IL-12p40 and IL-18 in crescentic glomerulonephritis: IL-12p40 is the key Th1-defining cytokine chain, whereas IL-18 promotes local inflammation and leukocyte recruitment

Experimental crescentic glomerulonephritis (GN) is characterized by T helper 1 (Th1) directed nephritogenic immune responses and cell-mediated glomerular injury. IL-12p40, the common cytokine chain for both IL-12 and IL-23, is important in the generation and potentially the maintenance of Th1 responses, whereas IL-18 is a co-factor for Th1 responses that may have systemic and local proinflammatory effects. For testing the hypothesis that both endogenous IL-12p40 and endogenous IL-18 play pathogenetic roles in crescentic GN, accelerated anti-glomerular basement membrane GN was induced in mice genetically deficient in IL-12p40 (IL-12p40-/-), IL-18 (IL-18-/-), or both IL-12p40 and IL-18 (IL-12p40-/-IL-18-/-). Compared with wild-type C57BL/6 mice, IL-12p40-/- mice failed to make a nephritogenic Th1 response and developed markedly reduced crescent formation and renal leukocytic infiltration, despite renal production of chemoattractants and adhesion molecules. IL-18-/- mice developed an intact antigen-specific systemic Th1 response, a similar degree of crescent formation, but fewer glomeruli affected by other severe histologic changes and fewer leukocytes in glomeruli and interstitium. IL-18 was expressed within diseased kidneys. Local production of TNF, IL-1beta, IFN-gamma, CCL3 (MIP-1alpha), and CCL4 (MIP-1beta) was reduced in IL-18-/- mice, demonstrating a local proinflammatory role for IL-18. Combined deletion of IL-12p40 and IL-18 did not result in synergistic effects. Consistent with the hypothesis that inflammation leads to fibrosis, all three groups of deficient mice expressed lower levels of intrarenal TGF-beta1 and/or alpha1(I) procollagen mRNA. These studies demonstrate that in severe experimental crescentic GN, IL-12p40 is the key Th1-defining cytokine chain, whereas IL-18 has local proinflammatory roles.     

Interbirth interval is associated with childhood type 1 diabetes risk

Short interbirth interval has been associated with maternal complications and childhood autism and leukemia, possibly due to deficiencies in maternal micronutrients at conception or increased exposure to sibling infections. A possible association between interbirth interval and subsequent risk of childhood type 1 diabetes has not been investigated. A secondary analysis of 14 published observational studies of perinatal risk factors for type 1 diabetes was conducted. Risk estimates of diabetes by category of interbirth interval were calculated for each study. Random effects models were used to calculate pooled odds ratios (ORs) and investigate heterogeneity between studies. Overall, 2,787 children with type 1 diabetes were included. There was a reduction in the risk of childhood type 1 diabetes in children born to mothers after interbirth intervals <3 years compared with longer interbirth intervals (OR 0.82 [95% CI 0.72-0.93]). Adjustments for various potential confounders little altered this estimate. In conclusion, there was evidence of a 20% reduction in the risk of childhood diabetes in children born to mothers after interbirth intervals <3 years.     

Susceptibility to type 1 diabetes is associated with ApoCIII gene haplotypes

Type 1 diabetes is a disease of beta-cell destruction leading to insulin deficiency. Genes for type 1 diabetes have been identified; however, much of the genetic risk remains unexplained. Genetic variation within the apolipoprotein CIII (apoCIII) gene alters apoCIII levels, which are increased in type 1 diabetes and induce beta-cell apoptosis. We therefore hypothesize haplotypes within the apoCIII gene are associated with type 1 diabetes. DNA from 584 type 1 diabetic patients and 591 control subjects were genotyped for six single nucleotide polymorphisms (SNPs) in the apoCIII gene (C-641A, C-482T, T-455C, C1100T, C3175G, and T3206G). Two alleles of a haplotype block (promoter SNPs + C3175G) were associated with type 1 diabetes. The A-T-C-C allele frequency was higher in type 1 diabetes (0.19 vs. 0.16, P = 0.05), and the C-C-T-C allele was reduced in type 1 diabetes (0.60 vs. 0.65, P = 0.04). The odds ratio (OR) for A-T-C-C allele increased with 0, 1, and 2 copies (OR of 1.00, 1.24, and 1.60, respectively; P = 0.05) and decreased for the C-C-T-C allele (1.00, 0.97, and 0.73, respectively; P = 0.03). This haplotype block contains an insulin response element. Screening for this haplotype may identify at-risk individuals, and this pathway may offer a target for prevention of type 1 diabetes.     

Hip strength in adults with type 1 diabetes is associated with age at onset of diabetes

We investigated the association of age at onset of type 1 diabetes with areal bone mineral density (aBMD), estimates of bone strength, and outer diameter. Using dual-energy X-ray absorptiometry (DXA), aBMD, axial strength (cross-sectional area [CSA]), bending strength (section modulus [SM]), and outer diameter at the narrow neck, intertrochanter, and shaft of the proximal femur were determined for 60 adults. Analysis of covariance (ANCOVA) was used to determine if the DXA-based measures of bone were related to age at onset and if this relationship differed by gender. Age at onset, gender, and the interaction of age at onset by gender were included in the ANCOVA models along with current age, duration, height, lean soft tissue mass, and hemoglobin A1c as covariates. In the adjusted models with CSA, SM, or outer diameter as the dependent variable, age at onset (p<0.01) and gender (p<0.0001) were significant with no interaction. For shaft aBMD, there was a significant age at onset by gender interaction (p=0.0285), where an earlier onset was associated with lower aBMD in the femoral shaft of females but not males. The findings suggest that an earlier onset of type 1 diabetes is associated with lower measures of bone strength and outer diameter.     

Rising incidence of type 1 diabetes is associated with altered immunophenotype at diagnosis

The incidence of type 1 diabetes has increased rapidly over recent decades, particularly in young children. We aimed to determine whether this rise was associated with changes in patterns of humoral islet autoimmunity at diagnosis. Autoantibodies to insulin (IAA), GAD (GADA), islet antigen-2 (IA-2A), and zinc transporter 8 (ZnT8A) were measured by radioimmunoassay in sera collected from children and young adults with newly diagnosed type 1 diabetes between 1985 and 2002. The influence of date of diagnosis on prevalence and level of autoantibodies was investigated by logistic regression with adjustment for age and HLA class II genetic risk. Prevalence of IA-2A and ZnT8A increased significantly over the period studied, and this was mirrored by raised levels of IA-2A, ZnT8A, and IA-2β autoantibodies (IA-2βA). IAA and GADA prevalence and levels did not change. Increases in IA-2A, ZnT8A, and IA-2βA at diagnosis during a period of rising incidence suggest that the process leading to type 1 diabetes is now characterized by a more intense humoral autoimmune response. Understanding how changes in environment or lifestyle alter the humoral autoimmune response to islet antigens should help explain why the incidence of type 1 diabetes is increasing and may suggest new strategies for preventing disease.     

Genetic analysis of HNF4A polymorphisms in Caucasian-American type 2 diabetes

Hepatocyte nuclear factor 4alpha (HNF4A), the gene for the maturity-onset diabetes of the young type 1 monogenic form of type 2 diabetes, is within the type 2 diabetes-linked region on chromosome 20q12-q13.1 and, consequently, is a positional candidate gene for type 2 diabetes in the general population. Previous studies have identified only a few rare coding mutations. However, recent studies suggest that single nucleotide polymorphisms (SNPs) located near the P2 (beta-cell) promoter of HNF4A are associated with diabetes susceptibility. In this study, we evaluated 23 SNPs spanning 111 kb including the HNF4A gene for association with type 2 diabetes in a collection of Caucasian type 2 diabetic patients with end-stage renal disease (n = 300) and control subjects (n = 310). None of the individual SNPs were associated with type 2 diabetes in this collection of case subjects (P values ranging from 0.06 to 0.99). However, haplotype analysis identifies significant differences between haplotype frequencies in type 2 diabetic case and control subjects (P = 0.013 to P < 0.001), with two uncommon "risk" haplotypes (2.4 and 2.2% of chromosomes) and two uncommon "protective" haplotypes (7.1 and 5.0% of chromosomes) accounting for the evidence of association. Our results suggest that type 2 diabetes linked to 20q12-13 is a heterogeneous disease in which different populations may have different type 2 diabetes susceptibility loci.     

Interleukin-1 receptor antagonist genotype is associated with coronary atherosclerosis in patients with type 2 diabetes

Recently, inflammation has received considerable attention in the pathogenesis of both type 2 diabetes and atherosclerosis. The interleukin-1 receptor antagonist (IL-1ra) is a major modulator of the interleukin-1 pro-inflammatory pathway. We studied the relationship between a variable number tandem repeat (VNTR) polymorphism in intron 2 of the IL-1ra gene (IL1RN) and coronary artery disease (CAD) in patients with and without type 2 diabetes, following 787 consecutive patients admitted for suspected CAD. According to the current criteria of the American Diabetes Association, 250 patients had type 2 diabetes. In this group of patients, allele 2 carriers (n = 108) had an increased prevalence of CAD compared with noncarriers (85.2 vs. 73.2%), a difference that remained significant in a multivariate logistic regression model (odds ratio 2.2, 95% CI 1.1-4.3, P = 0.02). No association of CAD with allele 2 carrier status was present among nondiabetic patients (n = 537). Enzyme-linked immunosorbent assays showed decreased baseline plasma levels of IL-1ra in patients with type 2 diabetes, which may in part explain the role of the IL1RN VNTR in these patients.     

Poor glycemic control is associated with low BMD detected in premenopausal women with type 1 diabetes

Summary  The etiology of bone fragility in individuals with type 1 diabetes is unknown. This study demonstrated that bone turnover favors resorption and that poor glycemic control is associated with low bone mineral density (BMD) and low bone turnover, in premenopausal women with type 1 diabetes. The results could inform future interventions. Introduction  Low BMD and fracture may be complications of type 1 diabetes. We sought to determine the roles of bone turnover and glycemic control in the etiology of low BMD. Methods  Premenopausal women from the Wisconsin Diabetes Registry Study and matched controls were compared (n = 75 pairs). Heel and forearm BMD were measured, and hip and spine BMD were measured in a subset. Markers of bone formation (osteocalcin) and resorption (NTx), and glycemic control (HbA1c) were determined. Results  Age ranged from 18 to 50 years with a mean of 28, and 97% were Non-Hispanic white. Among women with diabetes, mean disease duration was 16 years and current HbA1c was 8%. Compared to controls, women with diabetes had a high prevalence of previous fracture (37% vs. 24%) and low BMD for age (heel or forearm: 49% vs. 31%), low heel and forearm BMD, and low osteocalcin levels. Levels of NTx were similar, suggesting uncoupled turnover favoring resorption. Poor glycemic control was associated with low BMD at all bone sites except the spine, and with low osteocalcin and NTx levels. Conclusions  Optimal glycemic control may prevent low BMD and altered bone turnover in type 1 diabetes, and decrease fracture risk.     

Pro12Ala substitution in the peroxisome proliferator-activated receptor-gamma2 is not associated with type 2 diabetes.

Peroxisome proliferator-activated receptor (PPAR)-gamma is a major regulator of adipogenesis and insulin sensitivity. The PPAR-gamma gene generates two isoforms through alternative splicing, PPAR-gamma1 and -gamma2, the latter having an additional stretch of 28 amino acids at its NH2-terminus in the ligand-independent activation domain. This extension renders PPAR-gamma2 more sensitive to insulin action. Since there is a Pro12Ala substitution in this domain, we tested whether it is related to type 2 diabetes or insulin resistance. Therefore, 131 type 2 diabetic patients and 312 normoglycemic control subjects were screened for the presence of the mutation and for major clinical and metabolic features. The frequency of the mutation did not differ significantly between diabetic patients and control subjects. BMI, insulin, and other metabolic and anthropometric variables were also not associated with the mutation. Although the study was carried out on a sufficiently large sample, the conclusions do not support a major role for the Pro12Ala substitution of the PPAR-gamma gene in the etiology of type 2 diabetes.     

Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives

Zonulin, a protein that modulates intestinal permeability, is upregulated in several autoimmune diseases and is involved in the pathogenesis of autoimmune diabetes in the BB/Wor animal model of the disease. To verify the association between serum zonulin levels and in vivo intestinal permeability in patients with type 1 diabetes, both parameters were investigated in different stages of the autoimmune process. Forty-two percent (141 of 339) of the patients had abnormal serum zonulin levels, as compared with age-matched control subjects. The increased zonulin levels correlated with increased intestinal permeability in vivo and changes in claudin-1, claudin-2, and myosin IXB genes expression, while no changes were detected in ZO1 and occludin genes expression. When tested in serum samples collected during the pre-type 1 diabetes phase, elevated serum zonulin was detected in 70% of subjects and preceded by 3.5 +/- 0.9 years the onset of the disease in those patients who went on to develop type 1 diabetes. Combined, these results suggest that zonulin upregulation is associated with increased intestinal permeability in a subgroup of type 1 diabetic patients. Zonulin upregulation seems to precede the onset of the disease, providing a possible link between increased intestinal permeability, environmental exposure to non-self antigens, and the development of autoimmunity in genetically susceptible individuals.     

Inherited variation in vitamin D genes is associated with predisposition to autoimmune disease type 1 diabetes

OBJECTIVE

Vitamin D deficiency (25-hydroxyvitamin D [25(OH)D] <50 nmol/L) is commonly reported in both children and adults worldwide, and growing evidence indicates that vitamin D deficiency is associated with many extraskeletal chronic disorders, including the autoimmune diseases type 1 diabetes and multiple sclerosis.

RESEARCH DESIGN AND METHODS

We measured 25(OH)D concentrations in 720 case and 2,610 control plasma samples and genotyped single nucleotide polymorphisms from seven vitamin D metabolism genes in 8,517 case, 10,438 control, and 1,933 family samples. We tested genetic variants influencing 25(OH)D metabolism for an association with both circulating 25(OH)D concentrations and disease status.

RESULTS

Type 1 diabetic patients have lower circulating levels of 25(OH)D than similarly aged subjects from the British population. Only 4.3 and 18.6% of type 1 diabetic patients reached optimal levels (≥75 nmol/L) of 25(OH)D for bone health in the winter and summer, respectively. We replicated the associations of four vitamin D metabolism genes (GC, DHCR7, CYP2R1, and CYP24A1) with 25(OH)D in control subjects. In addition to the previously reported association between type 1 diabetes and CYP27B1 (P = 1.4 × 10⁻⁴), we obtained consistent evidence of type 1 diabetes being associated with DHCR7 (P = 1.2 × 10⁻³) and CYP2R1 (P = 3.0 × 10⁻³).

CONCLUSIONS

Circulating levels of 25(OH)D in children and adolescents with type 1 diabetes vary seasonally and are under the same genetic control as in the general population but are much lower. Three key 25(OH)D metabolism genes show consistent evidence of association with type 1 diabetes risk, indicating a genetic etiological role for vitamin D deficiency in type 1 diabetes.Vitamin D deficiency is commonly reported in both children and adults (1), and the well-established musculoskeletal consequences include osteomalacia, a softening of bones caused by defective bone mineralization (known as rickets in children), and osteoporosis, a reduced bone mineral density and deterioration in structural bone strength. Other more recently reported consequences are the extraskeletal conditions, which include common cancers (2,3) and coronary artery (4) and autoimmune diseases. The autoimmune or immune-mediated diseases include type 1 diabetes, multiple sclerosis, Crohn’s disease, and rheumatoid arthritis (5–8). In type 1 diabetes, vitamin D supplementation has been shown to be protective against this chronic disorder (5), caused by T-cell–mediated destruction of insulin-producing β-cells in the pancreas.The main source of vitamin D is through the action of sunlight (ultraviolet B irradiance) on the skin, which results in the endogenous production of vitamin D₃ (cholecalciferol). The only other source is exogenous, through diet as either vitamin D₂ (ergocalciferol) or D₃. Vitamin D enters the circulation bound to vitamin D–binding proteins (DBPs) and lipoproteins and is released to the liver and hydroxylated to form 25-hydroxyvitamin D [25(OH)D]. A subject’s vitamin D status is routinely determined by their levels of 25(OH)D, the inactive circulating form of vitamin D and an established marker of vitamin D availability (7), which has a half-life of 2 weeks (9). 25(OH)D is hydroxylated in the kidneys or in cells of the immune system by the CYP27B1 enzyme (CYP1α) to form 1,25-dihydroxyvitamin D [1,25(OH)₂D, calcitriol], the biologically active form responsible for maintaining calcium and phosphorus homeostasis (9).A substantial proportion of 25(OH)D variation has been attributed to genetic factors, with heritability estimates of 28.8% (10) and 43% (11) reported. A recent genome-wide association (GWA) meta-analysis of circulating levels of 25(OH)D in 33,996 samples of European descent from 14 cohorts reported convincing evidence for four loci, namely GC/4p12 (rs2282679 P = 1.9 × 10⁻¹⁰⁹), DHCR7/11q12 (rs12785878 P = 2.1 × 10⁻²⁷), CYP2R1/11p15 (rs10741657 P = 3.3 × 10⁻²⁰), and CYP24A1/20q13 (rs6013897 P = 6.0 × 10⁻¹⁰) (12). These single nucleotide polymorphisms (SNPs) are within or near genes involved in vitamin D transport (GC), cholesterol synthesis (DHCR7), and hydroxylation (CYP2R1 and CYP24A1). No loci linked to skin pigmentation were detected, despite being a major factor in determining 25(OH)D concentrations. More recently, vitamin D receptor (VDR)-binding sites were reported to be overrepresented near genes associated with type 1 diabetes, Crohn’s disease, and rheumatoid arthritis (13).Recent evidence indicates that the production and degradation of 1,25(OH)₂D is a major signaling component in both the innate (14) and adaptive (15) immune systems. Vitamin D signaling plays an essential role in the activation of monocytes/macrophages in response to infection (14) and possibly in naïve T-cell activation (15,16). These cell populations are central to the development of the autoimmune disease type 1 diabetes (17). However, the relationship between circulating levels of 25(OH)D and immune responsiveness is largely undefined (14).Type 1 diabetes is a strongly inherited autoimmune disease that affects ~0.4% of European ancestry populations, and incidence has been increasing at 3% per year, with a decreasing trend in age at diagnosis since the 1950s (18). A large number of potential environmental exposures correlate with type 1 diabetes incidence, including viral infection, sanitation and improvements in health care, and dietary intake. The effect of the vitamin D hormone [1,25(OH)₂D] in type 1 diabetes was first proposed based upon the observation that incidence rates of type 1 diabetes were negatively correlated with sunlight exposure, resulting in higher incidence at higher latitudes (1), and the distinctive seasonal pattern in type 1 diabetes incidence, with the largest proportion of cases diagnosed during the winter and the lowest during the summer (19). Subsequent evidence includes that type 1 diabetic patients have lower levels of 25(OH)D than age- and sex-matched control subjects (20,21), type 1 diabetic patients have decreased bone mineral density and a greater risk of fractures compared with the general population (22), vitamin D supplementation is reported to be protective against type 1 diabetes (5), the vitamin D hormone has widespread effects in the immune system (14,15,23), and the gene CYP27B1, which encodes the enzyme CYP1α that converts precursor 25(OH)D to 1,25(OH)D, shows association with type 1 diabetes (24,25) and multiple sclerosis (13,26) risk.In the current study, we investigate the genetic relationship between vitamin D and type 1 diabetes. This includes a comparison between the vitamin D status of similarly aged type 1 diabetic patients and subjects from the British population and testing genetic variants influencing 25(OH)D metabolism for an association with both circulating levels of 25(OH)D and type 1 diabetes status.     

The Gly972-->Arg IRS-1 variant is associated with type 1 diabetes in continental Italy

The Arg(972) insulin receptor substrate-1 (IRS-1) variant has been hypothesized to play a role in pancreatic beta-cell stimulus-coupled insulin secretion and survival. We analyzed the relations between type 1 diabetes and the Arg(972) IRS-1 variant. The frequency of the IRS-1 Arg(972) variant was investigated in two independent sets of unrelated patients: a case-control study and a collection of type 1 diabetes simplex families. In the former group, frequency of the IRS-1 Arg(972) variant was significantly increased in the patients (P = 0.0008), conferring an OR of 2.5. Transmission disequilibrium analysis of data obtained from the family set revealed that the Arg(972) IRS-1 variant was transmitted from heterozygous parents to affected probands at a frequency of 70.2% (P < 0.02). Arg(972) IRS-1 frequency showed no significant correlation with HLA genotypic risk for type 1 diabetes. Arg(972) IRS-1 type 1 diabetic patients also had lower fasting plasma concentrations of C-peptide at the time of diagnosis with respect to patients carrying the wild-type IRS-1 (0.49 +/- 0.058, n = 34, and 0.76 +/- 0.066, n = 134, respectively [means +/- SE]; P = 0.051). Our findings suggest a role for Arg(972) IRS-1 in conferring risk for the development of type 1 diabetes.     

IL-6 promoter polymorphism -174 is associated with new-onset diabetes after transplantation

New-onset diabetes after transplantation (NODAT) is a serious complication of transplantation. This study tested whether IL-6 production capacity may influence the development of NODAT in two different groups of patients. The occurrence of NODAT was analyzed with respect to IL-6 gene promoter polymorphism at position -174 (G-->C) and other relevant risk factors retrospectively in 217 renal transplant recipients and prospectively in 132. A linear increase in both circulating IL-6 (P = 0.09) and C-reactive protein (an indicator of basal IL-6 secretion; P = 0.03) concentrations from the CC genotype to the GG genotype was observed. In the multivariate model, the CC genotype was associated with a decreased risk for NODAT compared with the GG genotype in the two cohorts. Homeostasis Model Assessment for Insulin Resistance also revealed lesser insulin sensitivity in the GG carriers than in the CC carriers (2.15 +/- 2 versus 1.32 +/- 1.03; P = 0.03). Subgroup analysis showed that the influence of IL-6 gene promoter polymorphism on the development of NODAT was restricted mostly to overweight patients. These results highly suggest that IL-6 production capacity influences the development of NODAT and that diabetes-inducing drug administration should be limited in overweight patients who carry the GG genotype.     

Fractalkine is a novel human adipochemokine associated with type 2 diabetes

OBJECTIVE

Leukocyte infiltration of adipose is a critical determinant of obesity-related metabolic diseases. Fractalkine (CX3CL1) and its receptor (CX3CR1) comprise a chemokine system involved in leukocyte recruitment and adhesion in atherosclerosis, but its role in adipose inflammation and type 2 diabetes is unknown.

RESEARCH DESIGN AND METHODS

CX3CL1 mRNA and protein were quantified in subcutaneous adipose and blood during experimental human endotoxemia and in lean and obese human adipose. CX3CL1 cellular source was probed in human adipocytes, monocytes, and macrophages, and CX3CL1-blocking antibodies were used to assess its role in monocyte-adipocyte adhesion. The association of genetic variation in CX3CR1 with metabolic traits was determined in a community-based sample. Finally, plasma CX3CL1 levels were measured in a case-control study of type 2 diabetes.

RESULTS

Endotoxemia induced adipose CX3CL1 mRNA (32.7-fold, P < 1 × 10⁻⁵) and protein (43-fold, P = 0.006). Obese subjects had higher CX3CL1 levels in subcutaneous adipose compared with lean (0.420 ± 0.387 vs. 0.228 ± 0.187 ng/mL, P = 0.04). CX3CL1 was expressed and secreted by human adipocytes and stromal vascular cells. Inflammatory cytokine induction of CX3CL1 in human adipocytes (27.5-fold mRNA and threefold protein) was completely attenuated by pretreatment with a peroxisome proliferator–activated receptor-γ agonist. A putative functional nonsynonymous single nucleotide polymorphism (rs3732378) in CX3CR1 was associated with adipose and metabolic traits, and plasma CX3CL1 levels were increased in patients with type 2 diabetes vs. nondiabetics (0.506 ± 0.262 vs. 0.422 ± 0.210 ng/mL, P < 0.0001).

CONCLUSIONS

CX3CL1-CX3CR1 is a novel inflammatory adipose chemokine system that modulates monocyte adhesion to adipocytes and is associated with obesity, insulin resistance, and type 2 diabetes. These data provide support for CX3CL1 as a diagnostic and therapeutic target in cardiometabolic disease.Adipose tissue inflammation plays a central role in obesity-related metabolic and cardiovascular complications, including type 2 diabetes (1). A key event in adipose inflammation is recruitment of leukocytes (2–4), which produces local inflammatory signaling molecules creating a feed-forward cycle of adipose and systemic inflammation and insulin resistance. Upregulation of adipose chemokines has emerged as an important mechanism in leukocyte recruitment, early adipose inflammation, and insulin resistance in obesity. In particular, monocyte chemotactic protein-1 (MCP-1 or CCL2) and its receptor CCR2 are significant contributors to adipose macrophage recruitment and insulin resistance in obesity (3,5). However, adverse metabolic consequences are only partially attenuated in CCL2- or CCR2-deficient mice, suggesting involvement of additional chemokine pathways (6). Several other CC and CXC chemokines implicated in recruitment of inflammatory T-cells and monocytes (4), including CCL5 (also called RANTES [regulated on activation, normal T-cell expressed and secreted]), CXCL8 (interleukin-8) and CXCL 10 (interferon γ-induced protein) are increased in obesity in rodents (7). However, which chemokines play a causal role in human adipose inflammation and its metabolic complications remains uncertain.Fractalkine (CX3CL1), a chemokine that signals through a single known receptor (CX3CR1), is implicated in recruitment and adhesion of both monocytes and T-cells in atherosclerosis, rheumatologic disorders, and HIV-1 (8). CX3CL1, the sole CX3C chemokine, is unique among chemokines in having both soluble and transmembrane forms, the latter of which mediates firm cell adhesion (9). Many leukocyte subtypes, in particular monocytes, T-cells, and NK cells, express CX3CR1 (9,10), a G-protein–coupled receptor that promotes leukocyte activation and survival (11). In fact, CX3CR1 is required for vascular recruitment of inflammatory monocytes and development of macrophage-rich atherosclerotic lesions (12,13). Knowledge of CX3CL1’s role in adipose biology is limited but recent data suggest that CX3CL1 is expressed in adipocytes and that CX3CR1 signaling in macrophages is downregulated by peroxisome proliferator–activated receptor (PPAR)-γ agonists (14). Furthermore, the fact that manipulation of the CX3CL1/CX3CR1 system can modulate chronic inflammatory diseases, including atherosclerosis, independent of CCL2/CCR2 (15) suggests that this may also occur in adipose inflammation and its complications.Recently, using microarray of adipose mRNA during experimental endotoxemia, we found that CX3CL1 is one of several genes markedly upregulated in human adipose by in vivo inflammation (16). Here, we define CX3CL1 as a novel inflammatory adipose chemokine in humans. First, adipose CX3CL1 is increased in obesity as well as in evoked adipose inflammation. Second, CX3CL1 promotes monocyte adhesion to human adipocytes. Third, genetic variation in CX3CR1 is associated with metabolic traits in humans while plasma CX3CL1 levels are higher in type 2 patients with diabetes compared with control subjects.     

Reduced serum CTRP12 levels in type 2 diabetes are associated with renal dysfunction

International Urology and Nephrology - Serum C1q/TNF-related protein-12 (CTRP12) is one of the newly studied families of adipokines, which is believed to be associated with type 2 diabetes....     

Type 1 diabetes is associated with enterovirus infection in gut mucosa

Enterovirus infections have been linked to type 1 diabetes in several studies. Enteroviruses also have tropism to pancreatic islets and can cause β-cell damage in experimental models. Viral persistence has been suspected to be an important pathogenetic factor. This study evaluates whether gut mucosa is a reservoir for enterovirus persistence in type 1 diabetic patients. Small-bowel mucosal biopsy samples from 39 type 1 diabetic patients, 41 control subjects, and 40 celiac disease patients were analyzed for the presence of enterovirus using in situ hybridization (ISH), RT-PCR, and immunohistochemistry. The presence of virus was compared with inflammatory markers such as infiltrating T cells, HLA-DR expression, and transglutaminase 2-targeted IgA deposits. Enterovirus RNA was found in diabetic patients more frequently than in control subjects and was associated with a clear inflammation response in the gut mucosa. Viral RNA was often detected in the absence of viral protein, suggesting defective replication of the virus. Patients remained virus positive in follow-up samples taken after 12 months' observation. The results suggest that a large proportion of type 1 diabetic patients have prolonged/persistent enterovirus infection associated with an inflammation process in gut mucosa. This finding opens new opportunities for studying the viral etiology of type 1 diabetes.     

Risk of advanced diabetic nephropathy in type 1 diabetes is associated with endothelial nitric oxide synthase gene polymorphism

Risk of advanced diabetic nephropathy in type 1 diabetes is associated with endothelial nitric oxide synthase gene polymorphism. BACKGROUND: Polymorphisms in the endothelial nitric oxide synthase gene (eNOS) may be implicated in the development of nephropathy in patients with type 1 or insulin-dependent diabetes mellitus (IDDM). METHODS: Three groups of IDDM patients were selected to study this hypothesis: cases with advanced diabetic nephropathy (N = 78), cases with overt proteinuria but normal serum creatinine (N = 74), and controls with normoalbuminuria despite 15 years of diabetes (N = 195). Parents of 132 cases and 53 controls were also examined and were used for the transmission disequilibrium test, a family-based study design to test association. RESULTS: We examined four eNOS polymorphisms, and two were associated with diabetic nephropathy in the case-control comparisons: a T to C substitution in the promoter at position -786 and the a-deletion/b-insertion in intron 4. For the former, the risk of developing advanced nephropathy was higher for C allele homozygotes than for the other two genotypes (odds ratio 2.8, 95% CI, 1.4 to 5.6). For the latter polymorphism, it was the a-deletion carriers that had the higher risk (odds ratio 2.3, 95% CI, 1.3 to 4.0) in comparison with noncarriers. Both polymorphisms were analyzed together as haplotypes in a family-based study using the transmission disequilibrium test. The C/a-deletion haplotype was transmitted from heterozygous parents to cases with advanced diabetic nephropathy with a significantly higher frequency than expected (P = 0.004). CONCLUSION: The findings of the case-control and family-based studies demonstrate clearly that DNA sequence differences in eNOS influence the risk of advanced nephropathy in type 1 diabetes.