Biomarker Commons

Metabolic endotoxaemia: is it more than just a gut feeling?

Curr Opin Lipidol. 2013 Feb;24(1):78-85

Authors: Piya MK, Harte AL, McTernan PG

Abstract
PURPOSE OF REVIEW: This article reviews the evidence linking gut bacteria, endotoxin, and its circulating levels with inflammatory induced obesity and metabolic disease (metabolic endotoxaemia).
RECENT FINDINGS: Gut flora analyses have allowed gut microbiota signatures (GMS) to be observed in animal studies of obesity/metabolic disease. In these studies, specific GMS result in a change in obesity and metabolic disease state whereas in humans, analysis remains unclear. Serum studies, examining metabolic endotoxaemia as a biomarker, appear to link long-term cardiovascular disease and type 2 diabetes mellitus (T2DM) through activation of inflammatory pathways. More recent studies note the importance of diet, which shows the dramatic rise in endotoxin following acute or long-term high-fat diet, with the effects exacerbated in T2DM.
SUMMARY: Gut flora appears to act as an important determinant in the pathogenesis of inflammatory induced obesity/T2DM. Endotoxin may act as the systemic insult, impacted by a high-fat diet, which may regulate this effect, combined with an altered GMS. As such, clinical and dietary intervention to affect this process - on the gut flora, the 'leaky' mucosal membrane and endotoxin coupled lipid absorption or removal of circulating endotoxin - could reduce the progression of inflammatory induced metabolic disease.

PMID: 23298961 [PubMed - in process]

Periodontal therapy - an adjuvant for glycemic control.

Diabetes Metab Syndr. 2012 Oct;6(4):218-23

Authors: Gurav AN

Abstract
AIMS: Periodontitis is an oral infection affecting the tooth- supporting tissues. Although the prime etiology for this condition is bacterial plaque, the host immune response also has substantial contribution to the destruction of the periodontal apparatus. Periodontitis elicits a "low grade systemic inflammation". Diabetes mellitus is intricately related to the development, progression and severity of periodontitis. The literature is abundant with studies depicting this association. Periodontal therapy (PT) involves removal of bacterial component leading to the resolution of clinical signs and symptoms of disease. This review aims to create awareness amongst the medical professionals regarding the two-way relationship between diabetes and periodontitis, emphasizing on the positive effects of PT.
MATERIAL AND METHODS: Studies addressing the effects of PT on glycemic control in type 2 Diabetes (T2DM) subjects were identified using PubMed search with key search terms such as "Glycemic control", "Periodontitis", "Periodontal therapy", "Type 2 diabetes mellitus". The review has been prepared by screening PUBMED database from January 1990 to March 2012.
RESULTS: PT bears an unexplored potential and can serve as an adjuvant to the conventional treatment for diabetes.
CONCLUSION: A major conclusion of this review is that PT instituted in type 2 diabetic human subjects assists in amelioration of the inflammatory biomarker levels and glycemic status. There is a wide scope for further studies to highlight the beneficial effects of PT in diabetic subjects and the dire need for periodontal screening of these individuals for glycemic maintenance.

PMID: 23199544 [PubMed - in process]

A urinary peptide biomarker set predicts worsening of albuminuria in type 2 diabetes mellitus.

Diabetologia. 2013 Feb;56(2):259-67

Authors: Roscioni SS, de Zeeuw D, Hellemons ME, Mischak H, Zürbig P, Bakker SJ, Gansevoort RT, Reinhard H, Persson F, Lajer M, Rossing P, Lambers Heerspink HJ

Abstract
AIMS/HYPOTHESIS: Microalbuminuria is considered the first clinical sign of kidney dysfunction and is associated with a poor renal and cardiovascular prognosis in type 2 diabetes. Detection of patients who are prone to develop micro- or macroalbuminuria may represent an effective strategy to start or optimise therapeutic intervention. Here we assessed the value of a urinary proteomic-based risk score (classifier) in predicting the development and progression of microalbuminuria.
METHODS: We conducted a prospective case-control study. Cases (n = 44) and controls (n = 44) were selected from the PREVEND (Prevention of Renal and Vascular End-stage Disease) study and from the Steno Diabetes Center (Gentofte, Denmark). Cases were defined by transition from normo- to microalbuminuria or from micro- to macroalbuminuria over a follow-up of 3 years. Controls with no transitions in albuminuria were pair-matched for age, sex and albuminuria status. A model for the progression of albuminuria was built using a proteomic classifier based on 273 urinary peptides.
RESULTS: The proteomic classifier was independently associated with transition to micro- or macroalbuminuria (OR 1.35 [95% CI 1.02, 1.79], p = 0.035). The classifier predicted the development and progression of albuminuria on top of albuminuria and estimated GFR (eGFR, area under the receiver operating characteristic [ROC] curve increase of 0.03, p = 0.002; integrated discrimination index [IDI]: 0.105, p = 0.002). Fragments of collagen and α-2-HS-glycoprotein showed significantly different expression between cases and controls.
CONCLUSIONS/INTERPRETATION: Although limited by the relatively small sample size, these results suggest that analysis of a urinary biomarker set enables early renal risk assessment in patients with diabetes. Further work is required to confirm the role of urinary proteomics in the prevention of renal failure in diabetes.

PMID: 23086559 [PubMed - in process]

Salivary proteomics in biomedical research.

Clin Chim Acta. 2013 Jan 16;415:261-5

Authors: Zhang A, Sun H, Wang P, Wang X

Abstract
Proteins that are important indicators of physiological or pathological states, can provide information for the identification of early and differential markers for disease. Saliva, contains an abundance of proteins, offers an easy, inexpensive, safe, and non-invasive approach for disease detection, and possesses a high potential to revolutionize the diagnostics. Discovery of salivary biomarkers could be used to scrutinize health and disease surveillance. The impact of human saliva proteome analysis in the search for clinically relevant disease biomarkers will be realized through advances made using proteomic technologies. The advancements of emerging proteomic techniques have benefited biomarker research to the point where saliva is now recognized as an excellent diagnostic medium for the detection of disease. This review presents an overview of the value of saliva as a credible diagnostic tool and we aim to summarize the proteomic technologies currently used for global analysis of saliva proteins and to elaborate on the application of saliva proteomics to the discovery of disease biomarkers, and discuss some of the critical challenges and perspectives in this field.

PMID: 23146870 [PubMed - indexed for MEDLINE]

Insulin and cardiovascular disease: biomarker or association?

Diabetologia. 2012 Dec;55(12):3145-51

Authors: Jandeleit-Dahm KA, Gray SP

Abstract
In the 1980s prospective studies using whole populations suggested a relationship between insulin and cardiovascular disease, and these studies proposed that both metabolic and haemodynamic factors were associated with cardiovascular events. The initial analysis of the Paris Prospective Study (Diabetologia 19: 205-210), published in 1980, showed a positive correlation between insulin and cardiovascular events in healthy middle-aged policemen after a 5 year follow-up. In the Bedford Survey (Diabetologia 22: 79-84), also performed in the 1980s, a higher cardiovascular risk was demonstrated in diabetic patients and in those with borderline diabetes; however, in contrast to the Paris Prospective Study, insulin was negatively correlated to cardiovascular endpoints in the Bedford Survey. The initial enthusiasm for insulin as a cardiovascular risk marker was dampened when the 15 year follow-up data of the Paris Prospective Study (Diabetologia 34: 356-361) showed that the correlation between insulin and cardiovascular risk subsided with increased duration of follow-up. Despite the fact that hyperinsulinaemia was always strongly associated with other classical cardiovascular risk factors, univariate analyses usually failed to show a strong correlation between insulin and cardiovascular risk. The San Antonio Heart Study (Diabetologia 34: 416-422) performed in a bi-ethnic population that included a large proportion of Mexican-American participants again emphasised that insulin resistance may be the underlying factor associated with a cluster of metabolic and haemodynamic abnormalities. However, recently performed meta-analyses that included larger studies have not been able to confirm a critical role for insulin levels in cardiovascular risk. Indeed, it has been suggested that proinsulin or other factors may be better markers than insulin per se.

PMID: 23052054 [PubMed - indexed for MEDLINE]

Mutations in HNF1A result in marked alterations of plasma glycan profile.

Diabetes. 2013 Apr;62(4):1329-37

Authors: Thanabalasingham G, Huffman JE, Kattla JJ, Novokmet M, Rudan I, Gloyn AL, Hayward C, Adamczyk B, Reynolds RM, Muzinic A, Hassanali N, Pucic M, Bennett AJ, Essafi A, Polasek O, Mughal SA, Redzic I, Primorac D, Zgaga L, Kolcic I, Hansen T, Gasperikova D, Tjora E, Strachan MW, Nielsen T, Stanik J, Klimes I, Pedersen OB, Njølstad PR, Wild SH, Gyllensten U, Gornik O, Wilson JF, Hastie ND, Campbell H, McCarthy MI, Rudd PM, Owen KR, Lauc G, Wright AF

Abstract
A recent genome-wide association study identified hepatocyte nuclear factor 1-α (HNF1A) as a key regulator of fucosylation. We hypothesized that loss-of-function HNF1A mutations causal for maturity-onset diabetes of the young (MODY) would display altered fucosylation of N-linked glycans on plasma proteins and that glycan biomarkers could improve the efficiency of a diagnosis of HNF1A-MODY. In a pilot comparison of 33 subjects with HNF1A-MODY and 41 subjects with type 2 diabetes, 15 of 29 glycan measurements differed between the two groups. The DG9-glycan index, which is the ratio of fucosylated to nonfucosylated triantennary glycans, provided optimum discrimination in the pilot study and was examined further among additional subjects with HNF1A-MODY (n = 188), glucokinase (GCK)-MODY (n = 118), hepatocyte nuclear factor 4-α (HNF4A)-MODY (n = 40), type 1 diabetes (n = 98), type 2 diabetes (n = 167), and nondiabetic controls (n = 98). The DG9-glycan index was markedly lower in HNF1A-MODY than in controls or other diabetes subtypes, offered good discrimination between HNF1A-MODY and both type 1 and type 2 diabetes (C statistic ≥ 0.90), and enabled us to detect three previously undetected HNF1A mutations in patients with diabetes. In conclusion, glycan profiles are altered substantially in HNF1A-MODY, and the DG9-glycan index has potential clinical value as a diagnostic biomarker of HNF1A dysfunction.

PMID: 23274891 [PubMed - indexed for MEDLINE]

Increase of palmitic acid concentration impairs endothelial progenitor cell and bone marrow-derived progenitor cell bioavailability: role of the STAT5/PPARγ transcriptional complex.

Diabetes. 2013 Apr;62(4):1245-57

Authors: Trombetta A, Togliatto G, Rosso A, Dentelli P, Olgasi C, Cotogni P, Brizzi MF

Abstract
Metabolic profiling of plasma nonesterified fatty acids discovered that palmitic acid (PA), a natural peroxisome proliferator-activated receptor γ (PPARγ) ligand, is a reliable type 2 diabetes biomarker. We investigated whether and how PA diabetic (d-PA) concentrations affected endothelial progenitor cell (EPC) and bone marrow-derived hematopoietic cell (BM-HC) biology. PA physiologic (n-PA) and d-PA concentrations were used. Proliferating cell nuclear antigen content and signal transducer and activator of transcription 5 (STAT5), PPARγ, cyclin D1, and p21(Waf) expression were evaluated. Small interfering RNA technology, gene reporter luciferase assay, electrophoretic mobility shift assay, chromatin immunoprecipitation assay, and coimmunoprecipitation were exploited. In vivo studies and migration assays were also performed. d-PA, unlike n-PA or physiological and diabetic oleic and stearic acid concentrations, impaired EPC migration and EPC/BM-HC proliferation through a PPARγ-mediated STAT5 transcription inhibition. This event did not prevent the formation of a STAT5/PPARγ transcriptional complex but was crucial for gene targeting, as p21(Waf) gene promoter, unlike cyclin D1, was the STAT5/PPARγ transcriptional target. Similar molecular events could be detected in EPCs isolated from type 2 diabetic patients. By expressing a constitutively activated STAT5 form, we demonstrated that STAT5 content is crucial for gene targeting and EPC fate. Finally, we also provide in vivo data that d-PA-mediated EPC dysfunction could be rescued by PPARγ blockade. These data provide first insights on how mechanistically d-PA drives EPC/BM-HC dysfunction in diabetes.

PMID: 23223023 [PubMed - indexed for MEDLINE]

Adipose tissue concentrations of persistent organic pollutants and prevalence of type 2 diabetes in adults from Southern Spain.

Environ Res. 2013 Apr;122:31-7

Authors: Arrebola JP, Pumarega J, Gasull M, Fernandez MF, Martin-Olmedo P, Molina-Molina JM, Fernández-Rodríguez M, Porta M, Olea N

Abstract
There is increasing evidence that environmental factors play an important role in the development of type 2 diabetes. Several persistent organic pollutants are suspected to contribute to the increasing prevalence and risk of type 2 diabetes. The aim of this study was to investigate the association of the body burden of three organochlorine pesticides and three polychlorinated biphenyls and the overall estrogenic activity with the risk of type 2 diabetes in a sample of adults from Southern Spain. Samples of adipose tissue and serum were obtained from 386 subjects undergoing non-cancer-related surgery and were extracted using validated methodologies. Residues of persistent organic pollutants were analyzed by means of high-resolution gas chromatography with a mass spectrometry detector in tandem mode. The overall estrogenicity of the adipose tissue extracts was measured by using the total effective xenoestrogen burden (TEXB) biomarker. Data on lifestyle, dietary habits, and health status were gathered from face-to-face interviews and clinical records. Statistical analyses were performed with unconditional logistic regression and different adjustment levels. In the models adjusted for adipose tissue origin, sex, age, and body mass index, the 2nd and 3rd tertiles of adipose tissue concentrations of p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) were positively associated with the risk of diabetes [odds ratios (95% confidence interval)=3.6 (0.8-17.3) and 4.4 (1.0-21.0), respectively]. A positive association with β-hexachlorocyclohexane was also found when body mass index and adipose tissue origin were removed from the models, with odds ratios (95% confidence interval) of 3.3 (1.0-10.4) and 5.5 (1.7-17.3), for the 2nd and 3rd tertiles of exposure, respectively. In addition, a statistically significant interaction was observed between p,p'-DDE and body mass index, such that the risk of diabetes increased with tertiles of exposure in a linear manner in non-obese subjects but not in the obese, in whom an inverted U-shape pattern was observed.

PMID: 23290489 [PubMed - indexed for MEDLINE]

Delineating the degree of association between biomarkers of arsenic exposure and type-2 diabetes mellitus.

Int J Hyg Environ Health. 2013 Jan;216(1):35-49

Authors: Andra SS, Makris KC, Christophi CA, Ettinger AS

Abstract
Non-carcinogenic effects in low-level (< 100 μgL(-1)) arsenic (As)-impacted populations, such as the development and progression of type-2 diabetes mellitus (T2DM), are often neglected given the primary emphasis of public health authorities on As carcinogenicity. We gathered studies reporting urinary biomarkers of As exposure (U-As) and biomarkers associated with T2DM and its complications (U-T2DM), such as renal damage, oxidation stress, low-grade inflammation, and endothelial damage. Studied U-T2DM biomarkers were: 8-hydroxy-2'deoxyguanosine, N-acetyl-β-d-glucosaminidase, β2-microglobulin, and albumin. Data was expressed as: either arithmetic means and standard deviations, or geometric means and geometric standard deviations, or correlation coefficients of U-As and U-T2DM. Urinary As concentrations were consistently associated with the aforementioned biomarkers of T2DM pathologic complications. Despite the limited selectivity of the selected T2DM biomarkers, a per unit change in As exposure level was reflected in the corresponding T2DM biomarker urinary concentrations. Our systematic review provides new evidence on the role of environmental As exposures influencing the T2DM disease process. Additional epidemiologic studies onto the association between As and T2DM should incorporate both urinary As and T2DM biomarkers, as suggested in this study, in order to evaluate subclinical effects of low-level As exposures.

PMID: 22920650 [PubMed - indexed for MEDLINE]

Secreted frizzled-related protein 4 reduces insulin secretion and is overexpressed in type 2 diabetes.

Cell Metab. 2012 Nov 7;16(5):625-33

Authors: Mahdi T, Hänzelmann S, Salehi A, Muhammed SJ, Reinbothe TM, Tang Y, Axelsson AS, Zhou Y, Jing X, Almgren P, Krus U, Taneera J, Blom AM, Lyssenko V, Esguerra JL, Hansson O, Eliasson L, Derry J, Zhang E, Wollheim CB, Groop L, Renström E, Rosengren AH

Abstract
A plethora of candidate genes have been identified for complex polygenic disorders, but the underlying disease mechanisms remain largely unknown. We explored the pathophysiology of type 2 diabetes (T2D) by analyzing global gene expression in human pancreatic islets. A group of coexpressed genes (module), enriched for interleukin-1-related genes, was associated with T2D and reduced insulin secretion. One of the module genes that was highly overexpressed in islets from T2D patients is SFRP4, which encodes secreted frizzled-related protein 4. SFRP4 expression correlated with inflammatory markers, and its release from islets was stimulated by interleukin-1β. Elevated systemic SFRP4 caused reduced glucose tolerance through decreased islet expression of Ca(2+) channels and suppressed insulin exocytosis. SFRP4 thus provides a link between islet inflammation and impaired insulin secretion. Moreover, the protein was increased in serum from T2D patients several years before the diagnosis, suggesting that SFRP4 could be a potential biomarker for islet dysfunction in T2D.

PMID: 23140642 [PubMed - indexed for MEDLINE]

Soluble serum Klotho in diabetic nephropathy: relationship to VEGF-A.

Clin Biochem. 2012 Nov;45(16-17):1415-20

Authors: Kacso IM, Bondor CI, Kacso G

Abstract
OBJECTIVES: Both kidney expression and soluble serum Klotho are influenced by chronic kidney disease (CKD) and diabetes. Serum Klotho is a yet poorly explored biomarker. We describe, for the first time to our knowledge, serum Klotho in diabetic patients with CKD and its relationship to vascular endothelial growth factor A (VEGF-A).
DESIGN AND METHODS: We included 43 controls and 146 diabetic patients with different stages of CKD. Laboratory evaluation, urinary albumin/creatinine ratio (UACR), Klotho (ELISA), VEGF-A (ELISA) were performed.
RESULTS: Klotho was 0.40(0.10-1.30)ng/mL in diabetic patients without CKD and 0.80(0.30-1.30)ng/mL in controls, p=0.20; VEGF-A was higher in diabetic patients 73.85(57.32-119.00)pg/mL than in controls 43.20(30.1-65.9)pg/mL, p<0.0001. Klotho increased with CKD stage: 0.2(0.10-0.40)ng/mL in CKD 1/2, 0.60(0.20-1.1)ng/mL in CKD 3/4 and 1.45(0.425-2.90)ng/mL in dialysis patients, p<0.0001; it also increased with decreasing glomerular filtration rate (GFR). Klotho was lower in albuminuric (UACR>30 mg/g) patients 0.20(0.10-0.70)ng/mL than in normoalbuminuric (UACR<30 mg/g) ones 0.50(0.20-1.30)ng/mL, p=0.03; lowest Klotho was found in microalbuminuric (UACR 30-300 mg/g) patients, p=0.07. VEGF was lower in microalbuminuric patients but was not influenced by GFR. In diabetic patients but not in controls, Klotho correlated to VEGF-A (r=0.29, p=0.0003); in multiple regression VEGF-A was the only significant predictor of Klotho: b=0.27, 95%CI (0.01-0.04), p=0.001.
CONCLUSIONS: In diabetic patients, Klotho is decreased in early CKD and increases thereafter, paralleling reduced GFR. VEGF-A is higher in diabetic patients than in controls. Both Klotho and VEGF-A are decreased in the presence of microalbuminuria. In diabetes, Klotho strongly correlates to VEGF-A.

PMID: 22836100 [PubMed - indexed for MEDLINE]

Behavioral and clinical correlates of high-sensitivity C-reactive protein in Japanese men and women.

Clin Chem Lab Med. 2012 Aug;50(8):1469-76

Authors: Hirata A, Ohnaka K, Morita M, Toyomura K, Kono S, Yamamoto K, Adachi M, Kawate H, Takayanagi R

Abstract
BACKGROUND: Inflammation has been implicated in the pathogenesis of cardiovascular disease, type 2 diabetes mellitus and cancer. Serum concentration of high-sensitivity C-reactive protein is a good biomarker of chronic low-grade inflammation. Few studies have evaluated relative importance of behavioral and clinical covariates of high-sensitivity C-reactive protein in Japanese population.
METHODS: The study subjects were men and women aged 49-76 years from the cohort study of lifestyle-related diseases between February 2004 and July 2006. Analysis of covariance and multiple linear regression analysis were used to estimate geometric means of high-sensitivity C-reactive protein and trends of association.
RESULTS: Smoking, body mass index, hypertension, type 2 diabetes mellitus, elevated non-high density lipoprotein cholesterol, prudent dietary pattern were independently associated with serum high-sensitivity C-reactive protein in both men and women. High-sensitivity C-reactive protein concentrations were lowest in men with a moderate intake of alcohol (<30 mL/day). In men, smoking and body mass index accounted for 28% and 26% of the variation in high-sensitivity C-reactive protein, respectively, while body mass index accounted for 60% of the variation of high-sensitivity C-reactive protein in women.
CONCLUSIONS: Smoking and body mass index in men, and body mass index in women, were major correlates of serum high-sensitivity C-reactive protein in Japanese people.

PMID: 22868815 [PubMed - indexed for MEDLINE]

MicroRNA-15a and microRNA-16 impair human circulating proangiogenic cell functions and are increased in the proangiogenic cells and serum of patients with critical limb ischemia.

Circ Res. 2013 Jan 18;112(2):335-46

Authors: Spinetti G, Fortunato O, Caporali A, Shantikumar S, Marchetti M, Meloni M, Descamps B, Floris I, Sangalli E, Vono R, Faglia E, Specchia C, Pintus G, Madeddu P, Emanueli C

Abstract
RATIONALE: Circulating proangiogenic cells (PACs) support postischemic neovascularization. Cardiovascular disease and diabetes mellitus impair PAC regenerative capacities via molecular mechanisms that are not fully known. We hypothesize a role for microRNAs (miRs). Circulating miRs are currently investigated as potential diagnostic and prognostic biomarkers.
OBJECTIVE: The objectives were the following: (1) to profile miR expression in PACs from critical limb ischemia (CLI) patients; (2) to demonstrate that miR-15a and miR-16 regulate PAC functions; and (3) to characterize circulating miR-15a and miR-16 and to investigate their potential biomarker value.
METHODS AND RESULTS: Twenty-eight miRs potentially able to modulate angiogenesis were measured in PACs from CLI patients with and without diabetes mellitus and controls. miR-15a and miR-16 were further analyzed. CLI-PACs expressed higher level of mature miR-15a and miR-16 and of the primary transcript pri-miR-15a/16-1. miR-15a/16 overexpression impaired healthy PAC survival and migration. Conversely, miR-15a/16 inhibition improved CLI-PAC-defective migration. Vascular endothelial growth factor-A and AKT-3 were validated as direct targets of the 2 miRs, and their protein levels were reduced in miR-15a/16-overexpressing healthy PACs and in CLI-PACs. Transplantation of healthy PACs ex vivo-engineered with anti-miR-15a/16 improved postischemic blood flow recovery and muscular arteriole density in immunodeficient mice. miR-15a and miR-16 were present in human blood, including conjugated to argonaute-2 and in exosomes. Both miRs were increased in the serum of CLI patients and positively correlated with amputation after restenosis at 12 months postrevascularization of CLI type 2 diabetes mellitus patients. Serum miR-15a additionally correlated with restenosis at follow-up.
CONCLUSIONS: Ex vivo miR-15a/16 inhibition enhances PAC therapeutic potential, and circulating miR-15a and miR-16 deserves further investigation as a prognostic biomarker in CLI patients undergoing revascularization.

PMID: 23233752 [PubMed - indexed for MEDLINE]

A comparison between MALDI-MS and CE-MS data for biomarker assessment in chronic kidney diseases.

J Proteomics. 2012 Oct 22;75(18):5888-97

Authors: Molin L, Seraglia R, Lapolla A, Ragazzi E, Gonzalez J, Vlahou A, Schanstra JP, Albalat A, Dakna M, Siwy J, Jankowski J, Bitsika V, Mischak H, Zürbig P, Traldi P

Abstract
Non-invasive detection of diseases, based on urinary proteomics, is becoming an increasingly important area of research, especially in the area of chronic kidney disease (CKD). Different platforms have been used in independent studies, mostly capillary-electrophoresis coupled ESI-MS (CE-MS), liquid chromatography coupled mass spectrometry, and matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). We have compared the performance of CE-MS with MALDI-MS in detecting CKD, based on a cohort of 137 urine samples (62 cases and 75 controls). Data cross-talk between the two platforms was established for the comparison of detected biomarkers. The results demonstrate superior performance of the CE-MS approach in terms of peptide resolution and obtained disease prediction accuracy rates. However, the data also demonstrate the ability of the MALDI-MS approach to separate CKD patients from controls, at slightly reduced accuracy, but expected reduced cost and time. As a consequence, a practical approach can be foreseen where MALDI-MS is employed as an inexpensive, fast, and robust screening tool to detect probable CKD. In a second step, high resolution CE-MS could be used in those patients only that scored negative for CKD in the MALDI-MS analysis, reducing costs and time of such a program.

PMID: 22842158 [PubMed - indexed for MEDLINE]

A method for the early health technology assessment of novel biomarker measurement in primary prevention programs.

Stat Med. 2012 Oct 15;31(23):2733-44

Authors: Postmus D, de Graaf G, Hillege HL, Steyerberg EW, Buskens E

Abstract
Many promising biomarkers for stratifying individuals at risk of developing a chronic disease or subsequent complications have been identified. Research into the potential cost-effectiveness of applying these biomarkers in actual clinical settings has however been lacking. Investors and analysts may improve their venture decision making should they have indicative estimates of the potential costs and effects associated with a new biomarker technology already at the early stages of its development. To assist in obtaining such estimates, this paper presents a general method for the early health technology assessment of a novel biomarker technology. The setting considered is that of primary prevention programs where initial screening to select high-risk individuals eligible for a subsequent intervention occurs, for example, prevention of type 2 diabetes. The method is based on quantifying the health outcomes and downstream healthcare consumption of all individuals who get reclassified as a result of moving from a screening variant based on traditional risk factors to a screening variant based on traditional risk factors plus a novel biomarker. As these individuals form well-defined subpopulations, a combination of disease progression modeling and sensitivity analysis can be used to perform an initial assessment of the maximum increase in screening cost for which the use of the new biomarker technology is still likely to be cost effective.

PMID: 22806952 [PubMed - indexed for MEDLINE]

A randomized trial of selenium supplementation and risk of type-2 diabetes, as assessed by plasma adiponectin.

PLoS One. 2012;7(9):e45269

Authors: Rayman MP, Blundell-Pound G, Pastor-Barriuso R, Guallar E, Steinbrenner H, Stranges S

Abstract
BACKGROUND: Evidence that selenium affects the risk of type-2 diabetes is conflicting, with observational studies and a few randomized trials showing both lower and higher risk linked to the level of selenium intake and status. We investigated the effect of selenium supplementation on the risk of type-2 diabetes in a population of relatively low selenium status as part of the UK PRECISE (PREvention of Cancer by Intervention with SElenium) pilot study. Plasma adiponectin concentration, a recognised independent predictor of type-2 diabetes risk and known to be correlated with circulating selenoprotein P, was the biomarker chosen.
METHODS: In a randomized, double-blind, placebo-controlled trial, five hundred and one elderly volunteers were randomly assigned to a six-month intervention with 100, 200 or 300 µg selenium/d as high-selenium or placebo yeast. Adiponectin concentration was measured by ELISA at baseline and after six months of treatment in 473 participants with one or both plasma samples available.
RESULTS: Mean (SD) plasma selenium concentration was 88.5 ng/g (19.1) at baseline and increased significantly in the selenium-treatment groups. In baseline cross-sectional analyses, the fully adjusted geometric mean of plasma adiponectin was 14% lower (95% CI, 0-27%) in the highest than in the lowest quartile of plasma selenium (P for linear trend = 0.04). In analyses across randomized groups, however, selenium supplementation had no effect on adiponectin levels after six months of treatment (P = 0.96).
CONCLUSIONS: These findings are reassuring as they did not show a diabetogenic effect of a six-month supplementation with selenium in this sample of elderly individuals of relatively low selenium status.

PMID: 23028897 [PubMed - indexed for MEDLINE]

Urinary podocalyxin is an early marker for podocyte injury in patients with diabetes: establishment of a highly sensitive ELISA to detect urinary podocalyxin.

Diabetologia. 2012 Nov;55(11):2913-9

Authors: Hara M, Yamagata K, Tomino Y, Saito A, Hirayama Y, Ogasawara S, Kurosawa H, Sekine S, Yan K

Abstract
UNLABELLED: AIMS/OBJECTIVE: Nephropathy, a major complication of diabetes, is the leading cause of end-stage renal disease. Recent studies have demonstrated that podocyte injury is involved in the onset of and progression to renal insufficiency. Here, we describe a novel, highly sensitive ELISA for detecting urinary podocalyxin, a glycoconjugate on the podocyte apical surface that indicates podocyte injury, particularly in the early phase of diabetic nephropathy.
METHODS: Urine samples from patients with glomerular diseases (n = 142) and type 2 diabetes (n = 71) were used to quantify urinary podocalyxin by ELISA. Urine samples were obtained from 69 healthy controls for whom laboratory data were within normal values. Podocalyxin was detected in urine by immunofluorescence, immunoelectron microscopy and western blotting.
RESULTS: Morphologically, urinary podocalyxin was present as a vesicular structure; western blotting showed it as a positive band at 165-170 kDa. Levels of urinary podocalyxin were elevated in patients with various glomerular diseases and patients with diabetes. In patients with diabetes, urinary podocalyxin was higher than the cut-off value in 53.8% patients at the normoalbuminuric stage, 64.7% at the microalbuminuric stage and 66.7% at the macroalbuminuric stage. Positive correlations were observed between urinary podocalyxin levels and HbA(1c), urinary β(2) microglobulin, α(1) microglobulin and urinary N-acetyl-β-D-glucosaminidase, although urinary podocalyxin levels were not correlated with other laboratory markers such as blood pressure, lipid level, serum creatinine, estimated GFR or proteinuria.
CONCLUSIONS/INTERPRETATION: Urinary podocalyxin may be a useful biomarker for detecting early podocyte injury in patients with diabetes.

PMID: 22854890 [PubMed - indexed for MEDLINE]