A role for parasite-induced PGE2 in IL-10-mediated host immunoregulation by skin stage schistosomula of Schistosoma mansoni

Significant quantities of PGE(2) were produced by cercariae of Schistosoma mansoni following incubation with linoleic acid, a free fatty acid found on the surface of the skin. Cyclooxygenase (COX) 2 inhibitors failed to block this PGE(2) production, suggesting that a different biochemical pathway may be involved in the production of PGE(2) by the parasite. In addition, the parasites were also able to induce PGE(2) and IL-10 from human and mouse keratinocytes. Analysis of mouse skin during skin migratory phases of infection confirmed these in vitro observations. COX2 inhibitors blocked the parasite-induced PGE(2) and IL-10 from keratinocytes. Further analysis of the parasite secretions showed that the PGE(2)/IL-10-inducing effect was associated with a fraction <30 kDa molecular size. Addition of this fraction or parasite-stimulated keratinocyte culture supernatant to Con A-stimulated spleen cells resulted in the suppression of cell proliferation. This effect could be blocked by anti-IL-10 treatment. In sharp contrast, attenuation of the parasites with gamma-irradiation significantly abrogated their ability to induce PGE(2) or IL-10 from skin cells. Significance of IL-10 in host immunoregulation by skin stage schistosomula of S. mansoni was further confirmed by using IL-10-deficient mice. In these mice the normal subdued cutaneous reaction to the parasite was absent. Instead, a prominent cellular reaction occurred around the parasite, and there was considerable delay in parasitic migration through the skin. Thus these results suggest a key role for parasite-induced PGE(2) in IL-10-dependent down-regulation of host immune responses in the skin.     

Early variations of host thyroxine and interleukin-7 favor Schistosoma mansoni development

Schistosoma mansoni induces, in the vertebrate host, cutaneous production of interleukin-7 (IL-7), which is beneficial for parasite establishment and development. Infection of mice deficient in IL-7 expression leads to parasite dwarfism. Because similar findings were previously described in hypothyroid mice, this study aimed to elucidate the potential link between IL-7 and thyroid hormones (THs), using several models including hypo- and hyperthyroid mice, modified either transiently or constitutively. Mice treated with thyroxine led to increased worm numbers and development of giant worms, whereas an iodine-deficient diet reduced parasite maturation, egg laying, and liver pathology. Conversely, mice genetically deficient for either of the nuclear TH receptors displayed normal worm development despite modifications in hormone levels, suggesting that thyroxine action is mediated through host receptors. In addition, no modification of antibody titers has been evidenced in thyroxine-treated mice, whereas antibody levels were altered in transgenic animals. These observations suggest that the immune system is not likely to be involved in the modifications of parasite development reported in this study. Interestingly, concomitant treatment with IL-7 and thyroxine had a synergistic effect, leading to recovery of very large worms, thus raising questions about the complexity of interactions between IL-7 and metabolic hormones.     

成纤维细胞生长因子21对1型糖尿病动物模型的肝糖代谢影响及机制研究

成纤维细胞生长因子(FGF)-21是FGF家族的成员之一.作为近年发现的一种新的糖代谢调节因子,大量研究表明,FGF-21是一种不依赖胰岛素,能够独立降糖的2型糖尿病治疗潜力型药物.但是,能否应用于1型糖尿病的治疗,国内外目前尚无报道.通过改良传统造模方法,诱导小鼠缓慢产生糖耐量异常,研究FGF-21对此类模型的糖代谢影响及肝糖代谢机制.通过检测FGF-21短期注射和长期注射后模型动物血糖的变化,研究FGF-21在模型动物上对血糖的调控效果.采用实时定量PCR检测FGF-21对模型动物肝脏中葡萄糖转运蛋白(GLUT)1、4 mRNA的表达影响.利用蒽酮法检测模型动物肝脏中糖原合成量.实验结果显示,FGF-21能够调节1型糖尿病动物的血糖水平,并呈剂量依赖性.同时,首次在1型糖尿病动物模型上证实了低剂量FGF-21(0.125 mg/kg)与胰岛素的协同作用效果优于相同剂量FGF-21和胰岛素单独注射的效果.治疗结果表明,FGF-21能够维持1型糖尿病动物模型血糖在正常范围,效果优于胰岛素.实时定量PCR结果发现,与胰岛素上调GLUT4 mRNA表达量不同的是,FGF-21作用动物模型8周后,GLUT1 mRNA表达量显著提高,长期的FGF-21与胰岛素协同注射使GLUT1、4 mRNA表达量同时显著提高.长期FGF-21与胰岛素协同注射组和高剂量FGF-21注射均可显著提高模型动物肝糖原的合成.结果表明,FGF-21促进动物模型糖代谢机制与增加GLUT1表达、增加糖原合成作用有关.为临床应用FGF-21治疗1型糖尿病,增加胰岛素敏感性提供了理论依据.     

Antibodies to IL-3 and IL-4 suppress helminth-induced intestinal mastocytosis

Rodents infected with the nematode parasite Nippostrongylus brasiliensis (Nb) develop intestinal mastocytosis, eosinophilia, and elevated serum IgE levels. Although IL-4 and IL-5 are necessary for stimulation of IgE synthesis and eosinophilia, respectively, the cytokines that regulate gut mast cell hyperplasia have not been identified. To address this question, 6- to 8-wk-old BALB/c mice were injected on day 0 and day 7 of Nb infection with a rat anti-mouse IL-4 mAb, and with polyclonal sheep (day 0) and rabbit (day 7) anti-mouse IL-3 IgG antibodies. Additional Nb-infected mice received equal doses of isotype- and species-matched control antibodies. Mice were sacrificed on days 12 or 13 post-infection, and mucosal mast cells (MMC) in sections of the small intestine were enumerated. Nb infection induced a 25- to 40-fold increase in MMC over that observed in uninfected controls. Anti-IL-3 or anti-IL-4 alone suppressed the Nb-induced MMC response by 40 to 50%, whereas both antibodies combined suppressed the MMC response by 85 to 90%. Anti-IL-3 alone had no effect on the serum IgE levels, which were essentially abrogated in the Nb-infected mice treated with anti-IL-4. Blood eosinophilia was not affected by treatment with anti-IL-3 and/or anti-IL-4. These studies demonstrate that IL-3 and IL-4 are physiologically important stimuli of mastocytosis in vivo, and suggest therapeutic interventions that may counteract adverse host responses to allergens as well as to parasites.     

The pathogenic Th17 cell response to major schistosome egg antigen is sequentially dependent on IL-23 and IL-1β

CBA/J mice infected with the helminth Schistosoma mansoni develop severe CD4 T cell-mediated hepatic granulomatous inflammation against parasite eggs associated with a robust Th17 cell response. We investigated the requisites for Th17 cell development using novel CD4 T cells expressing a transgenic TCR specific for the major Sm-p40 egg Ag, which produce IL-17 when stimulated with live schistosome eggs. Neutralization of IL-23 or blockade of the IL-1 receptor, but not IL-6 neutralization, abrogated egg-induced IL-17 secretion by transgenic T cells, whereas exogenous IL-23 or IL-1β reconstituted their ability to produce IL-17 when stimulated by syngeneic IL-12p40-deficient dendritic cells. Kinetic analysis demonstrated that IL-17 production was initiated by IL-23 and amplified by IL-1β. Significantly, schistosome-infected IL-12p40-deficient or IL-1R antagonist-treated CBA/J mice developed markedly reduced hepatic immunopathology with a dampened egg Ag-specific IL-17 response. These results demonstrate that the IL-23-IL-1-IL-17 axis has a central role in the development of severe schistosome egg-induced immunopathology.     

Resistance in murine schistosomiasis is contingent on activated IL-2 receptor-bearing L3T4+ lymphocytes, negatively regulated by Lyt-2+ cells, and uninfluenced by the presence of IL-4

These studies assess the roles of subpopulations of T lymphocytes in inducing and modulating resistance to Schistosoma mansoni. C57BL/6 mice were depleted in vivo of L3T4+, Lyt-1+, Lyt-2+, IL-2R+ cells, or IL-4 by administration of appropriate mAb. Resistance and various correlative parameters of the immune response were studied in normal, depleted, and congenitally athymic mice. Depletion of T lymphocytes by anti-L3T4 or anti-IL-2R mAb reduced the development and expression of resistance, IgG2a and IgE antibody formation, and delayed type hypersensitivity reactivity against schistosome Ag. Depletion with anti-IL-4 antibody led to profound suppression of IgE-eosinophil-mediated antibody-dependent cell-mediated cytotoxicity and passive cutaneous anaphylaxis responses against the parasite and no effect on IgG2a antibody, Ag-mediated blast transformation, or resistance. Depletion of Lyt-2+ cells produced augmented development and expression of resistance and an increase in the immunological parameters of anti-schistosome reactivity. These studies suggest that protective immunity to S. mansoni in mice, induced by irradiated cercariae, is dependent on L3T4+, IL-2R+ lymphocytes and negatively regulated by Lyt-2+ cells. IL-4 does not appear to be essential for the development of resistance but is essential for the IgE response to the parasite.     

Characterization of an insulin receptor-related receptor in Biomphalaria glabrata embryonic cells

Tyrosine kinase receptors play a key role in the communication of cells with their environment. Growth hormone receptors, such as insulin receptors, are involved in the regulation of cell growth, differentiation and metabolism in multicellular organisms. Insulin-related peptides and members of the insulin receptor subfamily have been described in a wide variety of invertebrates, including freshwater molluscs. In this paper, we describe the metabolic effect of insulin on a mollusc cell line (Bge) derived from embryos of the snail Biomphalaria glabrata. Using a PCR strategy, we have cloned from Bge cells a cDNA encoding a protein (BgIR) homologous to, and exhibiting all of the typical features of insulin receptors. Northern blot analysis confirmed the expression of BgIR in B. glabrata snails and suggested its wide distribution in the snail body. Bge cells have been shown to provide the environmental conditions necessary for the in vitro development of the sporocysts of Schistosoma mansoni, a trematode parasite that uses B. glabrata as an intermediate host. The possible implication of BgIR in the activating and proliferating processes observed in Bge cells during their coculture with S. mansoni larvae is discussed.     

IL-10 and TGF-beta redundantly protect against severe liver injury and mortality during acute schistosomiasis

The cytokines IL-10 and TGF-beta regulate immunity and inflammation. IL-10 is known to suppress the extent of hepatic damage caused by parasite ova during natural infection with Schistosoma mansoni, but the role of TGF-beta is less clear. Cytokine blockade studies in mice revealed that anti-IL-10R mAb treatment during acute infection modestly increased cytokine production and liver damage, whereas selective anti-TGF-beta mAb treatment had marginal effects. In contrast, mice administered both mAbs developed severe hepatic inflammation, with enlarged, necrotic liver granulomas, cachexia, and >80% mortality by 8 wk postinfection, despite increased numbers of CD4(+)CD25(+)Foxp3(+) T regulatory cells. Blocking both IL-10 and TGF-beta at the onset of egg production also significantly increased IL-4, IL-6, TNF, IFN-gamma, and IL-17 production and markedly increased hepatic, peritoneal, and splenic neutrophilia. In contrast, coadministration of anti-IL-10R and TGF-beta mAbs had little effect upon parasite ova-induced intestinal pathology or development of alternatively activated macrophages, which are required to suppress intestinal pathology. This suggests that inflammation is controlled during acute S. mansoni infection by two distinct, organ-specific mechanisms: TGF-beta and IL-10 redundantly suppress hepatic inflammation while intestinal inflammation is regulated by alternatively activated macrophages.     

Role of IL-4 and IFN-gamma in Schistosoma mansoni egg-induced hypersensitivity granuloma formation. Orchestration, relative contribution, and relationship to macrophage function.

A well defined model of T cell-mediated hypersensitivity-type granulomatous inflammation induced by Schistosoma mansoni eggs was used to assess the role of IL-4 and IFN-gamma in granuloma development. Synchronized pulmonary granulomas were induced and isolated from S. mansoni-infected mice during vigorous (8 wk) and modulated (20 wk) stages of the disease. The sequential production of IL-4 and IFN was determined and related to temporal changes in granuloma macrophage production of IL-1, TNF, and superoxide anion (O2-). During the vigorous stage, IL-4 was produced on days 1 and 2 of granuloma formation, whereas IFN was released in greatest amounts on days 4 to 8. The peak of IL-4 occurred in a window between the peak of IL-1 (1 day) and maximal TNF production (8 to 16 days). Maximal O2- release tended to parallel IFN production. During the modulated stage when the inflammatory response is attenuated, IL-4 production was dramatically reduced as were levels of IL-1 and TNF, but IFN production persisted and maximum O2(-)-producing capacity was only delayed in onset. mAb specific for IL-4 and IFN were used to examine the effect of in vivo depletion of these cytokines on granuloma development. Administration of a single 1.0-mg dose of anti-IL-4 antibodies to mice with synchronously developing granulomas dramatically reduced granuloma size (40 to 50% suppression of area) during an 8-day study period, whereas antibodies to IFN had no effect on size. However, the latter treatment reduced giant cell formation. Our results indicate that granuloma development involves an orchestrated production of cytokines possibly resulting from sequential participation of different Th cell populations. Moreover, IL-4 is a pivotal cytokine in anamnestic cellular recruitment and subject to endogenous regulation.     

Effects of chronic calorie restriction or dietary resveratrol supplementation on insulin sensitivity markers in a primate, Microcebus murinus

The prevalence of diabetes and hyperinsulinemia increases with age, inducing metabolic failure and limiting lifespan. Calorie restriction (CR) without malnutrition delays the aging process, but its long-term application to humans seems difficult. Resveratrol (RSV), a dietary polyphenol, appears to be a promising CR mimetic that can be easily administered in humans. In this work, we hypothesized that both CR and RSV impact insulin sensitivity in a non-human primate compared to standard-fed control (CTL) animals. Four- to five-year-old male grey mouse lemurs (Microcebus murinus) were assigned to three dietary groups: a CTL group, a CR group receiving 30% fewer calories than the CTL and a RSV group receiving the CTL diet supplemented with RSV (200 mg·day(-1)·kg(-1)). Insulin sensitivity and glycemia were assessed using an oral glucose tolerance test (OGTT) and the homeostasis model assessment of insulin resistance (HOMA-IR index) evaluation after 21 or 33 months of chronic treatment. Resting metabolic rate was also measured to assess the potential relationships between this energy expenditure parameter and insulin sensitivity markers. No differences were found after a 21-month period of treatment, except for lower glucose levels 30 min after glucose loading in CR animals. After 33 months, CR and RSV decreased glycemia after the oral glucose loading without decreasing fasting blood insulin. A general effect of treatment was observed on the HOMA-IR index, with an 81% reduction in CR animals and 53% in RSV animals after 33 months of treatment compared to CTL. Chronic CR and dietary supplementation with RSV affected insulin sensitivity by improving the glucose tolerance of animals without disturbing their baseline insulin secretion. These results suggest that both CR and RSV have beneficial effects on metabolic alterations, although these effects are different in amplitude between the two anti-aging treatments and potentially rely on different metabolic changes.     

Association of the antidiabetic effects of bromocriptine with a shift in the daily rhythm of monoamine metabolism within the suprachiasmatic nuclei of the Syrian hamster

Bromocriptine, a dopamine D2 agonist, inhibits seasonal fattening and improves seasonal insulin resistance in Syrian hamsters. Alterations in daily rhythms of neuroendocrine activities are involved in the regulation of seasonal metabolic changes. Changes in circadian neuroendocrine activities that regulate metabolism are believed to be modulated by central circadian oscillators within the hypothalamic suprachiasmatic nuclei (SCN) of seasonal animals. We examined the association of metabolic responses to bromocriptine with its effects on the daily rhythms of metabolic hormones and daily monoamine profiles within the SCN, a primary circadian pacemaker known to regulate metabolism, in Syrian hamsters. Obese glucose-intolerant male Syrian hamsters (body weight [BW] 185 +/- 10 g) held on 14h daily photoperiods were treated at light onset with bromocriptine (800 microg/animal/day, ip) or vehicle for 2 weeks. Animals were then subjected to a glucose tolerance test (GTT) (3 g/kg BW, ip). Different subsets of animals (n = 6) from each treatment group were sacrificed at 0h/24h, 5h, 10h, 15h, or 20h after light onset for analyses of SCN monoamines, plasma insulin, prolactin, cortisol, thyroxin (T4), triiodothyronine (T3), glucose, and free fatty acids (FFAs). Compared with control values, bromocriptine treatment significantly reduced weight gain (14.9 vs. -2.9 g, p < .01) and the areas under the GTT glucose and insulin curves by 29% and 48%, respectively (p < .05). Basal plasma insulin concentration was markedly reduced throughout the day in bromocriptine-treated animals without influencing plasma glucose levels. Bromocriptine reduced the daily peak in FFA by 26% during the late light span (p < .05). Bromocriptine significantly shifted the daily plasma cortisol peak from the early dark to the light period of the day, reduced the plasma prolactin (mean 1.8 vs. 39.4 ng/dL) and T4 throughout the day (mean 1.6 vs. 3.8 microg/dL), and selectively reduced T3 during the dark period of the day (p < .01). Concurrently, bromocriptine treatment significantly reduced SCN dopamine turnover during the light period and shifted daily peaks of SCN serotonin and 5-hydroxy-indoleacetic acid (5-HIAA) content by 12h from the light to the dark period of the day (p < .05). This was confirmed by a further in vivo microdialysis study in which bromocriptine increased SCN extracellular 5-HIAA of glucose-intolerant hamsters during the dark phase (47% increase, p < .05) toward levels observed in normal glucose-tolerant hamsters. Thus, bromocriptine-induced resetting of daily patterns of SCN neurotransmitter metabolism is associated with the effects of bromocriptine on attenuation of the obese insulin-resistant and glucose-intolerant condition. A large body of corroborating evidence suggests that such bromocriptine-induced changes in SCN monoamine metabolism may be functional in its effects on metabolism.     

Portal vein hypoglycemia is essential for full induction of hypoglycemia-associated autonomic failure with slow-onset hypoglycemia

Antecedent hypoglycemia leads to impaired counterregulation and hypoglycemic unawareness. To ascertain whether antecedent portal vein hypoglycemia impairs portal vein glucose sensing, thereby inducing counterregulatory failure, we compared the effects of antecedent hypoglycemia, with and without normalization of portal vein glycemia, upon the counterregulatory response to subsequent hypoglycemia. Male Wistar rats were chronically cannulated in the carotid artery (sampling), jugular vein (glucose and insulin infusion), and mesenteric vein (glucose infusion). On day 1, the following three distinct antecedent protocols were employed: 1) HYPO-HYPO: systemic hypoglycemia (2.52 +/- 0.11 mM); 2) HYPO-EUG: systemic hypoglycemia (2.70 +/- 0.03 mM) with normalization of portal vein glycemia (portal vein glucose = 5.86 +/- 0.10 mM); and 3) EUG-EUG: systemic euglycemia (6.33 +/- 0.31 mM). On day 2, all groups underwent a hyperinsulinemic-hypoglycemic clamp in which the fall in glycemia was controlled so as to reach the nadir (2.34 +/- 0.04 mM) by minute 75. Counterregulatory hormone responses were measured at basal (-30 and 0) and during hypoglycemia (60-105 min). Compared with EUG-EUG, antecedent hypoglycemia (HYPO-HYPO) significantly blunted the peak epinephrine (10.44 +/- 1.35 vs. 15.75 +/- 1.33 nM: P = 0.01) and glucagon (341 +/- 16 vs. 597 +/- 82 pg/ml: P = 0.03) responses to next-day hypoglycemia. Normalization of portal glycemia during systemic hypoglycemia on day 1 (HYPO-EUG) prevented blunting of the peak epinephrine (15.59 +/- 1.43 vs. 15.75 +/- 1.33 nM: P = 0.94) and glucagon (523 +/- 169 vs. 597 +/- 82 pg/ml: P = 0.66) responses to day 2 hypoglycemia. Consistent with hormonal responses, the glucose infusion rate during day 2 hypoglycemia was substantially elevated in HYPO-HYPO (74 +/- 12 vs. 49 +/- 4 micromol x kg(-1) x min(-1); P = 0.03) but not HYPO-EUG (39 +/- 7 vs. 49 +/- 4 micromol x kg(-1) x min(-1): P = 0.36). Antecedent hypoglycemia local to the portal vein is required for the full induction of hypoglycemia-associated counterregulatory failure with slow-onset hypoglycemia.     

人源FGF-21在脂肪细胞糖代谢中的作用

近年来研究发现,成纤维细胞生长因子(FGF)-21是一种新的代谢调节因子.为了深入研究人源FGF-21（hFGF-21）的生物活性,本实验利用SUMO高效表达载体,高效表达成熟的hFGF-21,并利用小鼠3T3-L1脂肪细胞检测hFGF-21的糖代谢活性．实验结果表明,hFGF-21可促进脂肪细胞的葡萄糖吸收,且葡萄糖吸收效率呈剂量依赖性．hFGF-21作用4 h即可促进脂肪细胞糖吸收,其活性可持续24 h以上．hFGF-21与胰岛素共同作用的葡萄糖吸收效果,明显优于它们的单独作用结果,说明hFGF-21与胰岛素发挥协同作用．脂肪细胞经hFGF-21预处理后,显著增加了胰岛素促进脂肪细胞吸收葡萄糖的效率,说明hFGF-21可以增加胰岛素的敏感性．本实验为临床应用hFGF-21治疗糖尿病,增加胰岛素敏感性提供了依据．     

Accumulation of gammadelta T cells in the lungs and their regulatory roles in Th1 response and host defense against pulmonary infection with Cryptococcus neoformans

The present study was designed to elucidate the role of gammadelta T cells in the host defense against pulmonary infection with Cryptococcus neoformans. The gammadelta T cells in lungs commenced to increase on day 1, reached a peak level on day 3 or 6, and then decreased on day 10 after intratracheal infection. The increase of these cells was similar in monocyte chemoattractant protein (MCP)-1-deficient mice, although that of NK and NKT cells was significantly reduced. The number of live microorganisms in lungs on days 14 and 21 was significantly reduced in mice depleted of gammadelta T cells by a specific mAb compared with mice treated with control IgG. Similarly, elimination of this fungal pathogen was promoted in gammadelta T cell-deficient (TCR-delta(-/-)) mice compared with control littermate mice. Finally, lung and serum levels of IFN-gamma on days 7 and 14 and on day 7 postinfection, respectively, were significantly higher in TCR-delta(-/-) mice than in littermate mice, whereas levels of TGF-beta showed the opposite results. IL-4 and IL-10 were not different between these mice. IFN-gamma production by draining lymph node cells upon restimulation with cryptococcal Ags was significantly higher in the infected TCR-delta(-/-) mice than in control mice. Our results demonstrated that gammadelta T cells accumulated in the lungs in a manner different from NK and NKT cells after cryptococcal infection and played a down-modulatory role in the development of Th1 response and host resistance against this fungal pathogen.     

Vitamin K1 inversely correlates with glycemia and insulin resistance in patients with type 2 diabetes (T2D) and positively regulates SIRT1/AMPK pathway of glucose metabolism in liver of T2D mice and hepatocytes cultured in high glucose

There is no previous study in the literature that has examined the relationship between circulating vitamin K1 (VK1) with glycemic status in type 2 diabetes (T2D). Moreover, scientific explanation for the beneficial role of VK1 supplementation in lowering glycemia in diabetes is yet to be determined. This study for the first time demonstrated that circulating VK1 was significantly lower in T2D patients compared to age-matched control subjects, and VK1 levels in T2D were significantly and inversely associated with fasting glucose and insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR)], which suggest that boosting plasma VK1 may reduce the fasting glucose and insulin resistance in T2D patients. Using high-fat-diet-fed T2D animal model, this study further investigated the positive effect of VK1 supplementation on glucose metabolism and examined the underlying molecular mechanism. Results showed that VK1 supplementation [1, 3, 5 μg/kg body weight (BW), 8 weeks] dose dependently improved the glucose tolerance; decreased BW gain, fasting glucose and insulin, glycated hemoglobin, HOMA-IR and cytokine secretion (monocyte chemoattractant protein-1 and interleukin-6); and regulated the signaling pathway of hepatic glucose metabolism [sirtuin 1 (SIRT1)/AMP-activated protein kinase (AMPK)/phosphoinositide 3-kinase/phosphatase and tensin homolog/glucose transporter 2/glucokinase/glucose 6 phosphatase], lipid oxidation (peroxisome proliferator-activated receptor alpha/carnitine palmitoyltransferase 1A) and inflammation (nuclear factor kappa B) in T2D mice. Comparative signal silencing studies also depicted the role of SIRT1/AMPK in mediating the effect of VK1 on glucose metabolism, lipid oxidation and inflammation in high-glucose-treated cultured hepatocytes. In conclusion, this study demonstrates that circulating VK1 has a positive effect on lowering fasting glucose and insulin resistance in T2D via regulating SIRT1/AMPK signaling pathway.     

Serum Proteome Pool Changes in Type 2 Diabetic Patients Treated with Anakinra

Introduction

High glucose concentrations induce the production of IL-1β in human pancreatic beta cells leading to impaired insulin secretion, decreased cell proliferation and apoptosis. Blockade of IL-1 signalling with the recombinant human IL-1 receptor antagonist anakinra reduces HbA_1c in patients with type 2 diabetes. The aims of the present study were to identify: (1) candidate surrogates for improved glycemia in type 2 diabetic patients following treatment with anakinra, (2) proteins that change serum concentration because of anakinra treatment and (3) candidate biomarkers that may predict improved glycemia in type 2 diabetic subjects treated with anakinra.

Methods

Surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry was used to analyse serum from 67 type 2 diabetic patients who had received either placebo or anakinra for 13 weeks. Immunodepletion with magnetic protein G bead-coupled antibodies were used to identify three proteins and Western blotting confirmed the biomarker concentration pattern of four proteins.

Results

Twelve proteins, including transthyretin (TTR) and transferrin (Tf), were identified as candidate surrogates for improved glycemia. Six proteins, including retinol-binding protein 4 (RPB4) and a protein tentatively identified as modified apolipoprotein-A1 (apo-AI), increased expression as a consequence of anakinra treatment and four proteins were candidate biomarkers that may predict improved glycemia following anakinra treatment. Furthermore, we found increased RBP4 to be associated with improved beta cell secretory function and increased TTR, RBP4 and modified apo-AI (peak at 28,601 Da) to be associated with decreased inflammation.

Conclusions

Anakinra-induced changes in the serum proteome pool associated with a decreased cardiovascular disease risk, reduced inflammation and improved beta cell secretory function.     

Miglitol (BAY m 1099) Treatment of Diabetic Hypothalamic-Dietary Obese Rats Improves Islet Response to Glucose

AXEN, KATHLEEN V., XUE LI, AND ANTHONY SCLAFANI. Miglitol (BAY m 1099) treatment of diabetic hypothalamic-dietary obese rats improves islet response to glucose. Obes Res. 1999;7:83–89. Objective : The well-absorbed α-glucosidase inhibitor, miglitol (BAY m 1099), was included in the diets of hypothalamic-dietary obese diabetic rats to investigate its ability to improve glycemia and thereby reverse glucotoxic effects on islet secretory response. Research Methods and Procedures : Female rats received bilateral electrolytic lesions of the ventromedial hypothalamus and were fed high-fat, sucrosesupplemented diets until hyperinsulinemia and hyperglycemia were observed after 3 hours of food deprivation (nonfed). Diabetic animals were assigned to miglitol-treated (40 mg/17 g of diet) or untreated groups for 3 weeks; pancreatic islets were isolated for incubation experiments. Results : No differences in food intake, body weights, or nonfed plasma glucose or insulin levels were seen between treated and untreated diabetic rats. Islets isolated from untreated diabetic rats showed elevated basal insulin release and no insulin secretory response to an elevation in glucose concentration. In contrast, islets obtained from miglitol-treated rats showed more normal basal release and a significant insulin secretory response to glucose. Incubation of islets, obtained from normal control rats or untreated diabetic rats, in media containing miglitol at levels estimated to exist in plasma of treated rats had no effect on islet insulin secretory responses to glucose. Discussion : Islet secretory response was improved despite continued hyperglycemia and severe insulin resistance. Miglitol treatment may improve islet sensitivity to glucose either through effects on islet metabolism requiring prolonged exposure or by improvement in postmeal glycemia, despite persistent hyperglycemia.     

Sativa seeds against Schistosoma mansoni different stages

The schistosomicidal properties of Nigella sativa seeds were tested in vitro against Schistosoma mansoni miracidia, cercariae, and adult worms. Results indicate its strong biocidal effects against all stages of the parasite and also showed an inhibitory effect on egg-laying of adult female worms. In the present work we also studied the effects of crushed seeds on some antioxidant enzymes; which have a role in protection of adult worms against host oxidant killing; as well as some enzymes of glucose metabolism; which have a crucial role in the survival of adult worms inside their hosts. The data revealed that the used drug induce an oxidative stress against adult worms which indicated by a decrease in the activities of both antioxidant enzymes, superoxide dismutase, glutathione peroxidase, and glutathione reductase and enzymes of glucose metabolism, hexokinase and glucose-6-phosphate dehydrogenase. Disturbing of such enzymes of adult worms using N. sativa seeds could in turn render the parasite vulnerable to damage by the host and may play a role in the antischistosomal potency of the used drug.     

HIV-1 protease inhibitors induce an increase of triglyceride level in HIV-infected men without modification of insulin sensitivity: a longitudinal study.

We investigated longitudinally the effect of protease inhibitors (PI) on insulin sensitivity, glycemia, and serum lipids in HIV-infected patients. Ninety-one consecutive patients treated with PI for at least 12 months were included in this study. Fasting glycemia, lipid profile, insulinemia, CD4 T lymphocytes, and plasma HIV-1 RNA were performed at baseline and on PI therapy. Insulin sensitivity and insulin secretion were measured by the homeostasis model assessment (HOMA MODEL) using the fasting glucose and insulin concentrations. Triglycerides (+ 0.34 mmol/l, SD = 1.07, p = 0.001) and cholesterol (+ 1.07 mmol/l, SD = 1.21, p= 0.001) significantly increased on PI therapy. Fasting glycemia, insulin sensitivity, and insulin secretion were not modified after PI therapy. PI therapy significantly increased body mass index (0.35 kg/m2, p < 0.05). Serum lipid changes correlated with changes in the CD4+ cell count. Lipodystrophy was observed in 40.6% of patients treated with PI. Our longitudinal study found that PI therapy had no major impact on fasting glycemia, insulin sensitivity, and insulin secretion. These findings are not consistent with previous cross-sectional studies, which did not include baseline measurements before PI initiation. However, we observed a similar profile of lipid changes induced by PI therapy. These results suggest that PI could be responsible for the development of hypertriglyceridemia by a mechanism independent of insulin resistance which remains to be elucidated.