Long Non-Coding RNA Signatures in the Ileum and Colon of Crohn's Disease Patients and Effect of Anti-TNF-α Treatment on Their Modulation.

Biological therapies only benefit one-third of patients with Crohn's disease (CD). For this reason, a deeper understanding of the mechanisms by which biologics elicit their effect on intestinal mucosa is needed. Increasing evidence points toward the involvement of long noncoding RNAs (lncRNAs) in the pathogenesis of CD, although their role remains poorly studied. We aimed to characterize lncRNA profiles in the ileum and colon from CD patients and evaluate the effect of anti-TNF-α treatment on their transcription. Terminal ileum and left colon samples from 30 patients (active CD = 10, quiescent CD = 10, and healthy controls (HCs) = 10) were collected for RNA-seq. The patients were classified according to endoscopic activity. Furthermore, biopsies were cultured with infliximab, and their transcriptome was determined by Illumina gene expression array. A total of 678 differentially expressed lncRNAs between the terminal ileum and left colon were identified in HCs, 438 in patients with quiescent CD, and 468 in patients with active CD. Additionally, we identified three new lncRNAs in the ileum associated with CD activity. No differences were observed when comparing the effect of infliximab according to intestinal location, presence of disease (CD vs. HC), and activity (active vs. quiescent). The expression profiles of lncRNAs are associated with the location of intestinal tissue, being very different in the ileum and colon. The presence of CD and disease activity are associated with the differential expression of lncRNAs. No modulatory effect of infliximab has been observed in the lncRNA transcriptome.

New Pieces for an Old Puzzle: Approaching Parkinson's Disease from Translatable Animal Models, Gut Microbiota Modulation, and Lipidomics.

Parkinson's disease (PD) is a severe neurodegenerative disease characterized by disabling motor alterations that are diagnosed at a relatively late stage in its development, and non-motor symptoms, including those affecting the gastrointestinal tract (mainly constipation), which start much earlier than the motor symptoms. Remarkably, current treatments only reduce motor symptoms, not without important drawbacks (relatively low efficiency and impactful side effects). Thus, new approaches are needed to halt PD progression and, possibly, to prevent its development, including new therapeutic strategies that target PD etiopathogeny and new biomarkers. Our aim was to review some of these new approaches. Although PD is complex and heterogeneous, compelling evidence suggests it might have a gastrointestinal origin, at least in a significant number of patients, and findings in recently developed animal models strongly support this hypothesis. Furthermore, the modulation of the gut microbiome, mainly through probiotics, is being tested to improve motor and non-motor symptoms and even to prevent PD. Finally, lipidomics has emerged as a useful tool to identify lipid biomarkers that may help analyze PD progression and treatment efficacy in a personalized manner, although, as of today, it has only scarcely been applied to monitor gut motility, dysbiosis, and probiotic effects in PD. Altogether, these new pieces should be helpful in solving the old puzzle of PD.

Gut Microbiota and Dietary Factors as Modulators of the Mucus Layer in Inflammatory Bowel Disease.

The gastrointestinal tract is optimized to efficiently absorb nutrients and provide a competent barrier against a variety of lumen environmental compounds. Different regulatory mechanisms jointly collaborate to maintain intestinal homeostasis, but alterations in these mechanisms lead to a dysfunctional gastrointestinal barrier and are associated to several inflammatory conditions usually found in chronic pathologies such as inflammatory bowel disease (IBD). The gastrointestinal mucus, mostly composed of mucin glycoproteins, covers the epithelium and plays an essential role in digestive and barrier functions. However, its regulation is very dynamic and is still poorly understood. This review presents some aspects concerning the role of mucus in gut health and its alterations in IBD. In addition, the impact of gut microbiota and dietary compounds as environmental factors modulating the mucus layer is addressed. To date, studies have evidenced the impact of the three-way interplay between the microbiome, diet and the mucus layer on the gut barrier, host immune system and IBD. This review emphasizes the need to address current limitations on this topic, especially regarding the design of robust human trials and highlights the potential interest of improving our understanding of the regulation of the intestinal mucus barrier in IBD.

Lunasin Peptide is a Modulator of the Immune Response in the Human Gastrointestinal Tract.

INTRODUCTION: Lunasin is a soybean bioactive peptide with a variety of beneficial properties against chronic disorders. However, its effect in human primary intestinal cells remains unknown. Hence, this study aims to characterize its ex vivo biological activity in the human intestinal mucosa. METHODS AND RESULTS: Human intestinal biopsies, obtained from healthy controls, are ex vivo conditioned with lunasin both in the presence/absence of lipopolysaccharide (LPS). Peptide maintains its stability during biopsy culture by HPLC-MS/MS analysis. Lunasin is bioactive in the human mucosa, as it induces IL-1ß, TNF-α, IL-17A, CCL2, and PGE2/COX-2 gene expression together with an increased expression of tolerogenic IL-10 and TGFß, while it also downregulates the expression of iNOS and subunit p65 from NF-κB. Indeed, lunasin also abrogates the LPS-induced pro-inflammatory response, downregulating IL-17A, IFNγ, and IL-8 expression, and inducing IL-10 and TGFß expression. These results are also mirrored in the cell-free culture supernatants at the protein level by Multiplex. Moreover, lunasin further induces a regulatory phenotype and function on human intestinal conventional dendritic cell and macrophage subsets as assessed by flow cytometry. CONCLUSIONS: We hereby have characterized lunasin as an immunomodulatory peptide with potential capacity to prevent immune and inflammatory-mediated disorders in the human gastrointestinal tract.

Profiling of Human Circulating Dendritic Cells and Monocyte Subsets Discriminates Between Type and Mucosal Status in Patients With Inflammatory Bowel Disease.

BACKGROUND: Intestinal dendritic cells (DC) and macrophages drive disease progression in patients with inflammatory bowel disease (IBD). We aimed to characterize the activation and homing profile of human circulating DC and monocyte subsets in healthy control patients (CP) and IBD patients. METHODS: Eighteen CP and 64 patients with IBD were categorized by diagnoses of Crohn disease (CD) and ulcerative colitis (UC), either endoscopically active (inflamed) or quiescent. Circulating type 1 conventional DC, type 2 conventional DC, plasmacytoid DC, classical monocytes, nonclassical monocytes, and intermediate monocytes were identified by flow cytometry in each individual and characterized for the expression of 18 markers. Association between DC/monocytes and IBD risk was tested by logistic regression. Discriminant canonical analyses were performed to classify the patients in their own endoscopy category considering all markers on each subset. RESULTS: CCRL1, CCR3, and CCR5 expression on circulating type 1 DC; CCRL1 expression on nonclassical monocytes; and CCR9 and ß7 expression on classical monocytes allowed us to discriminate among the different study groups. Indeed, the same markers (excluding ß7) were also associated with IBD when all DC and monocyte subsets were considered at the same time. CONCLUSIONS: Monitoring the phenotype of human circulating DC and monocyte subsets may provide novel tools as biomarkers for disease diagnosis (CD/UC) or mucosal status (inflamed/noninflamed) in the absence of an invasive colonoscopy.

Serum adipokines as non-invasive biomarkers in Crohn's disease.

Adipose tissue secretes molecules that can promote activity in Crohn's disease. We aimed to evaluate the role of serum adipokines as possible biomarkers in Crohn's disease. Serum samples were obtained from 40 patients with endoscopically active or quiescent Crohn's disease and 36 healthy controls. Serum leptin, ghrelin, resistin and adiponectin levels were analysed by Multiplex in a Luminex 200 system technology. Receiver Operating Characteristic curves were performed to evaluate the adipokines discriminatory capacity. A logistic regression adjusted by possible confounders (i.e. gender, age, BMI) was performed for those adipokines that showed an area under the curve > 0.7. No differences were found in age, gender or BMI among groups. Distribution for serum resistin was different among the three groups of study, and only this adipokine showed an area under the curve of 0.75 comparing actives patients and healthy control groups. Resistin median concentration was selected as a cut-off for a logistic regression analysis; odds ratio along its 95% confidence interval adjusted by gender, age, and BMI yielded a value of 5.46 (1.34-22.14) comparing actives patients and healthy controls. High concentration of serum resistin is probably associated to activity, being this association independent of gender, age or BMI.

Modelo de riesgo de mortalidad precoz en pacientes ancianos con enfermedad aguda atendidos por servicios de emergencias prehospitalarias / Risk for early death in acutely ill older adults attended by prehospital emergency medical services

OBJETIVOS: Diseñar y validar un modelo predictivo de mortalidad hospitalaria precoz (≤ 48 horas) en pacientes $ 65 años y basado en variables determinadas a nivel prehospitalario. MÉTODO: Estudio multicéntrico de cohorte prospectivo y observacional. Se incluyeron pacientes $ 65 años atendi¬dos por unidades de soporte vital avanzado y trasladados a un servicio de urgencias hospitalario. Se recogieron va-riables demográficas, clínicas y analíticas. Se construyó y validó una escala de puntuación mediante la categoriza¬ción de las variables seleccionadas mediante regresión logística en función de la mortalidad en ≤ 48 horas. RESULTADOS: Se reclutaron 1.759 pacientes, la edad mediana fue de 79 años (RIC 72-85), 766 eran mujeres (43,5%), y fallecieron 108 pacientes (6,1%) en ≤ 48 horas. El modelo predictivo -escala POAWS (Prehospital Older Adults Warning Score)- incluyó la edad, presión arterial sistólica, temperatura, saturación de oxígeno en relación con la frac¬ción inspirada de oxígeno, escala de coma de Glasgow y ácido láctico en sangre venosa. El área bajo la curva de la característica operativa del receptor para la mortalidad en ≤ 48 horas fue de 0,853 (IC 95%: 0,80-0,91; p < 0,001). La mortalidad en los pacientes de alto riesgo (> 7 puntos en la escala) fue del 69%. CONCLUSIONES: La escala POAWS desarrollada en el presente estudio puede ser de utilidad para estratificar el riesgo de muerte de los patientes de 65 o más años durante las 48 horas siguientes a la atención en el ámbito prehospitalario

OBJECTIVE: To develop and validate a prehospital risk model to predict early in-hospital mortality (󖽀 hours) in patients aged 65 years or older. METHODS: Prospective multicenter observational study in a cohort of patients aged 65 years or older attended by advanced life support emergency services and transferred to 5 Spanish hospitals between April 2018 and July 2019. We collected demographic, clinical and laboratory variables. A risk score was constructed and validated based on the analysis of prehospital variables associated with death within 48 hours. Predictors were selected by logistic regression. RESULTS: A total of 1759 patients were recruited. The median age was 79 years (interquartile range, 72-85 years), and 766 (43.5%) were women. One hundred eight patients (6.1%) died within 48 hours. Predictors in the Prehospital Older Adults Warning Scale (POAWS) were age, systolic blood pressure, temperature, the ratio of oxygen saturation to the fraction of inspired oxygen, score on the Glasgow coma scale, and lactic acid concentration in venous blood. The area under the receiver operating characteristic curve of the model to predict early mortality was 0.853 (95% CI, 0.80-0.91; P < .001). Mortality in patients at high risk (POAWS score, > 7) was 69%. CONCLUSIONS: The prehospital POAWS score can be used to stratify risk for death within 48 hours in patients aged 65 years or older

Risk for early death in acutely ill older adults attended by prehospital emergency medical services. / Modelo de riesgo de mortalidad precoz en pacientes ancianos con enfermedad aguda atendidos por servicios de emergencias prehospitalarias.

OBJECTIVES: To develop and validate a prehospital risk model to predict early in-hospital mortality (#48 hours) in patients aged 65 years or older. MATERIAL AND METHODS: Prospective multicenter observational study in a cohort of patients aged 65 years or older attended by advanced life support emergency services and transferred to 5 Spanish hospitals between April 2018 and July 2019. We collected demographic, clinical and laboratory variables. A risk score was constructed and validated based on the analysis of prehospital variables associated with death within 48 hours. Predictors were selected by logistic regression. RESULTS: A total of 1759 patients were recruited. The median age was 79 years (interquartile range, 72-85 years), and 766 (43.5%) were women. One hundred eight patients (6.1%) died within 48 hours. Predictors in the Prehospital Older Adults Warning Scale (POAWS) were age, systolic blood pressure, temperature, the ratio of oxygen saturation to the fraction of inspired oxygen, score on the Glasgow coma scale, and lactic acid concentration in venous blood. The area under the receiver operating characteristic curve of the model to predict early mortality was 0.853 (95% CI, 0.80-0.91; P<.001). Mortality in patients at high risk (POAWS score, >7) was 69%. CONCLUSION: The prehospital POAWS score can be used to stratify risk for death within 48 hours in patients aged 65 years or older.

OBJETIVO: Diseñar y validar un modelo predictivo de mortalidad hospitalaria precoz (# 48 horas) en pacientes $ 65 años y basado en variables determinadas a nivel prehospitalario. METODO: Estudio multicéntrico de cohorte prospectivo y observacional. Se incluyeron pacientes $ 65 años atendidos por unidades de soporte vital avanzado y trasladados a un servicio de urgencias hospitalario. Se recogieron variables demográficas, clínicas y analíticas. Se construyó y validó una escala de puntuación mediante la categorización de las variables seleccionadas mediante regresión logística en función de la mortalidad en # 48 horas. RESULTADOS: Se reclutaron 1.759 pacientes, la edad mediana fue de 79 años (RIC 72-85), 766 eran mujeres (43,5%), y fallecieron 108 pacientes (6,1%) en # 48 horas. El modelo predictivo ­escala POAWS (Prehospital Older Adults Warning Score)­ incluyó la edad, presión arterial sistólica, temperatura, saturación de oxígeno en relación con la fracción inspirada de oxígeno, escala de coma de Glasgow y ácido láctico en sangre venosa. El área bajo la curva de la característica operativa del receptor para la mortalidad en # 48 horas fue de 0,853 (IC 95%: 0,80-0,91; p < 0,001). La mortalidad en los pacientes de alto riesgo (> 7 puntos en la escala) fue del 69%. CONCLUSIONES: La escala POAWS desarrollada en el presente estudio puede ser de utilidad para estratificar el riesgo de muerte de los patientes de 65 o más años durante las 48 horas siguientes a la atención en el ámbito prehospitalario.

Immunomodulatory Effect of Gut Microbiota-Derived Bioactive Peptides on Human Immune System from Healthy Controls and Patients with Inflammatory Bowel Disease.

Bioactive peptides secreted by probiotic Bifidobacterium longum (peptide B7) and opportunistic pathogen Bacteroides fragilis (peptide B12) modulate the intestinal cytokine milieu in health. Here, we characterized their capacity to modulate both the mucosal cytokine production and the phenotype of circulating antigen presenting cells (APCs) in active inflammatory bowel disease (IBD). The IBD mucosa produced higher levels of pro-inflammatory cytokines referred to healthy controls (HCs). Peptides B7 and B12, however, did not ameliorate the mucosal cytokine milieu in IBD. Human circulating APCs (B-cells, monocytes, plasmacytoid dendritic cells (pDCs), and conventional dendritic cells (cDCs)) were characterized by flow cytometry in presence/absence of the peptides. Circulating B-cells, monocytes, and cDCs from IBD patients were more activated than those from HCs. Peptide B7, but not B12, decreased CCR2 expression on all APC subsets from HC, but not IBD patients. Moreover, both peptides tend to further increase their pro-inflammatory profile in IBD. In summary, IBD patients display mucosal and circulating APC pro-inflammatory properties. Peptide B7 immunomodulatory capacity elicited over circulating APCs from HC, but not IBD patients, suggests the presence of disrupted modulatory mechanisms for this peptide in IBD. Future studies should address the effect of bacteria-derived immunomodulatory peptides in non-inflamed (quiescent) IBD patients.

Serum resistin is causally related to mortality risk in patients with type 2 diabetes: preliminary evidences from genetic data.

Resistin has been firmly associated with all-cause mortality. We investigated, whether, in patients with type 2 diabetes (T2D), this association is sustained by a cause-effect relationship. A genotype risk score (GRS), created by summing the number of resistin increasing alleles of two genome-wide association studies (GWAS)-derived single nucleotide polymorphisms (SNPs), serum resistin measurements and all-cause death records were obtained in 1,479 (403 events/12,454 person-years), patients with T2D from three cohorts, Gargano Heart Study-prospective design (n = 350), Gargano Mortality Study (n = 698) and Foggia Mortality Study (n = 431), from Italy. GRS was strongly associated with serum resistin in a non-linear fashion (overall p = 3.5 * 10-7) with effect size modest for GRS = 1 and 2 and much higher for GRS >3, with respect to GRS = 0. A significant non-linear association was observed also between GRS and all-cause mortality (overall p = 3.3 * 10-2), with a low effect size for GRS = 1 and 2, and nearly doubled for GRS ≥ 3, with respect to GRS = 0. Based on the above-reported associations, each genetic equivalent SD increase in log-resistin levels showed a causal hazard ratio of all-cause mortality equal to 2.17 (95%CI: 1.22-3.87), thus providing evidence for a causal role of resistin in shaping the risk of mortality in diabetic patients.

Suggestive evidence of a multi-cytokine resistin pathway in humans and its role on cardiovascular events in high-risk individuals.

In cells and tissues resistin affects IL-1ß, IL-6, IL-8, IL-12 and TNF-α expression, thus suggesting the existence of a multi-cytokine "resistin pathway". We investigated whether such pathway does exist in humans and, if so, if it is associated with cardiovascular risk factors and with major adverse cardiovascular events (MACE). Serum cytokines were measured in 280 healthy subjects from the Gargano Study 2 (GS2) whose BMI, waist circumference, HOMAIR, triglycerides, HDL-cholesterol, systolic and diastolic blood pressure data were available and in 353 patients with type 2 diabetes and coronary artery disease from the Gargano Heart Study (GHS)-prospective design (follow-up 5.4 ± 2.5 years; 71 MACE). In GS2, cytokines mRNA levels in white blood cells were also measured. In GS2, resistin mRNA was correlated with all cytokines expression (all p < 0.001), but IL-12B. Consistently, serum resistin was correlated with all serum cytokines (all p < 0.001), but IL-12. Expression (eRPS) and serum (sRPS) resistin pathway scores (excluding IL-12) were each other correlated (p < 0.001) and both associated with cardiovascular risk factors (all p < 0.01). In GHS, sRPS was independently associated with MACE (HR = 1.44, 95% CI = 1.10-1.90). Our data indicate the existence of a resistin pathway, which is associated with cardiovascular risk factors and which strongly and independently predicts MACE.

The combined effect of adiponectin and resistin on all-cause mortality in patients with type 2 diabetes: Evidence of synergism with abdominal adiposity.

BACKGROUND AND AIMS: While elevated serum adiponectin and resistin levels have been singly associated with all-cause mortality in patients with type 2 diabetes (T2D), their combined effect has never been studied. We investigated such joint effect in patients with T2D and its possible modulation by several demographic and clinical conditions, known to affect per se mortality rate. METHODS: Patients with T2D from the Gargano Mortality Study (GMS; N = 895, follow-up = 10.5 ± 3.7 years; 290 events) and the Foggia Mortality Study (FMS; N = 519, follow-up = 7.1 ± 2.5 years; 140 events) were examined. RESULTS: As singly considered, adiponectin and resistin were independently associated with mortality rate in GMS and FMS (p < 0.0001 for both). The two studies were then pooled, for investigating the nature of the joint effect of the two adipokines. In such sample, both adipokines were associated with death, independent of each other and of several additional covariates (p = 0.01-4.58 × 10(-12)). Of note, no adiponectin-by-resistin interaction was observed (p = 0.40), thus pointing to an additive effect of the two adipokines. As compared to individuals with low levels of both adiponectin and resistin (i.e. below median values), those with high levels of both adipokines had an HR (95%CI) for death of 3.02 (2.26-4.03). Such increased risk was more pronounced in individuals with relatively low abdominal adiposity (p for HR heterogeneity below or above the median value of waist circumference = 0.03). CONCLUSIONS: Adiponectin and resistin show an additive independent effect on all-cause mortality in patients with T2D. Such effect is modified by abdominal adiposity.

Evidence of a causal relationship between high serum adiponectin levels and increased cardiovascular mortality rate in patients with type 2 diabetes.

BACKGROUND: Despite its beneficial role on insulin resistance and atherosclerosis, adiponectin has been repeatedly reported as an independent positive predictor of cardiovascular mortality. METHODS: A Mendelian randomization approach was used, in order to evaluate whether such counterintuitive association recognizes a cause-effect relationship. To this purpose, single nucleotide polymorphism rs822354 in the ADIPOQ locus which has been previously associated with serum adiponectin at genome-wide level, was used as an instrument variable. Our investigation was carried out in the Gargano Heart Study-prospective design, comprising 356 patients with type 2 diabetes, in whom both total and high molecular weight (HMW) adiponectin were measured and cardiovascular mortality was recorded (mean follow-up = 5.4 ± 2.5 years; 58 events/1922 person-year). RESULTS: The A allele of rs822354 was associated with both total and HMW adiponectin [ß (SE) = 0.10 (0.042), p = 0.014 and 0.17 (0.06), p = 0.003; respectively]. In a Poisson model comprising age, sex, smoking habits, BMI, HbA1c, total cholesterol, HDL-cholesterol, triglycerides, insulin therapy and hypertension, both rs822354 (IRR = 1.94, 95 % CI 1.23-3.07; p = 0.005), as well as the genetic equivalent of total adiponectin change (IRR = 1.07, 95 % CI 1.02-1.12; p = 0.003) were significantly associated with cardiovascular mortality. The observed genetic effect was significantly greater than that exerted by the genetic equivalent change of serum adiponectin (p for IRR heterogeneity = 0.012). In the above-mentioned adjusted model, very similar results were obtained when HMW, rather than total, adiponectin was used as the exposure variable of interest. CONCLUSIONS: Our data suggest that the paradoxical association between high serum adiponectin levels and increased cardiovascular mortality rate is based on a cause-effect relationship, thus pointing to an unexpected deleterious role of adiponectin action/metabolism on atherosclerotic processes.

The paradoxical association of adiponectin with mortality rate in patients with type 2 diabetes: evidence of synergism with kidney function.

BACKGROUND: The paradoxical relationship between high adiponectin and increased mortality, described in several clinical subsets, has been reported only once in type 2 diabetes (T2D) and only in selected elderly patients. We investigated this relationship in unselected patients with T2D and, then, addressed its possible modulation by several demographic and clinical conditions, known to affect per se mortality rate. METHODS: Patients from the Gargano Mortality Study (GMS; N = 897, follow-up = 10.5 ± 3.7 years; 290 events) and the Foggia Mortality Study (FMS; N = 529, follow-up = 7.1 ± 2.5 years; 143 events), were investigated. RESULTS: For each SD adiponectin increase, HRs (95% CI) for all-cause mortality were 1.30 (1.19-1.43) in GMS, 1.43 (1.26-1.64) in FMS and 1.34 (1.24-1.45) in the combined studies. This association was independent of the possible confounding effect of demographics, adiposity measures, diabetes-related features, kidney function-related parameters and medications (p = 9.34 × 10(-9)). While no interaction was observed between adiponectin and sex, age, smoking habits, BMI, waist circumference, HbA1c, diabetes duration, micro-/macro-albuminuria and medications, a strong interaction was observed with GFR, with a significant adiponectin-mortality association observed in individuals with GFR ≥ but not those with GFR < 60 ml/min/1.73 m(2); p for adiponectin-by-GFR status interaction = 2.13 × 10(-6)). CONCLUSION: This is the first study reporting a paradoxical association of adiponectin with all-cause mortality in a large sample of unselected diabetic patients and indicating that such counterintuitive effect is observed only among patients with preserved kidney function. Further studies are needed to address if the strong interwoven effect of adiponectin and GFR turns to be useful in improving previously validated tools for predicting mortality in T2D.

Serum Adiponectin and Glomerular Filtration Rate in Patients with Type 2 Diabetes.

High serum adiponectin has been increased in several conditions of kidney disease. Only sparse and conflicting results have been reported in patients with type 2 diabetes (T2D), a subgroup of individuals who are at high risk for renal dysfunction. The aim of this study was to fill up this gap of knowledge by investigating such association in a large sample of Italian diabetic patients. The association between serum adiponectin levels and estimated glomerular filtration rate (eGFR by Chronic Kidney Disease-Epidemiology Collaboration CKD-EPI equation) was investigated in 1,243 patients with T2D from two cross-sectional Italian studies: 878 from San Giovanni Rotondo (SGR) and 365 from Foggia (FG). Serum adiponectin was inversely associated with eGFR in SGR [ß (standard error, SE) for 1 standard deviation (SD) of adiponectin = -3.26 (0.64)] and in FG [ß(SE)=-5.70(1.28)] sample, as well as in the two studies combined [ß(SE)=-3.99(0.59)];(p<0.0001 for all). In this combined analysis, the association was still significant after adjusting for sex, smoking habits, body mass index (BMI), waist circumference, diabetes duration, glycated hemoglobin (HbA1c), albumin creatinine ratio (ACR) and anti-hyperglycemic, anti-hypertensive and anti-dyslipidemic treatments [ß (SE)= -2.19 (0.59), p = 0.0001]. A stronger association between each SD adiponectin increment and low eGFR was observed among patients with micro-/macro-albuminuria, as compared to those with normo-albuminuria [adjusted ß(SE)=-4.42(1.16) ml/min/1.73m2 vs. -1.50 (0.67) ml/min/1.73m2, respectively; p for adiponectin-by-albuminuric status = 0.022]. For each adiponectin SD increment, the odds of having eGFR < 60 ml/min/1.73m2 increased by 41% (odds ratio, OR = 1.41; 95% confidence interval, CI 1.21-1.64) in SGR sample, 53% (OR = 1.53; 95% CI 1.21-1.94) in FG sample, and 44% (OR = 1.44; 95%CI 1.27-1.64) in the two studies considered together (p<0.0001 for all). In the combined sample, further adjustment for the above mentioned covariates did not change the observed association (OR = 1.36; 95%CI 1.16-1.60; p<0.0001). Our study, so far the largest addressing the relationship between serum adiponectin and GFR in T2D, strongly suggests that the paradoxical inverse association, previously reported in different clinical sets, is also observed in diabetic patients. Further studies are needed to unravel the biology underlying this counterintuitive relationship.