fed mothers and ii) increasing the amount of protein in the diet of offspring adapted to a LP diet after weaning may impair glucose metabolism (ß-cell function) in a gender-specific manner.

Effects of combination therapy with dipeptidyl peptidase-IV and histone deacetylase inhibitors in the non-obese diabetic mouse model of type 1 diabetes.

Type 1 diabetes (T1D) results from T helper type 1 (Th1)-mediated autoimmune destruction of insulin-producing ß cells. Novel experimental therapies for T1D target immunomodulation, ß cell survival and inflammation. We examined combination therapy with the dipeptidyl peptidase-IV inhibitor MK-626 and the histone deacetylase inhibitor vorinostat in the non-obese diabetic (NOD) mouse model of T1D. We hypothesized that combination therapy would ameliorate T1D by providing protection from ß cell inflammatory destruction while simultaneously shifting the immune response towards immune-tolerizing regulatory T cells (T(regs)). Although neither mono- nor combination therapies with MK-626 and vorinostat caused disease remission in diabetic NOD mice, the combination of MK-626 and vorinostat increased ß cell area and reduced the mean insulitis score compared to diabetic control mice. In prediabetic NOD mice, MK-626 monotherapy resulted in improved glucose tolerance, a reduction in mean insulitis score and an increase in pancreatic lymph node T(reg) percentage, and combination therapy with MK-626 and vorinostat increased pancreatic lymph node T(reg) percentage. We conclude that neither single nor combination therapies using MK-626 and vorinostat induce diabetes remission in NOD mice, but combination therapy appears to have beneficial effects on ß cell area, insulitis and T(reg) populations. Combinations of vorinostat and MK-626 may serve as beneficial adjunctive therapy in clinical trials for T1D prevention or remission.

Vanilloid receptors--do they have a role in whole body metabolism? Evidence from TRPV1.

With increasing lifespan, therapeutic interventions for the treatment of disorders such as type 2 diabetes mellitus are in great demand. Despite billions of dollars invested to reduce the symptoms and complications due to diabetes mellitus, current treatments (e.g., insulin replacements, sensitization) remain inadequate, justifying the search for novel therapeutic approaches or alternative solutions, including dietary supplementation, for the treatment of diabetes mellitus in every age group. The involvement of the vanilloid system in the regulation of metabolism has been identified, and the emerging role of its receptors, the transient receptor potential vanilloid type 1 (TRPV1), in diabetes was recently demonstrated. Indeed, beneficial effects of dietary capsaicin, an agonist of TRPV1 receptors, were identified for improving glucose, insulin and glucagon-like peptide-1 levels. Recent findings regarding TRPV1 receptors in association with whole body metabolism including glucose homeostasis will be reviewed in this article.

Anti-inflammatory action of Tamarind seeds reduces hyperglycemic excursion by repressing pancreatic ß-cell damage and normalizing SREBP-1c concentration.

CONTEXT: Tamarindus indica L. (Leguminosae) is widely used as a traditional medicine for the management of diabetes mellitus (DM) in India, in addition to its anti-inflammatory activity. The present study has been designed to understand the correlation involved between antidiabetic and anti-inflammatory action of aqueous seed extract of T. indica (TSE) in diabetic rats. OBJECTIVE: In view of the fact that fatty acid synthesis and insulin release from islets of pancreas are regulated by sterol regulatory element-binding proteins (SREBP-1c) and cytosolic calcium, respectively, the objectives of present study were to determine the influence of TSE on SREBP-1c mRNA and to investigate the intracellular islets calcium [Ca²âº](I) involvement and ß-cell mass preservation in insulin secretagogue action of TSE. MATERIALS AND METHODS: The effect of 4 weeks oral treatment (120 and 240 mg/kg) of high-performance liquid chromatography (HPLC) standardized TSE was studied in streptozotocin (STZ)-induced diabetic male Wistar rats. Reverse transcription-PCR (RT-PCR) and a spectrofluorometer were used for mRNA concentration and islets [Ca²âº](I) determination, respectively. The TUNEL assay was followed to study the pancreatic apoptosis. RESULTS: TSE (120 and 240 mg/kg) showed positive correlation with [Ca²âº](I) and insulin release. The anti-inflammatory action of TSE was significant on nitric oxide (NO) and tumor necrosis factor-α (TNF-α) in addition to a favorable effect on ß-cell neogenesis and improved mRNA concentration of SREBP-1c. DISCUSSION AND CONCLUSION: The results suggest that anti-inflammatory action of Tamarind seeds on ß-cell cells of islets and cytokines contribute toward its antidiabetic activity by way of complex mechanisms of [Ca²âº](I) handling and through SREBP-1c gene in liver.