Biomedical subjects

Jerry L Nadler

Publications and source records attributed to Jerry L Nadler.

At least 19 recordsLinked to original sources

PubMed2025

Large-scale multi-omics analyses in Hispanic/Latino populations identify genes for cardiometabolic traits.

Here, we present a multi-omics study of type 2 diabetes and quantitative blood lipid and lipoprotein traits conducted to date in Hispanic/Latino populations (nmax = 63,184). We conduct a meta-analysis of 16 type 2 diabetes and 19 lipid trait GWAS, identifying 20 genome-wide significant loci for type 2 diabetes, including one novel locus and novel signals at two known loci, based on fine-mapping. We also identify sixty-one genome-wide significant loci across the lipid/lipoprotein traits, including nine novel loci, and novel signals at 19 known loci through fine-mapping. Next, we analyze genetically regulated expression, perform Mendelian randomization, and analyze association with transcriptomic and proteomic measure using multi-omics data from a Hispanic/Latino population. Using this approach, we identify genes linked to type 2 diabetes and lipid/lipoprotein traits, including TMEM205 and NEDD9 for HDL cholesterol, TREH for triglycerides, and ANXA4 for type 2 diabetes.

Female↗

PubMed2006

The role of 12/15-lipoxygenase in the expression of interleukin-6 and tumor necrosis factor-alpha in macrophages.

12/15-lipoxygenase (12/15-LO) enzyme and products have been associated with inflammation and atherosclerosis. However, the mechanism of effects of the 12/15-LO products has not been fully clarified. To study the role of 12/15-LO in cytokine expression, experiments with direct additions of the12/15-LO products, 12(S)-hydroxyeicosa tetraenoic acid or 12(S)-hydroperoxyeicosa-5Z, 8Z, 10E, or 14Z-tetraenoic acid to macrophages were first carried out, and results showed that the 12/15-LO products stimulated mRNA and protein expression of IL-6 and TNF-alpha in a dose-dependent manner. In contrast, an inactive analogue of 12(S)-hydroxyeicosa tetraenoic acid had no effect. To further explore the role of endogenous 12/15-LO in cytokine expression, we used an in vitro and in vivo model to test the effect of 12/15-LO overexpression. The models included Plox-86 cells, a J774A.1 cell line that stably overexpresses leukocyte-type 12/15-LO and primary mouse peritoneal macrophages (MPMs) from 12/15-LO transgenic mice. The results showed a clear increase in IL-6 and TNF-alpha expression in Plox-86 cells and MPMs from 12/15-LO transgenic mice, compared with mock-transfected J774A.1 cells and MPMs from control C57BL6 mice. IL-1beta, IL-12, and monocyte chemoattractant protein (MCP)-1 mRNA were also increased in Plox-86 cells. These data clearly suggest a clear role of 12/15-LO pathway in cytokine production. We also demonstrated that signaling pathways including protein kinase C, p38 MAPK (p38), c-jun NH(2)-terminal kinase as well as nicotinamide adenine dinucleotide phosphate oxidase are important for 12-(S)-hydroxyeicosatetraenoic acid-induced increases in IL-6 and TNF-alpha gene expression. These results suggest a potentially important mechanism linking 12/15-LO activation to chronic inflammation and atherosclerosis.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗

PubMed2006

Insulin and glucose play a role in foam cell formation and function.

BACKGROUND: Foam cell formation in diabetic patients often occurs in the presence of high insulin and glucose levels. To test whether hyperinsulinemic hyperglycemic conditions affect foam cell differentiation, we examined gene expression, cytokine production, and Akt phosphorylation in human monocyte-derived macrophages incubated with two types of oxidized low density lipoprotein (LDL), minimally modified LDL (mmLDL) and extensively oxidized LDL (OxLDL). METHODS AND RESULTS: Using Affymetrix GeneChip arrays, we found that several genes directly related to insulin signaling were changed. The insulin receptor and glucose-6-phosphate dehydrogenase were upregulated by mmLDL and OxLDL, whereas insulin-induced gene 1 was significantly down-regulated. In hyperinsulinemic hyperglycemic conditions, modified LDL upregulated Akt phosphorylation and expression of the insulin-regulated aminopeptidase. The level of proinflammatory cytokines, IL-lbeta, IL-12, and IL-6, and of a 5-lipoxygenase eicosanoid, 5-hydroxyeicosatetraenoic acid (5-HETE), was also increased. CONCLUSION: These results suggest that the exposure of macrophages to modified low density lipoproteins in hyperglycemic hyperinsulinemic conditions affects insulin signaling and promotes the release of proinflammatory stimuli, such as cytokines and eicosanoids. These in turn may contribute to the development of insulin resistance.

Cell Differentiation↗

PubMed2006

Synthesis and biological evaluation of lisofylline (LSF) analogs as a potential treatment for Type 1 diabetes.

Lisofylline (LSF, 1-(5-R-hydroxyhexyl)-3,7-dimethylxanthine) is an anti-inflammatory agent that protects beta-cells from Th1 cytokine-induced dysfunction and reduces the onset of Type 1 diabetes in non-obese diabetic (NOD) mice. Due to its low potency, poor oral bioavailability, and short half-life, the widespread clinical utility of LSF may be limited. Our goal has been to develop new agents based on the LSF structural motif that resolve the potency and pharmacokinetic liabilities of LSF. In this study, we have generated a focused library of LSF analogs that maintain the side chain (5-R-hydroxyhexyl) constant, while substituting a variety of nitrogen-containing heterocyclic substructures for the xanthine moiety of LSF. This library includes the xanthine-like (5-aza-7-deazaxanthine), as well as non-xanthine-like skeletons. The LSF analogs were evaluated in a pancreatic beta-cell line for the effects on apoptosis protection and insulin release. The metabolic stability of selected compounds was also tested.

Animals↗

PubMed2006

Combined treatment with lisofylline and exendin-4 reverses autoimmune diabetes.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease leading to near complete pancreatic beta-cell destruction. New evidence suggests that beta-cell regeneration is possible, but ongoing autoimmune damage prevents restoration of beta-cell mass. We tested the hypothesis that simultaneously blocking autoimmune cytokine damage and supplying a growth-promoting stimulus for beta-cells would provide a novel approach to reverse T1DM. Therefore, in this study we combined lisofylline to suppress autoimmunity and exendin-4 to enhance beta-cell proliferation for treating autoimmune-mediated diabetes in the non-obese diabetic (NOD) mouse model. We found that this combined therapy effectively reversed new-onset diabetes within a week of therapy, and even maintained euglycemia up to 145 days after treatment withdrawal. The therapeutic effect of this regimen was associated with improved beta-cell metabolism and insulin secretion, while reducing beta-cell apoptosis. It is possible that such combined therapy could become a new strategy to defeat T1DM in humans.

Animals↗

PubMed2006

Elevated glucose and diabetes promote interleukin-12 cytokine gene expression in mouse macrophages.

Inflammation is emerging as an important mechanism for micro- and macrovascular complication of diabetes. The macrophage plays a key role in the chronic inflammatory response in part by generating particular cytokines. IL-1beta, IL-6, IL12, IL-18, TNFalpha, and interferon-gamma are produced primarily in macrophages and have been associated with accelerated atherosclerosis and altered vascular wall function. In this study, we evaluated the effect and mechanism of high glucose (HG) on gene expression of these cytokines in mouse peritoneal macrophages (MPM). HG led to a 2-fold increase in the mRNA expression of these cytokines, with IL-12 showing the highest activation (5.4-fold) in a time-dependent (3-12 h) and dose-dependent (10, 17.5, and 25 mmol/liter) manner. The effects were specific to HG because mannitol and 3-O-methyl-glucose had no effect on cytokine mRNA expression. HG also increased IL-12 protein accumulation from MPM. We also explored the role of induced and spontaneous diabetes on inflammatory cytokine expression in MPM. Increases in expression in MPM of multiple inflammatory cytokines, including a 20-fold increase in IL-12 mRNA, were observed in streptozotocin-induced type 1 diabetic mice as well as type 2 diabetic db/db mice, suggesting that cytokine gene expression is increased by hyperglycemia in vivo. We next explored potential mechanisms of HG-induced increases in IL-12 mRNA. HG increased the activity of protein kinase C, p38 MAPK (p38), c-Jun terminal kinase, and inhibitory-kappaB kinase in MPM. Furthermore, inhibitors of these signaling pathways significantly reduced HG-induced IL-12 mRNA expression in MPM. These results provide evidence for a potentially important mechanism linking elevated glucose and diabetes to inflammation.

Animals↗

PubMed2006

Lifestyle intervention in obese patients with type 2 diabetes: impact of the patient's educational background.

OBJECTIVE: To determine whether people with different educational backgrounds respond differently to a lifestyle intervention program for obese patients with type 2 diabetes. RESEARCH METHODS AND PROCEDURES: The study consisted of a 12-month randomized controlled trial of 147 health plan members with type 2 diabetes who were overweight or obese (BMI > or = 27 kg/m(2)). Participants were randomized to lifestyle case management or usual care. Case management (CM) involved group and individual education, support, and referral by registered dietitians. Usual care (UC) participants received educational material. Both groups received ongoing primary care. A post hoc analysis was performed, evaluating the impact of education level on intervention group differences with respect to change in weight and waist circumference. RESULTS: There was a significant education by group interaction for both changes in weight (p = 0.02) and waist circumference (p = 0.01) during the study period. Contrary to expectations, CM participants with less formal education had greater risk reductions compared with more educated participants. Models predicted that, by 12 months, those with less education in the UC group gained 1.71 kg more in weight and 3.67 cm more in waist circumference than those with greater education. However, by 12 months, those in the CM group with less education lost a model-predicted 3.30 kg more in weight and 4.95 cm more in waist circumference than those with more formal education. DISCUSSION: People with varied educational backgrounds may respond differently to a lifestyle intervention for weight management and diabetes control.

Adult↗

PubMed2006

The thromboxane receptor antagonist S18886 attenuates renal oxidant stress and proteinuria in diabetic apolipoprotein E-deficient mice.

Arachidonic acid metabolites, some of which may activate thromboxane A(2) receptors (TPr) and contribute to the development of diabetes complications, including nephropathy, are elevated in diabetes. This study determined the effect of blocking TPr with S18886 or inhibiting cyclooxygenase with aspirin on oxidative stress and the early stages of nephropathy in streptozotocin-induced diabetic apolipoprotein E(-/-) mice. Diabetic mice were treated with S18886 (5 mg . kg(-1) . day(-1)) or aspirin (30 mg . kg(-1) . day(-1)) for 6 weeks. Neither S18886 nor aspirin affected hyperglycemia or hypercholesterolemia. There was intense immunohistochemical staining for nitrotyrosine in diabetic mouse kidney. In addition, a decrease in manganese superoxide dismutase (MnSOD) activity was associated with an increase in MnSOD tyrosine-34 nitration. Tyrosine nitration was significantly reduced by S18886 but not by aspirin. Staining for the NADPH oxidase subunit p47(phox), inducible nitric oxide synthase, and 12-lipoxygenase was increased in diabetic mouse kidney, as were urine levels of 12-hydroxyeicosatetraenoic acid and 8-iso-prostaglandin F(2alpha). S18886 attenuated all of these markers of oxidant stress and inflammation. Furthermore, S18886 significantly attenuated microalbuminuria in diabetic mice and ameliorated histological evidence of diabetic nephropathy, including transforming growth factor-beta and extracellular matrix expression. Thus, in contrast to inhibiting cyclooxygenase, blockade of TPr may have therapeutic potential in diabetic nephropathy, in part by attenuating oxidative stress.

Animals↗

PubMed2005

Activation of the 12-lipoxygenase and signal transducer and activator of transcription pathway during neointima formation in a model of the metabolic syndrome.

Insulin resistance (IR) is associated with an increased risk of cardiovascular diseases. The obese Zucker rat (ZR) is a model of IR that shows markedly increased insulin and triglyceride concentrations without major changes in glucose. In this study, we evaluated the response of obese and lean ZR to carotid balloon injury and determined potential mechanisms and treatments. The neointima-to-media ratio of obese ZR was greater than that of lean ZR, starting at 14 days after injury, and persisted until at least day 30. An enhanced inflammatory response to balloon injury in the obese ZR was reflected by significantly higher ED1-positive macrophage cells in the injured vessel wall compared with that in lean ZR at 3, 7, and 14 days after balloon injury. Inflammatory mediators 12-lipoxygenase (12-LO) and STAT4 were studied in neointimal lesions. Expression of 12-LO RNA was increased beginning at day 7 and showed increases of 4.3-fold on day 14 and 7-fold on day 30 in obese ZR compared with lean animals. Staining of phosphorylated STAT4 (PSTAT4), the activated form of STAT4, in lesions from obese ZR was also increased compared with that in leans. We tested the effects of a novel anti-inflammatory agent, lisofylline (LSF), in the obese ZR. LSF markedly reduced neointimal formation in the obese ZR. LSF also reduced monocyte/macrophage infiltration into the vessel wall and the activation of PSTAT4. These studies suggest both the presence of an exaggerated injury response in the insulin-resistant obese ZR model and that inflammation plays a major role in mediating neointimal growth.

Angioplasty, Balloon↗

PubMed2005

The effects of leukocyte-type 12/15-lipoxygenase on Id3-mediated vascular smooth muscle cell growth.

OBJECTIVE: 12/15-lipoxygenase (12/15-LO) has been implicated in the pathogenesis of vascular disease. Vascular smooth muscle cell (VSMC) proliferation is a key component of the response to injury in vascular disease. The role of 12/15-LO in regulating VSMC proliferation is poorly understood. Id3 has been shown to regulate growth in various cell types and is expressed in VSMCs within atherosclerotic and restenotic lesions. This study examines the role of Id3 in 12/15-LO-mediated VSMC proliferation. METHODS AND RESULTS: Primary aortic VSMCs from leukocyte-type 12/15-LO transgenic, leukocyte-type 12/15-LO knockout (KO), and control mice were plated in equal densities and assayed for growth, Id3 protein expression, and Id3 transcription. Results demonstrated that 12/15-LO transgenic VSMCs grew faster, whereas 12/15-LO KO VSMCs grew slower relative to control VSMCs. Further, pharmacological and molecular inhibition of 12/15-LO resulted in decreased VSMC growth. Western blots demonstrated increased Id3 protein in 12/15-LO transgenic VSMCs, whereas luciferase promoter reporter assays revealed increased Id3 transcription. In addition, overexpression of 12/15-LO increased growth in control cells but not in Id3 KO cells. 12/15-LO transgenic VSMCs demonstrated increased protein kinase C (PKC) activity. Consistent with these data, PKC inhibition decreased Id3 promoter activation. CONCLUSIONS: 12/15-LO is an important mediator of VSMC growth. The growth-promoting effects of 12/15-LO are at least partially mediated through induction of Id3 transcription.

Animals↗

PubMed2005

Lisofylline: a potential lead for the treatment of diabetes.

Lisofylline (LSF), a synthetic modified methylxanthine, was originally designed and tested as an agent to reduce mortality during serious infections associated with cancer chemotherapy. Experimental studies and several clinical trials showed that LSF inhibited the generation of phosphatidic acid and free fatty acids. LSF also blocked the release of pro-inflammatory cytokines in oxidative tissue injury, in response to cancer chemotherapy and in experimental sepsis. Recent research has revealed a new potential to extend the therapeutic application of LSF especially for diabetes mellitus. These new studies demonstrate multiple actions of LSF in the regulation of immune cell function and autoimmune response by inhibition of IL-12 signalling and cytokine production. Supporting the new potential for LSF is the discovery of beneficial effects in protecting pancreatic beta cells and in preventing autoimmunity. In this article, these new observations about LSF are reviewed and a strategy proposed for using this compound in new clinical applications. LSF may, thus, have therapeutic value in the prevention of autoimmune disorders, including Type 1 diabetes, and autoimmune recurrence following islet transplantation, and in preservation of beta cell functional mass during islet isolation.

Animals↗

PubMed2005

Elevated glucose activates protein synthesis in cultured cardiac myocytes.

Diabetes mellitus results in chronic hyperglycemia, a serious metabolic disorder associated with a markedly increased risk of cardiovascular disease. However, the effects of high glucose (HG) on cardiac myocyte growth have not been fully clarified. In this study, the effect of glucose on cardiac myocyte growth was examined using leucine incorporation as an index of protein synthesis. High glucose (HG, 25 mmol/L) increased leucine incorporation (167% +/- 0.2% over normal glucose, n=4, P<.01) compared with a physiological glucose concentration (5.5 mmol/L, normal glucose). The HG-induced increase in leucine incorporation was time- and dose-dependent and was not due to osmotic changes because 25 mmol/L mannitol did not change leucine incorporation. High glucose also significantly reduced elongation factor 2 phosphorylation, an effect known to result in increased protein synthesis at the elongation step. Western blot analysis showed that HG-activated protein kinase B (PKB), also called Akt (PKB/Akt), at 18 hours. High glucose-induced leucine incorporation was attenuated with phosphatidylinositol 3-kinase (PI3K) inhibition using wortmannin and LY294002 and by rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, 72%, 64%, and 65% (P<.05), respectively. High glucose also activated extracellular signal-regulated kinase 1/2 activity with peak stimulation at 5 minutes. In addition, PD98059, an inhibitor of mitogen-activated protein kinase kinase, attenuated HG-induced leucine incorporation. These data show for the first time that elevated glucose increases protein synthesis in cardiac myocytes. The increase appears to be mediated by activation of PI3K-PKB/Akt and/or PI3K-mTOR as well as extracellular signal-regulated kinase 1/2. These results provide new evidence for a direct effect of glucose independent of insulin on cardiac myocyte growth.

Animals↗

PubMed2005

Viral IL-10-mediated immune regulation in pancreatic islet transplantation.

Protection of transplanted pancreatic islet grafts in recipients with autoimmune diabetes depends on the suppression of autoimmune recurrence and allogeneic rejection. The aim of this study was to investigate the efficiency of viral IL-10 gene delivery in the prevention of autoimmune recurrence following islet transplantation. We evaluated the effectiveness of a systemically delivered adeno-associated viral vector (AAV vIL-10) carrying viral IL-10 in protecting islet engraftment. We observed significant prolongation of graft survival after treatment with AAV vIL-10 when using islets from donors lacking autoimmunity. We found that the mechanism of vIL-10-mediated protection was associated with suppression of T cell activation and that donor immune cells that were simultaneously transferred with the islet grafts could induce autoimmune recurrence. AAV vIL-10 gene transfer suppressed previously activated T cells and protected grafted islets from autoimmune-mediated destruction. We conclude that vIL-10 can regulate autoimmune activity and that transfer of its gene may have potential for therapeutic islet transplantation.

Adenoviridae↗

PubMed2005

Inflammatory blockade improves human pancreatic islet function and viability.

The pathogenesis of pancreatic beta-cell death in diabetes mellitus is still under investigation. Inflammation is likely to be one of the factors responsible for beta-cell death during disease development. In this study, we have used a novel antiinflammatory compound, Lisofylline (LSF), to investigate the role of inflammatory blockade in protecting human pancreatic islets. LSF is a small synthetic molecule that reduces inflammatory cytokine production and action, improves beta-cell mitochondrial metabolism, and regulates immune activities. The present study has demonstrated that the treatment of human islets with LSF not only allows the retention of glucose responsiveness and insulin secretion in the presence of multiple proinflammatory cytokines, but also enhances basal insulin secretion of beta cells in vitro. LSF also significantly reduces islet apoptosis, protects beta cells from proinflammatory cytokine damage, and maintains cellular viability. In a mouse transplantation model, insulin independence could be reached in diabetic recipient mice by implantation of 30% fewer islets when LSF was used in islet culture compared to the control group. These results demonstrate that LSF profoundly enhances beta-cell function, and suggest the potential of using inflammatory blockade, such as LSF, to improve beta-cell function for islet transplantation.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2005

Magnesium deficiency is associated with insulin resistance in obese children.

OBJECTIVE: Magnesium deficiency has been associated with insulin resistance (IR) and increased risk for type 2 diabetes in adults. This study was designed to determine whether obese children exhibit serum or dietary magnesium deficiency and its potential association with IR. RESEARCH DESIGN AND METHODS: We studied 24 obese nondiabetic children (BMI > or =85th percentile) and 24 sex- and puberty-matched lean control subjects (BMI <85th percentile). We measured serum magnesium, indexes of insulin sensitivity, dietary magnesium intake (using a food frequency questionnaire), and body composition (by air displacement plethysmography). RESULTS: Serum magnesium was significantly lower in obese children (0.748 +/- 0.015 mmol/l, means +/- SE) compared with lean children (0.801 +/- 0.012 mmol/l) (P = 0.009). Serum magnesium was inversely correlated with fasting insulin (r(s) = -0.36 [95% CI -0.59 to -0.08]; P = 0.011) and positively correlated with quantitative insulin sensitivity check index (QUICKI) (0.35 [0.06-0.58]; P = 0.015). Dietary magnesium intake was significantly lower in obese children (obese: 0.12 +/- 0.004 vs. lean: 0.14 +/- 0.004 mg/kcal; P = 0.003). Dietary magnesium intake was inversely associated with fasting insulin (-0.43 [-0.64 to -0.16]; P = 0.002) and directly correlated with QUICKI (0.43 [0.16-0.64]; P = 0.002). CONCLUSIONS: The association between magnesium deficiency and IR is present during childhood. Serum magnesium deficiency in obese children may be secondary to decreased dietary magnesium intake. Magnesium supplementation or increased intake of magnesium-rich foods may be an important tool in the prevention of type 2 diabetes in obese children.

Adipose Tissue↗

PubMed2004

Critical role of macrophage 12/15-lipoxygenase for atherosclerosis in apolipoprotein E-deficient mice.

BACKGROUND: Mice lacking leukocyte type 12/15-lipoxygenase (12/15-LO) show reduced atherosclerosis in several models. 12/15-LO is expressed in a variety of cells, including vascular cells, adipocytes, macrophages, and cardiomyocytes. The purpose of this study was to determine which cellular source of 12/15-LO is important for atherosclerosis. METHODS AND RESULTS: Bone marrow from 12/15-LO-/-/apoE-/- mice was transplanted into apoE-/- mice and vice versa. Deficiency of 12/15-LO in bone marrow cells protected apoE-/- mice fed a Western diet from atherosclerosis to the same extent as complete absence of 12/15-LO, although plasma 8,12-iso-iPF2alpha-IV, a measure of lipid peroxidation, remained elevated. 12/15-LO-/-/apoE-/- mice regained the severity of atherosclerotic lesion typical of apoE-/- mice after replacement of their bone marrow cells with bone marrow from apoE-/- mice. Peritoneal macrophages obtained from wild-type but not 12/15-LO-/- mice caused endothelial activation in the presence of native LDL. Absence of 12/15-LO decreased the ability of macrophages to form foam cells when exposed to LDL. CONCLUSIONS: We conclude that macrophage 12/15-LO plays a dominant role in the development of atherosclerosis by promoting endothelial inflammation and foam cell formation.

Animals↗

PubMed2004

Lipid inflammatory mediators in diabetic vascular disease.

Type 2 diabetes is associated with significantly accelerated rates of macrovascular complications such as atherosclerosis. Emerging evidence now indicates that atherosclerosis is an inflammatory disease and that certain inflammatory markers may be key predictors of diabetic atherosclerosis. Proinflammatory cytokines and cellular adhesion molecules expressed by vascular and blood cells during stimulation by growth factors and cytokines seem to play major roles in the pathophysiology of atherosclerosis and diabetic vascular complications. However, more recently, data suggest that inflammatory responses can also be elicited by smaller oxidized lipids that are components of atherogenic oxidized low-density lipoprotein or products of phospholipase activation and arachidonic acid metabolism. These include oxidized lipids of the lipoxygenase and cyclooxygenase pathways of arachidonic acid and linoleic acid metabolism. These lipids have potent growth, vasoactive, chemotactic, oxidative, and proinflammatory properties in vascular smooth muscle cells, endothelial cells, and monocytes. Cellular and animal models indicate that these enzymes are induced under diabetic conditions, have proatherogenic effects, and also mediate the actions of growth factors and cytokines. This review highlights the roles of the inflammatory cyclooxygenase and 12/15-lipoxygenase pathways in the pathogenesis of diabetic vascular disease. Evidence suggests that inflammatory responses in the vasculature can be elicited by small oxidized lipids that are components of oxidized low-density lipoprotein or products of the lipoxygenase and cyclooxygenase pathways of arachidonic and linoleic acid metabolism. This review evaluates these inflammatory and proatherogenic pathways in the pathogenesis of diabetic vascular disease.

Animals↗

PubMed2004

The novel anti-inflammatory agent lisofylline prevents autoimmune diabetic recurrence after islet transplantation.

BACKGROUND: Pancreatic islet transplantation has become a promising treatment for type 1 diabetes. However, autoimmune reactivity destroys engrafted islets in type 1 diabetic recipients. The authors' previous studies demonstrated that a novel anti-inflammatory agent, lisofylline (LSF), suppressed autoimmune reactivity and protected nonobese diabetic (NOD) mice from diabetes. In this study, the authors investigated the potential of LSF in preventing autoimmune diabetes recurrence after islet transplantation. METHODS: Spontaneously diabetic NOD mice received NOD severe combined immunodeficiency islet transplants and were treated with daily LSF injections at 50 mg/kg for 3 weeks. Blood glucose levels were monitored. Serum cytokine levels were measured at 1 and 3 weeks after engraftment. Nephrectomy of the islet-implanted kidney was performed in LSF-treated recipients. Histology of islet grafts was assessed at the end of the study. The effect of LSF on beta-cell function was studied in vitro. RESULTS: Without immunosuppressants and insulin, the LSF-treated recipient mice maintained euglycemia significantly longer than the saline-treated recipients (mean, >65 days in the LSF-treated group vs. 6 days in saline controls; P=0.0004). Serum levels of interferon-gamma were markedly reduced in LSF-treated recipients at 1 and 3 weeks posttransplant. Diabetes recurred in the LSF-treated recipients after removing the islet-implanted kidneys. Immunohistochemistry showed retention of insulin-positive cells in the grafts of the LSF-treated recipients. LSF preserved beta-cell insulin secretory function in the presence of inflammatory cytokines in vitro. CONCLUSIONS: This study demonstrates that autoimmune diabetes recurrence after islet transplantation could be prevented by treatment with LSF. LSF and its analogues may have the potential to prevent islet autoimmune destruction in clinical transplantation.

Animals↗