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Guan R.,Nanjing University of Technology | Guan R.,China Agricultural University | Guan R.,Georgia Regents University | Purohit S.,Georgia Regents University | And 10 more authors.
PLoS ONE | Year: 2011

Background: Chemokine (C-C motif) ligand 2 (CCL2), commonly known as monocyte chemoattractant protein-1 (MCP-1), has been implicated in the pathogenesis of many diseases characterized by monocytic infiltration. However, limited data have been reported on MCP-1 in type 1 diabetes (T1D) and the findings are inconclusive and inconsistent. Methods: In this study, MCP-1 was measured in the sera from 2,472 T1D patients and 2,654 healthy controls using a Luminex assay. The rs1024611 SNP in the promoter region of MCP-1 was genotyped for a subset of subjects (1764 T1D patients and 1323 controls) using the TaqMan-assay. Results: Subject age, sex or genotypes of MCP-1 rs1024611SNP did not have a major impact on serum MCP-1 levels in either healthy controls or patients. While hemoglobin A1c levels did not have a major influence on serum MCP-1 levels, the mean serum MCP-1 levels are significantly higher in patients with multiple complications (mean = 242 ng/ml) compared to patients without any complications (mean = 201 ng/ml) (p = 3.5×10-6). Furthermore, mean serum MCP-1 is higher in controls (mean = 261 ng/ml) than T1D patients (mean = 208 ng/ml) (p<10-23). More importantly, the frequency of subjects with extremely high levels (>99th percentile of patients or 955 ng/ml) of serum MCP-1 is significantly lower in the T1D group compared to the control group (odds ratio = 0.11, p<10-33). Conclusion: MCP-1 may have a dual role in T1D and its complications. While very high levels of serum MCP-1 may be protective against the development of T1D, complications are associated with higher serum MCP-1 levels within the T1D group. © 2011 Guan et al.


Wang H.,Georgia Regents University | Jin Y.,Georgia Regents University | Reddy M.V.P.L.,Georgia Regents University | Podolsky R.,Georgia Regents University | And 10 more authors.
PLoS ONE | Year: 2010

Type 1 diabetes (T1D) is an autoimmune disease resulting from the complex interaction between multiple susceptibility genes, environmental factors and the immune system. Over 40 T1D susceptibility regions have been suggested by recent genome-wide association studies; however, the specific genes and their role in the disease remain elusive. The objective of this study is to identify the susceptibility gene(s) in the 12q13 region and investigate the functional link to the disease pathogenesis. A total of 19 SNPs in the 12q13 region were analyzed by the TaqMan assay for 1,434 T1D patients and 1,865 controls. Thirteen of the SNPs are associated with T1D (best p = 4×10-11), thus providing confirmatory evidence for at least one susceptibility gene in this region. To identify candidate genes, expression of six genes in the region was analyzed by real-time RT-PCR for PBMCs from 192 T1D patients and 192 controls. SNP genotypes in the 12q13 region are the main factors that determine ERBB3 mRNA levels in PBMCs. The protective genotypes for T1D are associated with higher ERBB3 mRNA level (p<10-10). Furthermore, ERBB3 protein is expressed on the surface of CD11c+ cells (dendritic cells and monocytes) in peripheral blood after stimulation with LPS, polyI:C or CpG. Subjects with protective genotypes have significantly higher percentages of ERBB3+ monocytes and dendritic cells (p = 1.1×10-9); and the percentages of ERBB++cells positively correlate with the ability of APC to stimulate T cell proliferation (R2 = 0.90, p<0.0001). Our results indicate that ERBB+ plays a critical role in determining APC function and potentially T1D pathogenesis. © 2010 Wang et al.


Reddy M.P.L.,Georgia Regents University | Wang H.,Georgia Regents University | Liu S.,Georgia Regents University | Bode B.,Georgia Regents University | And 6 more authors.
Genes and Immunity | Year: 2011

The present study was conducted to assess genetic associations for type 1 diabetes (T1D) reported in previous genome-wide association studies (GWAS). A total of 21 previously reported single-nucleotide polymorphisms (SNPs) were genotyped by TaqMan assays in 1434 Caucasian T1D patients and 1864 normal controls from Georgia. Analysis of the samples identified 18 SNPs (PTPN22, INS, IFIH1, SH2B3, ERBB3, CTLA4, C14orf181, CTSH, CLEC16A, CD69, ITPR3, C6orf173, SKAP2, PRKCQ, RNLS, IL27, SIRPG and CTRB2) with putative association. © 2011 Macmillan Publishers Limited All rights reserved.


Jin Y.,Georgia Regents University | Sharma A.,Georgia Regents University | Carey C.,Georgia Regents University | Hopkins D.,Georgia Regents University | And 8 more authors.
Diabetes Care | Year: 2013

OBJECTIVE-Our previous gene expression microarray studies identified a number of genes differentially expressed in patients with type 1 diabetes (T1D) and islet autoantibody-positive subjects. This study was designed to validate these gene expression changes in T1D patients and to identify gene expression changes in diabetes complications. RESEARCH DESIGH ANDMETHODS-We performed high-throughput real-time RTPCR to validate gene expression changes in peripheral blood mononuclear cells (PBMCs) from a large sample set of 928 T1D patients and 922 control subjects. RESULTS-Of the 18 genes analyzed here, eight genes (S100A8, S100A9, MNDA, SELL, TGFB1, PSMB3, CD74, and IL12A) had higher expression and three genes (GNLY, PSMA4, and SMAD7) had lower expression in T1D patients compared with control subjects, indicating that genes involved in inflammation, immune regulation, and antigen processing and presentation are significantly altered in PBMCs from T1D patients. Furthermore, one adhesion molecule (SELL) and three inflammatory genes mainly expressed by myeloid cells (S100A8, S100A9, and MNDA) were significantly higher in T1D patients with complications (odds ratio [OR] 1.3-2.6, adjusted P value = 0.005-10 -8), especially those patients with neuropathy (OR 4.8-7.9, adjusted P value < 0.005). CONCLUSIONS-These findings suggest that inflammatory mediators secreted mainly by myeloid cells are implicated in T1D and its complications. © 2013 by the American Diabetes Association.


PubMed | Pediatric Endocrine Associates and Georgia Regents University
Type: | Journal: Mediators of inflammation | Year: 2015

To examine the association of the serum levels of TNF receptors, adhesion molecules, and inflammatory mediators with diabetic retinopathy (DR) in T1D patients.Using the multiplex immunoassay, we measured serum levels of eight proteins in 678 T1D subjects aged 20-75 years. Comparisons were made between 482 T1D patients with no complications and 196 T1D patients with DR.The levels of sTNFR-I, sTNFR-II, CRP, SAA, sgp130, sIL6R, sVCAM1, and sICAM1 were significantly higher in the T1D patients with DR as compared to T1D patients with no complications. Multivariate logistic regression analysis revealed significant association for five proteins after adjustment for age, sex, and disease duration (sTNFR-I: OR = 1.57, sgp130: OR = 1.43, sVCAM1: OR = 1.27, sICAM1: OR = 1.42, and CRP: OR = 1.15). Conditional logistic regression on matched paired data revealed that subjects in the top quartile for sTNFR-I (OR = 2.13), sTNFR-II (OR = 1.66), sgp130 (OR = 1.82), sIL6R (OR = 1.75), sVCAM1 (OR = 1.98), sICAM1 (OR = 2.23), CRP (OR = 2.40) and SAA (OR = 2.03), had the highest odds of having DR.The circulating markers of inflammation, endothelial injury, and TNF signaling are significantly associated with DR in patients with T1D. TNFR-I and TNFR-II receptors are highly correlated, but DR associated more strongly with TNFR-I in these patients.


Lee P.A.,Penn State College of Medicine | Lee P.A.,Indiana University | Klein K.,University of California at San Diego | Mauras N.,Nemours Childrens Clinic | And 6 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: GnRH agonist (GnRHa) monthly injections are frequently used in the treatment of central precocious puberty (CPP). The 3-month leuprolide depot 11.25- and 30-mg formulations are newly approved treatment options. Objective: The aim of the study was to investigate the safety and efficacy of leuprolide acetate 3-month depot formulations for the treatment of CPP in children. Design: This was a phase III, randomized, open-label, dose-ranging 6-month study. Setting: Twenty-two U.S. medical centers (including Puerto Rico) participated. Patients: Children diagnosed with CPP (n = 84), who were either treatment naive or previously treated with GnRHa, were recruited. Chronological age at onset of pubertal signs was less than 8 yr in girls and less than 9 yr in boys, and bone age was advanced over chronological age at least 1 yr. Intervention: Leuprolide acetate depot (11.25 or 30 mg) was administered im every 3 months. Main Outcome Measures: Biochemical [peak-stimulated LH, estradiol (girls), and testosterone (boys)] and anthropometric (growth rate, bone age acceleration, pubertal progression) parameters and safety were assessed. Results: Peak-stimulated LH was suppressed in the 11.25-and 30-mg dose groups in 78.4 and 95.2%, respectively, of children from months 2 through 6. There were nine treatment failures (peakstimulated LH >4 IU/liter) in the 11.25-mg group and two in the 30-mg group. Basal sex steroid suppression, growth rates, pubertal progression, bone age advancement, and adverse events were similar with either dose. Conclusions: Treatment with leuprolide acetate 3-month depot formulations (11.25 and 30 mg) effectively suppressed the GnRH axis, was well tolerated, and may positively impact patient convenience and compliance. Copyright © 2012 by The Endocrine Society.


Sharma A.,Augusta University | Purohit S.,Augusta University | Sharma S.,Augusta University | Bai S.,Augusta University | And 7 more authors.
Frontiers in Endocrinology | Year: 2016

Aims: Reduced levels of free and total insulin-like growth factor 1 (IGF-I) have been observed in type-1 diabetes (T1D) patients. The bioavailability of IGF-I from the circulation to the target cells is controlled by multifunctional IGF-binding proteins (IGFBPs). The aim of this study was to profile serum IGFBPs in T1D and its complications. Design: We measured the IGFBP levels in 3662 patient serum samples from our ongoing Phenome and Genome of Diabetes Autoimmunity (PAGODA) study. IGFBP levels of four different groups of T1D patients (with 0, 1, 2, and ≥3 complications) were compared with healthy controls. Results: Three serum IGFBPs (IGFBP-1, -2, and -6) are significantly higher in T1D patients, and these alterations are greater in the presence of diabetic complications. IGFBP-3 is lower in patients with diabetic complications. Analyses using quintiles revealed that risk of T1D complications increases with increasing concentrations of IGFBP-2 (fifth quintile ORs: 18-60, p < 10-26), IGFBP-1 (fifth quintile ORs: 8-20, p < 10-15), and IGFBP-6 (fifth quintile ORs: 3-148, p < 10-3). IGFBP-3 has a negative association with T1D complications (fifth quintile ORs: 0.12-0.25, p < 10-5). Conclusion: We found that elevated serum levels of IGFBP-1, -2, and -6 were associated with T1D, and its complications and IGFBP-3 level was found to be decreased in T1D with complications. Given the known role of these IGFBPs, the overall impact of these alterations suggests a negative effect on IGF signaling. © 2016 Sharma, Purohit, Sharma, Bai, Zhi, Ponny, Hopkins, Steed, Bode, Anderson and She.


Lenz A.M.,Pediatric Endocrine Associates | Root A.W.,University of South Florida | Root A.W.,All Childrens Hospital
Pediatric Endocrinology Reviews | Year: 2012

An empty sella (ES) develops when cerebrospinal fluid (CSF) fills the sella turcica and compresses pituitary tissue until it lines the sellar floor and walls. Primary ES occurs when CSF enters the sella through a rent in the sellar diaphragm that may or may not be associated with increased intracranial pressure. Secondary ES is a result of an injury to the pituitary itself (e.g., pituitary apoplexy) or the consequence of surgical or radiation treatment. In adults, ES is most commonly found in older, obese, hypertensive, multiparous women and may be asymptomatic. In children, however, ES is more likely to be associated with clinical symptoms and endocrinopathies, particularly growth hormone deficiency, hypogonadotropism, or multiple pituitary hormone deficiencies. The incidence of ES in children varies greatly depending on the population surveyed, ranging from 1.2% (children without endocrine symptoms) to 68% (children with known endocrinopathy). Children with a finding of ES require endocrinologic and ophthalmologic evaluation. Treatment of ES includes replacement of hormone deficiencies and occasionally surgical measures to relieve obstructive intracranial lesions.


Zhi W.,University of Georgia | Sharma A.,University of Georgia | Purohit S.,University of Georgia | Miller E.,University of Georgia | And 7 more authors.
Molecular and Cellular Proteomics | Year: 2011

Type 1 diabetes (T1D) is expected to cause significant changes in the serum proteome; however, few studies have systematically assessed the proteomic profile change associated with the disease. In this study, a semiquantitative spectral counting-based two dimensional liquid chromatography mass spectrometry platform was used to analyze serum samples from T1D patients and controls. In this discovery phase, significant differences were found for 21 serum proteins implicated in inflammation, oxidation, metabolic regulation, and autoimmunity. To assess the validity of these findings, six candidate proteins including adiponectin, insulin-like growth factor binding protein 2, serum amyloid protein A, C-reactive protein, myeloperoxidase, and transforming growth factor beta induced were selected for subsequent immune assays for 1139 T1D patients and 848 controls. A series of statistical analyses using cases and controls matched for age, sex, and genetic risk confirmed that T1D patients have significantly higher serum levels for four of the six proteins: adiponectin (odds ratio (OR) = 1.95, p = 10 -27), insulin-like growth factor binding protein 2 (OR = 2.02, p <10 -20), C-reactive protein (OR = 1.13, p = 0.007), serum amyloid protein A (OR = 1.51, p < 10 -16); whereas the serum levels were significantly lower in patients than controls for the two other proteins: transforming growth factor beta induced (OR = 0.74, p < 10 -5) and myeloperoxidase (OR = 0.51, p < 10 -41). Compared with subjects in the bottom quartile, subjects in the top quartile for adiponectin (OR = 6.29, p < 10 -37), insulin-like growth factor binding protein 2 (OR = 7.95, p < 10 -46), C-reactive protein (OR = 1.38, p = 0.025), serum amyloid protein A (OR =3.36, p < 10 -16) had the highest risk of T1D, whereas subjects in the top quartile of transforming growth factor beta induced (OR = 0.41, p < 10 -11) and myeloperoxidase (OR = 0.10, p < 10 -43) had the lowest risk of T1D. These findings provided valuable information on the proteomic changes in the sera of T1D patients. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.


PubMed | Pediatric Endocrine Associates and Augusta University
Type: | Journal: Frontiers in endocrinology | Year: 2016

Reduced levels of free and total insulin-like growth factor 1 (IGF-I) have been observed in type-1 diabetes (T1D) patients. The bioavailability of IGF-I from the circulation to the target cells is controlled by multifunctional IGF-binding proteins (IGFBPs). The aim of this study was to profile serum IGFBPs in T1D and its complications.We measured the IGFBP levels in 3662 patient serum samples from our ongoing Phenome and Genome of Diabetes Autoimmunity (PAGODA) study. IGFBP levels of four different groups of T1D patients (with 0, 1, 2, and 3 complications) were compared with healthy controls.Three serum IGFBPs (IGFBP-1, -2, and -6) are significantly higher in T1D patients, and these alterations are greater in the presence of diabetic complications. IGFBP-3 is lower in patients with diabetic complications. Analyses using quintiles revealed that risk of T1D complications increases with increasing concentrations of IGFBP-2 (fifth quintile ORs: 18-60, p<10(-26)), IGFBP-1 (fifth quintile ORs: 8-20, p<10(-15)), and IGFBP-6 (fifth quintile ORs: 3-148, p<10(-3)). IGFBP-3 has a negative association with T1D complications (fifth quintile ORs: 0.12-0.25, p<10(-5)).We found that elevated serum levels of IGFBP-1, -2, and -6 were associated with T1D, and its complications and IGFBP-3 level was found to be decreased in T1D with complications. Given the known role of these IGFBPs, the overall impact of these alterations suggests a negative effect on IGF signaling.

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