ABSTRACT
BACKGROUND AND AIMS: NASH confers an increased liver-related and kidney morbidity. Phospholipid curcumin (Meriva) is a phospholipid formulation with ameliorated systemic curcumin absorption and delivery. We assessed the safety and efficacy of Meriva in NASH. APPROACH AND RESULTS: In this double-blind trial, 52 patients with biopsy-proven NASH (71% with stage ≥F2 fibrosis, 58% with stage A2-G2/A2-G3a chronic kidney disease) were randomized 1:1 to receive Meriva 2 g/d or placebo for 72 weeks. The primary endpoint was NASH resolution with no worsening of fibrosis. The secondary endpoints included a ≥1 stage liver fibrosis improvement with no NASH worsening; regression of significant (ie, stage ≥F2) fibrosis and CKD; and improvement in renal, glucose, lipid, and inflammatory parameters. We also explored the treatment effect on hepatic activation of NF-kB, a key proinflammatory transcription factor and a major target of curcumin. Fifty-one patients (26 on Meriva and 25 on placebo) completed the trial. Sixteen (62%) patients on Meriva versus 3 (12%) patients on placebo had NASH resolution (RR = 5.33 [95% CI = 1.76-12.13]; p = 0.003). Thirteen (50%) patients on Meriva versus 2 (8%) patients on placebo had ≥1 stage fibrosis improvement (RR = 6.50 [1.63-21.20]; p = 0.008). Eleven (42%) patients on Meriva versus 0 (0%) on placebo had regression of significant liver fibrosis (RR = 18.01 [1.43-36.07]; p = 0.02). Hepatic NF-kB inhibition predicted NASH resolution (AUC = 0.90, 95% CI = 0.84-0.95) and fibrosis improvement (AUC = 0.89, 95% CI = 0.82-0.96). Thirteen (50%) patients on Meriva versus 0 (0%) on placebo had chronic kidney disease regression (RR = 10.71 [1.94-17.99)]; p = 0.004). Compared with placebo, Meriva improved eGFR (difference in adjusted eGFR change: +3.59 [2.96-4.11] mL/min/1.73 m 2 /y, p = 0.009), fasting glucose(-17 mg/dL; 95% CI = -22, -12), HbA1c (-0.62%; 95% CI = -0.87%, -0.37%), LDL-C (-39 mg/dL; 95% CI = -45, -33), triglycerides (-36 mg/dL, 95% CI = -46, -26), HDL-C (+10 mg/dL; 95% CI = +8, +11), and inflammatory markers. Adverse events were rare, mild, and evenly distributed. CONCLUSIONS: In patients with NASH, Meriva administration for 72 weeks was safe, well-tolerated, and improved liver histology, possibly through NF-kB inhibition, kidney disease, and metabolic profile.
ABSTRACT
BACKGROUND: Type 2 diabetes mellitus (T2DM) is increasing at an alarming rate, and only 50% of patients with T2DM achieve or maintain adequate glycemic control with pharmacological therapies. Metabolic surgery demonstrated superior efficacy compared to medical therapy but is unfeasible for most patients with T2DM. Duodenal mucosal resurfacing (DMR) by hydrothermal mucosal ablation, recellularization via electroporation therapy (ReCET), and photodynamic therapy are novel endoscopic procedures that use thermal, electrical, and photochemical energy, respectively, to ablate and reset dysfunctional duodenal mucosa. We assessed the data on the effects of these techniques on glycemic control and nonalcoholic fatty liver disease (NAFLD). METHODS: We systematically searched independently and in duplicate English and non-English language publications through January 31st, 2024. Outcomes assessed were an improvement in different metabolic health parameters and the safety of duodenal mucosal ablation (DMA) procedures. Outcomes were presented descriptively. FINDINGS: We selected 12 reports reporting results from 3 randomized and 6 uncontrolled trials (seven evaluating DMR, two evaluating ReCET, all with a low risk of bias) for a total of 317 patients enrolled. DMA reduced HbA1c, fasting plasma glucose, and liver fat. When combined with newer antidiabetic drugs, it allowed insulin discontinuation in up to 86% patients. No major safety signal emerged. CONCLUSIONS: All DMA techniques improve glucose homeostasis; DMR and ReCET appear to be safe in patients with T2DM. If confirmed by future randomized trials and by trials with histological endpoints in NAFLD, then DMA appears to be a promising alternative or complement option to medications for T2DM and NAFLD treatment. FUNDING: This study received no funding.
Subject(s)
Diabetes Mellitus, Type 2 , Duodenum , Intestinal Mucosa , Non-alcoholic Fatty Liver Disease , Humans , Non-alcoholic Fatty Liver Disease/surgery , Non-alcoholic Fatty Liver Disease/pathology , Non-alcoholic Fatty Liver Disease/therapy , Diabetes Mellitus, Type 2/surgery , Diabetes Mellitus, Type 2/drug therapy , Duodenum/surgery , Duodenum/pathology , Intestinal Mucosa/surgery , Intestinal Mucosa/pathology , Ablation Techniques/methodsABSTRACT
Heat shock protein 27 (HSP27), an intracellular molecular chaperone, is involved in the pathogenesis of cancer by promoting both tumor cell proliferation and resistance to therapy. HSP27 is also present in the circulation and circulating HSP27 (sHSP27) can elicit an autoimmune response with production of antibodies. Levels of sHSP27 are enhanced in patients with hepatocellular carcinoma (HCC); it is, however, unknown whether changes in HSP27 antibody levels occur in patients with HCC and can be exploited as a circulating biomarker of HCC. Our aim was to assess the potential association between newly diagnosed HCC and serum anti-HSP27 antibody levels. In this cross-sectional study, anti-HSP27 antibody levels were measured in serum samples from 71 HCC patients, 80 subjects with chronic liver disease, and 38 control subjects by immunoenzymatic assay. Anti-HSP27 antibody levels did not differ significantly among groups. However, in patients with chronic active hepatitis/cirrhosis, anti-HSP27 levels were significantly higher in subjects with a positive history of alcoholism (p = 0.03). Our data do not support the hypothesis that anti-HSP27 antibody levels may help identify patients with HCC among subjects with chronic liver disease. However, our finding that alcohol-related liver disease is associated with higher anti-HSP27 levels is novel and deserves further investigations.
Subject(s)
Antibodies/immunology , Carcinoma, Hepatocellular/immunology , Heat-Shock Proteins/immunology , Liver Cirrhosis/immunology , Liver Neoplasms/immunology , Molecular Chaperones/immunology , Aged , Antibodies/blood , Carcinoma, Hepatocellular/blood , Chronic Disease , Cross-Sectional Studies , Female , Heat-Shock Proteins/blood , Humans , Liver Cirrhosis/blood , Liver Neoplasms/blood , Male , Middle Aged , Molecular Chaperones/bloodABSTRACT
OBJECTIVES: Hypertension has been linked to the presence and severity of nonalcoholic fatty liver disease (NAFLD) through unclear mechanisms. The gain-of-function rs5186 A1166C variant in angtiotensin receptor type 1 (AGTR1) gene has been linked to hypertension, cardiovascular disease and metabolic syndrome. We assessed the impact of AGTR1 A1166C variant on NAFLD incidence and severity and on glucose and lipid metabolism and explored the underlying mechanisms. METHODS: We followed up 314 healthy nonobese, nondiabetic, nonhypertensive, insulin-sensitive participants in a population-based study, characterized for AGTR1 rs5186 A1166C variant, adipokine profile, inflammatory and endothelial dysfunction markers. An independent cohort of 78 biopsy-proven nondiabetic NAFLD patients and controls underwent an oral glucose tolerance test with Minimal Model analysis of glucose homeostasis, and an oral fat tolerance test with measurement of plasma lipoproteins, adipokines, MCP-1, calprotectin, and nuclear factor-κB activation in circulating mononuclear cells. RESULTS: AGTR1 A1166C polymorphism predicted 9.8-year incident NAFLD (odds ratio: 1.67, 95% CI: 1.26-2.21) and hypertension (odds ratio: 1.49, 95% CI: 1.12-2.63) and 9-year increase in cardiovascular disease risk and endothelial dysfunction markers. In the cross-sectional cohort, AGTR1 C allele carriers had higher insulin resistance. Despite comparable fasting lipid profiles, AGTR1 C allele carriers showed postprandial triglyceride-rich and cholesterol-rich VLDL lipoprotein accumulation, higher resistin, MCP-1 and calprotectin responses and nuclear factor-κB activation in mononuclear cells, and a blunted postprandial adiponectin response to fat, which predicted liver histology, hepatocyte apoptosis activation, insulin resistance, and endothelial dysfunction. DISCUSSION: AGTR1 A1166C variant affects liver disease, insulin resistance, and endothelial dysfunction in NAFLD, at least in part by modulating adipokine, chemokine, and pro-inflammatory cell activation in response to fat ingestion.
Subject(s)
Dietary Fats/metabolism , Hypertension/genetics , Non-alcoholic Fatty Liver Disease/genetics , Polymorphism, Single Nucleotide , Receptor, Angiotensin, Type 1/genetics , Biomarkers/metabolism , Cross-Sectional Studies , Female , Genotype , Glucose/metabolism , Humans , Hypertension/metabolism , Lipid Metabolism , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/metabolism , Risk Factors , Severity of Illness IndexABSTRACT
BACKGROUND AND AIMS: NTproBNP and BNP levels are reduced in obese subjects, but population-based data comparing the pattern of this relationship in the full spectrum of insulin-resistance mediated conditions, overweight/obesity, metabolic syndrome and diabetes, are limited. METHODS: The study-base were 3244 individuals aged 45-74 years, none of whom had heart failure, 1880 without diabetes and 1364 with diabetes, identified as part of two surveys of the population-based Casale Monferrato Study. All measurements were centralized. We examined with multiple linear regression and cubic regression splines the relationship between NTproBNP and BMI, independently of known risk factors and confounders. A logistic regression analysis was also performed to assess the effect of overweight/obesity (BMI ≥ 25 kg/m2), diabetes and metabolic syndrome on NTproBNP values. RESULTS: Out of the overall cohort of 3244 people, overweight/obesity was observed in 1118 (59.4%) non-diabetic and 917 (67.2%) diabetic subjects, respectively. In logistic regression, compared to normal weight individuals, those with a BMI ≥ 25 kg/m2 had a OR of 0.70 (95% CI 0.56-0.87) of having high NTproBNP values, independently of diabetes. As interaction between diabetes and NTproBNP was evident (p < 0.001), stratified analyses were performed. Diabetes either alone or combined with overweight/obesity or metabolic syndrome enhanced fourfold and over the OR of having high NTproBNP levels, while the presence of metabolic syndrome alone had a more modest effect (OR 1.54, 1.18-2.01) even after having excluded individuals with CVD. In the non-diabetic cohort, obesity/overweight and HOMA-IR ≥ 2.0 decreased to a similar extent the ORs of high NTproBNP [0.76 (0.60-0.95) and 0.74 (0.59-0.93)], but the association between overweight/obesity and NTproBNP was no longer significant after the inclusion into the model of HOMA-IR, whereas CRP > 3 mg/dl conferred a fully adjusted OR of 0.65 (0.49-0.86). CONCLUSIONS: NT-proBNP levels are lower in overweight/obesity, even in those with diabetes. Both insulin-resistance and chronic low-grade inflammation are involved in this relationship. Further intervention studies are required to clarify the potential role of drugs affecting the natriuretic peptides system on body weight and risk of diabetes.
Subject(s)
Diabetes Mellitus/blood , Insulin Resistance/physiology , Metabolic Syndrome/blood , Natriuretic Peptide, Brain/blood , Overweight/blood , Peptide Fragments/blood , Population Surveillance , Aged , Biomarkers/blood , Cohort Studies , Cross-Sectional Studies , Diabetes Mellitus/diagnosis , Diabetes Mellitus/epidemiology , Female , Humans , Italy/epidemiology , Male , Metabolic Syndrome/diagnosis , Metabolic Syndrome/epidemiology , Middle Aged , Obesity/blood , Obesity/diagnosis , Obesity/epidemiology , Overweight/diagnosis , Overweight/epidemiology , Population Surveillance/methodsABSTRACT
Mechanisms underlying the opposite effects of transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 C>T polymorphism on liver injury and cardiometabolic risk in nonalcoholic fatty liver disease (NAFLD) are unclear. We assessed the impact of this polymorphism on postprandial lipoprotein metabolism, glucose homeostasis, and nutrient oxidation in NAFLD. Sixty nonobese nondiabetic normolipidemic biopsy-proven NAFLD patients and 60 matched controls genotyped for TM6SF2 C>T polymorphism underwent: indirect calorimetry; an oral fat tolerance test with measurement of plasma lipoprotein subfractions, adipokines, and incretin glucose-dependent insulinotropic polypeptide (GIP); and an oral glucose tolerance test with minimal model analysis of glucose homeostasis. The TM6SF2 T-allele was associated with higher hepatic and adipose insulin resistance, impaired pancreatic ß-cell function and incretin effect, and higher muscle insulin sensitivity and whole-body fat oxidation rate. Compared with the TM6SF2 C-allele, the T-allele entailed lower postprandial lipemia and nefaemia, a less atherogenic lipoprotein profile, and a postprandial cholesterol (Chol) redistribution from smaller atherogenic lipoprotein subfractions to larger intestinal and hepatic VLDL1 subfractions. Postprandial plasma VLDL1-Chol response independently predicted the severity of liver histology. In conclusion, the TM6SF2 C>T polymorphism affects nutrient oxidation, glucose homeostasis, and postprandial lipoprotein, adipokine, and GIP responses to fat ingestion independently of fasting values. These differences may contribute to the dual and opposite effect of this polymorphism on liver injury and cardiometabolic risk in NAFLD.
Subject(s)
Glucose/metabolism , Homeostasis/genetics , Lipoproteins/metabolism , Membrane Proteins/genetics , Non-alcoholic Fatty Liver Disease/metabolism , Polymorphism, Single Nucleotide , Postprandial Period , Adult , Female , Humans , Male , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/physiopathologyABSTRACT
The loss-of-function rs4374383 G > A variant in Myeloid-epithelial-reproductive Tyrosine Kinase (MERTK) gene has been linked to hepatic fibrosis in chronic liver diseases. MERTK is expressed by immune and non-immune cells involved in inflammation, metabolism and vascular homeostasis. We assessed the impact of MERTK rs4374383 G > A variant on nonalcoholic fatty liver disease (NAFLD) incidence and severity and on glucose and lipid metabolism. We followed-up 305 healthy nonobese nondiabetic, metabolic syndrome-free insulin sensitive participants in a population-based study, characterized for MERTK G > A polymorphism, adipokine profile and inflammatory markers.An independent cohort of 69 biopsy-proven nondiabetic NAFLD patients and 69 healthy controls underwent indirect calorimetry, an OGTT with Minimal Model analysis of glucose homeostasis, and an oral fat tolerance test with measurement of plasma lipoproteins, adipokines, MCP-1, and of Nuclear Factor (NF)-κB activation in circulating mononuclear cells (MNCs). In the longitudinal cohort, MERTK G > A polymorphism protected against 9-year incident NAFLD (OR:0.48,95%CI:0.26-0.79) and diabetes (OR: 0.47, 95% CI: 0.19-0.87).In the cross-sectional cohort, MERTK A-allele carriers had higher fat oxidation rates and tissue insulin sensitivity. Despite comparable fastign and postprandial lipid profiles, MERTK A-allele carriers showed lower resistin and MCP-1 responses, milder MNC NF-κB activation, and a higher postprandial adiponectin response to fat, which predicted tissue insulin resistance hepatocyte apoptosis and liver histology. MERTK G > A variant affects liver disease, nutrient oxidation and glucose metabolism in NAFLD. The modulation of adipokine, chemokine and pro-inflammatory MNC activation in response to fat ingestion may contribute to the observed effects on liver and metabolic disease.
Subject(s)
Diabetes Mellitus/genetics , Non-alcoholic Fatty Liver Disease/genetics , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Receptor Protein-Tyrosine Kinases/genetics , Receptor Protein-Tyrosine Kinases/metabolism , Adipokines/metabolism , Cohort Studies , Cross-Sectional Studies , Diabetes Mellitus/metabolism , Dietary Fats/metabolism , Female , Genetic Predisposition to Disease , Genetic Variation , Glucose/metabolism , Humans , Insulin Resistance/genetics , Leukocytes, Mononuclear/metabolism , Lipid Metabolism , Lipoproteins/genetics , Liver Cirrhosis/metabolism , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/metabolism , Polymorphism, Single Nucleotide , c-Mer Tyrosine KinaseABSTRACT
Chronic kidney disease (CKD) is a risk factor for end-stage renal disease (ESRD) and cardiovascular disease (CVD). ESRD or CVD develop in a substantial proportion of patients with CKD receiving standard-of-care therapy, and mortality in CKD remains unchanged. These data suggest that key pathogenetic mechanisms underlying CKD progression go unaffected by current treatments. Growing evidence suggests that nonalcoholic fatty liver disease (NAFLD) and CKD share common pathogenetic mechanisms and potential therapeutic targets. Common nutritional conditions predisposing to both NAFLD and CKD include excessive fructose intake and vitamin D deficiency. Modulation of nuclear transcription factors regulating key pathways of lipid metabolism, inflammation, and fibrosis, including peroxisome proliferator-activated receptors and farnesoid X receptor, is advancing to stage III clinical development. The relevance of epigenetic regulation in the pathogenesis of NAFLD and CKD is also emerging, and modulation of microRNA21 is a promising therapeutic target. Although single antioxidant supplementation has yielded variable results, modulation of key effectors of redox regulation and molecular sensors of intracellular energy, nutrient, or oxygen status show promising preclinical results. Other emerging therapeutic approaches target key mediators of inflammation, such as chemokines; fibrogenesis, such as galectin-3; or gut dysfunction through gut microbiota manipulation and incretin-based therapies. Furthermore, NAFLD per se affects CKD through lipoprotein metabolism and hepatokine secretion, and conversely, targeting the renal tubule by sodium-glucose cotransporter 2 inhibitors can improve both CKD and NAFLD. Implications for the treatment of NAFLD and CKD are discussed in light of this new therapeutic armamentarium.
Subject(s)
Fatty Liver/epidemiology , Kidney Failure, Chronic/epidemiology , Non-alcoholic Fatty Liver Disease/epidemiology , Renal Insufficiency, Chronic/epidemiology , Diet , Epigenesis, Genetic , Fatty Liver/complications , Fibrosis , Fructose/administration & dosage , Humans , Inflammation , Kidney Failure, Chronic/complications , Lipid Metabolism , Liver/metabolism , Non-alcoholic Fatty Liver Disease/complications , Peroxisome Proliferator-Activated Receptors/genetics , Peroxisome Proliferator-Activated Receptors/metabolism , Randomized Controlled Trials as Topic , Renal Insufficiency, Chronic/complications , Risk Factors , Vitamin D/administration & dosageABSTRACT
BACKGROUND: Free fatty acid (FFA) metabolism can impact on metabolic conditions, such as obesity and nonalcoholic fatty liver disease (NAFLD). This work studied the increase in total FFA shown in NAFLD subjects to possibly characterize which fatty acids significantly accounted for the whole increase. METHODS: 21 patients with NAFLD were selected according to specified criteria. The control group consisted of nine healthy subjects. All subjects underwent an oral standard fat load. Triglycerides; cholesterol; FFA; glucose and insulin were measured every 2 h with the determination of fatty acid composition of FFA. RESULTS: higher serum FFA levels in NAFLD subjects are mainly due to levels of oleic, palmitic and linoleic acids at different times. Significant increases were shown for docosahexaenoic acid, linolenic acid, eicosatrienoic acid, and arachidonic acid, although this was just on one occasion. In the postprandial phase, homeostatic model assessment HOMA index positively correlated with the ω3/ω6 ratio in NAFLD patients. CONCLUSIONS: the higher serum levels of FFA in NAFLD subjects are mainly due to levels of oleic and palmitic acids which are the most abundant circulating free fatty acids. This is almost exactly corresponded with significant increases in linoleic acid. An imbalance in the n-3/n-6 fatty acids ratio could modulate postprandial responses with more pronounced effects in insulin-resistant subjects, such as NAFLD patients.
Subject(s)
Diet, High-Fat , Fatty Acids, Nonesterified/blood , Non-alcoholic Fatty Liver Disease/pathology , Adult , Blood Glucose/analysis , Case-Control Studies , Cholesterol/blood , Chromatography, High Pressure Liquid , Colorimetry , Fatty Acids, Omega-3/analysis , Fatty Acids, Omega-6/analysis , Female , Humans , Insulin/blood , Insulin Resistance , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/blood , Triglycerides/bloodABSTRACT
Mounting evidence connects non-alcoholic fatty liver disease (NAFLD) to chronic kidney disease (CKD). We review emerging mechanistic links between NAFLD and CKD, including altered activation of angiotensin converting enzyme (ACE)-2, nutrient/energy sensors sirtuin-1 and AMP-activated kinase, as well as impaired antioxidant defense mediated by nuclear factor erythroid 2-related factor-2 (Nrf2). Dietary fructose excess may also contribute to NAFLD and CKD. NAFLD affects renal injury through lipoprotein dysmetabolism and altered secretion of the hepatokines fibroblast growth factor-21, fetuin-A, insulin-like growth factor-1, and syndecan-1. CKD may mutually aggravate NAFLD and associated metabolic disturbances through altered intestinal barrier function and microbiota composition, the accumulation of uremic toxic metabolites, and alterations in pre-receptor glucocorticoid metabolism. We conclude by discussing the implications of these findings for the treatment of NAFLD and CKD.
Subject(s)
Non-alcoholic Fatty Liver Disease/etiology , Renal Insufficiency, Chronic/etiology , Animals , Humans , Non-alcoholic Fatty Liver Disease/complications , Renal Insufficiency, Chronic/complicationsABSTRACT
BACKGROUND: A single nucleotide polymorphism (SNP) of the patatin-like phospholipase-3 (PNPLA3)/adiponutrin gene (rs738409 C>G) is strongly associated with nonalcoholic fatty liver disease; to our knowledge, no data are available on the impact of this PNPLA3 SNP on liver and metabolic outcomes during pregnancy in patients with gestational diabetes (GD). OBJECTIVE: We evaluated the impact of the PNPLA3 rs738409 SNP on liver enzymes, metabolic indexes, and maternal and neonatal outcomes in 200 GD patients enrolled in a lifestyle intervention. DESIGN: In a randomized trial with a 2 × 2 factorial design, exercise significantly improved maternal and neonatal outcomes in GD patients. Effects of the G allele on metabolic and liver indexes and maternal and neonatal outcomes were evaluated in these patients. RESULTS: At the end of the trial, fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) values were significantly lower and liver enzymes significantly higher in PNPLA3 G-allele carriers. In a multiple regression model, the G allele was associated directly with aspartate aminotransferase (ß = 2.60; 95% CI: 0.99, 4.20), alanine aminotransferase (ß = 3.70; 95% CI: 1.78, 5.62), and γ-glutamyl transferase (ß = 3.70; 95% CI: 0.80, 6.60) and inversely with insulin (ß = -2.01; 95% CI: -3.24, -0.78) and HOMA-IR (ß = -0.39; -0.64, -0.14) values at the end of the trial. In a multiple logistic regression model, the G allele was associated directly with risk of developing liver enzyme elevation during pregnancy (OR: 4.21; 95% CI: 1.78, 9.97) and inversely with the birth of large-for-gestational-age newborns (OR: 0.19; 95% CI: 0.06, 0.62). No diet × genotype or exercise × genotype interaction was shown. CONCLUSION: The PNPLA3 SNP rs738409 G allele was associated with risk of mildly elevated transaminases in GD independent of a lifestyle intervention and despite a significant reduction in insulin resistance and risk of macrosomic offspring. This trial was registered at clinicaltrials.gov as NCT01506310.
Subject(s)
Diabetes, Gestational/genetics , Isoleucine/chemistry , Lipase/genetics , Membrane Proteins/genetics , Methionine/chemistry , Adolescent , Adult , Alanine Transaminase/blood , Alleles , Aspartate Aminotransferases/blood , Diabetes, Gestational/metabolism , Diet , Energy Intake , Exercise , Female , Health Behavior , Humans , Insulin/blood , Life Style , Linear Models , Lipase/chemistry , Membrane Proteins/chemistry , Middle Aged , Polymorphism, Single Nucleotide , Pregnancy , Pregnancy Outcome/genetics , Surveys and Questionnaires , Young AdultABSTRACT
BACKGROUND: Both metabolic syndrome (MetS) and N-amino terminal fragment of the prohormone B-type natriuretic peptide (NT-proBNP) confer increased risk of cardiovascular diseases (CVD). We assessed if NT-proBNP levels were greater in people with uncomplicated MetS, who had neither CVD/chronic kidney disease (CKD) nor diabetes, as compared with subjects who met none of the defining criteria of the MetS. METHODS: A case-cohort study from the non-diabetic population-based Casale Monferrato study was performed, after exclusion of all subjects with established CVD, CKD [estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2)], and CRP values ≥3 mg/L. Cases (n = 161) with MetS were compared with all subjects within the cohort (n = 124) who were completely free of any component of the MetS. Serum NT-proBNP was centrally measured by immunoenzymatic assay. RESULTS: NT-proBNP levels were significantly higher in cases than in control subjects [35.4 (15.5-98.2) vs 24.4 (11.7-49.6) pg/mL, p = 0.014]. In logistic regression analysis, compared with NT-proBNP values in the lower quartiles (≤49.64 pg/mL), higher values conferred odds ratio 4.17 (1.30-13.44) of having the MetS, independently of age, sex, microalbuminuria, CRP, eGFR, and central obesity. This association was evident even after the exclusion of hypertensive subjects. Further adjustment for log-HOMA and diastolic blood pressure did not modify the strength of the association, while central obesity was a negative confounder. CONCLUSIONS: Compared with people without any component of the MetS, those with uncomplicated MetS, who had neither CVD/CKD nor diabetes, had increased NT-proBNP values, even if they were normotensive and although absolute values were still in the low range. The insulin resistance state did not mediate this association, while central obesity was a negative confounder.
Subject(s)
Metabolic Syndrome/blood , Natriuretic Peptide, Brain/blood , Peptide Fragments/blood , Up-Regulation , Aged , Body Mass Index , Case-Control Studies , Cohort Studies , Cross-Sectional Studies , Dyslipidemias/epidemiology , Dyslipidemias/etiology , Female , Humans , Hypertension/epidemiology , Hypertension/etiology , Insulin Resistance , Italy/epidemiology , Male , Metabolic Syndrome/etiology , Metabolic Syndrome/metabolism , Metabolic Syndrome/physiopathology , Middle Aged , Obesity, Abdominal/epidemiology , Obesity, Abdominal/etiology , Obesity, Abdominal/physiopathology , Overweight/epidemiology , Overweight/etiology , Overweight/physiopathology , Prediabetic State/epidemiology , Prediabetic State/etiology , Prevalence , Severity of Illness Index , Waist CircumferenceABSTRACT
A functionally active endocannabinoid system is present within the kidney. The cannabinoid receptor type 2 (CB2) is expressed by both inflammatory cells and podocytes, and its activation has beneficial effects in experimental diabetic nephropathy. To further explore the role of CB2 in diabetic nephropathy, we studied renal functional and structural abnormalities in streptozotocin-induced diabetic CB2 knockout mice. In diabetic mice, deletion of the CB2 receptor albuminuria, the downregulation of podocin and nephrin, mesangial expansion, overexpression of extracellular matrix components, monocyte infiltration, and reduced renal function were all exacerbated. To investigate the relative contributions of podocytes and monocytes to the phenotype of diabetic knockout mice, bone marrow transplantation experiments were performed. The lack of CB2 on bone marrow-derived cells was shown to be important in driving the enhanced glomerular monocyte accrual found in diabetic knockout mice. Absence of CB2 on resident glomerular cells had a major role in worsening diabetic nephropathy, both functional and structural abnormalities, likely by enhanced MCP-1 and CB1 signaling. Studies in cultured podocytes demonstrated that CB2 expression is not altered by a high glucose milieu but is downregulated by mechanical stretch, mimicking glomerular capillary hypertension. Thus, CB2 deletion worsens diabetic nephropathy, independent of bone marrow-derived cells.
Subject(s)
Diabetes Mellitus, Experimental/complications , Diabetic Nephropathies/etiology , Kidney Glomerulus/metabolism , Receptor, Cannabinoid, CB2/deficiency , Streptozocin , Acetylglucosamine/urine , Albuminuria/etiology , Albuminuria/metabolism , Animals , Bone Marrow Transplantation , Cell Line , Cell Proliferation , Chemokine CCL2/metabolism , Chemotaxis, Leukocyte , Creatinine/blood , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Experimental/physiopathology , Diabetic Nephropathies/genetics , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Diabetic Nephropathies/physiopathology , Extracellular Matrix/metabolism , Female , Kidney Glomerulus/pathology , Kidney Glomerulus/physiopathology , Mice, Inbred C57BL , Mice, Knockout , Monocytes/metabolism , Podocytes/metabolism , Receptor, Cannabinoid, CB2/genetics , Receptors, CCR2/metabolism , Time FactorsABSTRACT
MicroRNAs (miRNAs), a class of small non-protein-encoding RNAs, regulate gene expression via suppression of target mRNAs. MiRNAs are present in body fluids in a remarkable stable form as packaged in microvesicles of endocytic origin, named exosomes. In the present study, we have assessed miRNA expression in urinary exosomes from type 1 diabetic patients with and without incipient diabetic nephropathy. Results showed that miR-130a and miR-145 were enriched, while miR-155 and miR-424 reduced in urinary exosomes from patients with microalbuminuria. Similarly, in an animal model of early experimental diabetic nephropathy, urinary exosomal miR-145 levels were increased and this was paralleled by miR-145 overexpression within the glomeruli. Exposure of cultured mesangial cells to high glucose increased miR-145 content in both mesangial cells and mesangial cells-derived exosomes, providing a potential mechanism for diabetes-induced miR-145 overexpression. In conclusion, urinary exosomal miRNA content is altered in type 1 diabetic patients with incipient diabetic nephropathy and miR-145 may represent a novel candidate biomarker/player in the complication.
Subject(s)
Albuminuria/urine , Diabetes Mellitus, Type 1/urine , Diabetic Nephropathies/urine , Exosomes/metabolism , MicroRNAs/urine , Animals , Cells, Cultured , Gene Expression , Glucose/physiology , Humans , Male , Mice , Mice, Inbred C57BL , MicroRNAs/genetics , Middle Aged , Up-RegulationABSTRACT
Expression of intracellular heat shock protein 27 (Hsp27) rises in the brain of animal models of cerebral ischemia and stroke. Hsp27 is also released into the circulation and the aim of the present study was to investigated if serum Hsp27 (sHsp27) levels are altered in patients with acute ischemic stroke. sHsp27 was measured in 15 patients with acute ischemic stroke and in 14 control subjects comparable for age, sex, and cardiovascular risk factors. In patients, measurements were performed at admission and 1, 2, and 30 days thereafter. At admission, mean sHsp27 values were threefold higher in patients than in controls. In patients, sHsp27 values dropped after 24 h, rose again at 48 h, and markedly declined at 30 days, indicating the presence of a temporal trend of sHsp27 values following acute ischemic stroke.
Subject(s)
HSP27 Heat-Shock Proteins/blood , Stroke/blood , Acute Disease , Aged , Aged, 80 and over , Cardiovascular Diseases/etiology , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Risk Factors , Stroke/pathology , Tomography, X-Ray ComputedABSTRACT
Diabetic retinopathy is the leading cause of blindness in adults, and oxidative stress has been pathogenically associated with retinal neurodegeneration. Cellular stresses induce expression of heat shock proteins (HSPs) and this results in cytoprotection. Our aim was to assess retinal expression of HSP25 in early experimental diabetes. Mice were rendered diabetic by streptozotocin injection. Ten weeks after diabetes onset retinal HSP25 expression were studied by real-time PCR, immunoblotting and immunohistochemistry (IHC). Expression of nitrotyrosine and Cu/Zn superoxide dismutase (SOD), was assessed by IHC and apoptosis by TUNEL. Retinal HSP25 mRNA and protein expression was significantly increased in diabetic as compared to non-diabetic animals and localised predominantly within the retinal ganglion cells (RGC) layer. This was paralleled overexpression of nitrotyrosine and SOD and enhanced apoptosis. In early experimental diabetes, HSP25 is overexpressed in the RGC layer in parallel with markers of oxidative stress and apoptosis.
Subject(s)
Diabetes Mellitus, Experimental/complications , Diabetic Retinopathy/metabolism , Heat-Shock Proteins/metabolism , Neoplasm Proteins/metabolism , Retina/metabolism , Animals , Apoptosis , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/physiopathology , Diabetic Retinopathy/genetics , Diabetic Retinopathy/physiopathology , Female , Heat-Shock Proteins/genetics , Humans , Male , Mice , Mice, Inbred C57BL , Molecular Chaperones , Neoplasm Proteins/genetics , Oxidative Stress , Retina/cytology , Retinal Ganglion Cells/cytology , Retinal Ganglion Cells/metabolism , Up-RegulationABSTRACT
The metabolic syndrome (MetS) confers an increased risk of both type 2 diabetes and cardiovascular diseases (CVD). Heat shock protein 70 (Hsp70), an intracellular polypeptide, can be exposed on the plasma membrane and/or released into the circulation, eliciting both native and immune responses that may contribute to vascular damage. Our aim was to assess if serum anti-Hsp70 antibody levels were cross-sectionally associated with uncomplicated MetS. A cross-sectional case-control study from the nondiabetic cohort of the Casale Monferrato Study was performed. Subjects with established CVD and/or abnormal renal function were excluded. Case subjects (n = 180) were defined as those fulfilling the criteria for the diagnosis of MetS. Control subjects (n = 136) were completely free of any component of the MetS. Serum anti-Hsp70 levels were measured by immunoenzymatic assay. We found that anti-Hsp70 antibody levels were significantly higher in cases than in control subjects [122.6 (89.5-155.6) vs 107.1 (77.3-152.4) µg/ml, p = 0.04], even after age and sex adjustment. In logistic regression analysis, higher levels of log-anti-Hsp70 conferred greater odds ratio (OR) for MetS, independently of age and sex. There was a statistically significant trend of ORs across quartiles of anti-Hsp70 and values greater than 108.0 µg/ml conferred a 77% increased OR of MetS as compared with values in the lower quartiles. The strength of the association slightly decreased after further adjustment for apolipoprotein B, smoking, and albumin excretion rate. In conclusion, our results show that serum anti-Hsp70 antibody levels are independently associated with nascent MetS.
Subject(s)
Antibodies/blood , HSP70 Heat-Shock Proteins/immunology , Metabolic Syndrome/blood , Case-Control Studies , Female , Humans , Italy , Male , Middle Aged , Odds RatioABSTRACT
Levels of serum heat shock protein 27 (sHsp27) have been studied in numerous cancer types, but their potential relevance in patients with hepatocellular carcinoma (HCC) is undetermined. Our aim was to compare sHsp27 levels in patients with HCC and HCC-free controls. Specifically, we recruited 71 patients with HCC (80 % with early tumour), 80 patients with chronic liver disease (59 with liver cirrhosis and 21 with chronic active hepatitis) and 42 healthy subjects. sHsp27 was measured by immunoenzymatic assay. Results showed that sHsp27 levels were significantly (p < 0.001) higher in patients with HCC than in the other groups, particularly in those with hepatitis C virus (HCV)-related disease. In HCC patients, sHsp27 levels were not associated with prognostic risk factors, such as size/multiplicity of nodules and stage. In logistic regression analysis, performed in patients with liver disease, log-sHsp27 was associated with a significant age-adjusted 2.5-fold increased odds ratio of HCC and with a significant 4.4-fold higher odds ratio of HCC in the subgroup with HCV-related liver disease. In receiver operating characteristic curve analysis, sensitivity and specificity of the best sHsp27 cut-off value (456.5 pg/ml) for differentiating patients with HCC from those with HCC-free chronic liver disease were 70 and 73 %, respectively. In conclusion, sHsp27 levels are enhanced in patients with HCC and may represent a candidate biomarker of HCC.
Subject(s)
Carcinoma, Hepatocellular/blood , HSP27 Heat-Shock Proteins/blood , Liver Neoplasms/blood , Aged , Carcinoma, Hepatocellular/etiology , Carcinoma, Hepatocellular/pathology , Female , Hepatitis C/blood , Hepatitis C/complications , Hepatitis C/pathology , Humans , Liver Cirrhosis/blood , Liver Cirrhosis/pathology , Liver Diseases/blood , Liver Diseases/pathology , Liver Neoplasms/etiology , Liver Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Odds Ratio , Peptide Fragments/blood , Prognosis , Prothrombin , ROC Curve , Risk Factors , Severity of Illness Index , alpha-Fetoproteins/analysisABSTRACT
OBJECTIVE: Circulating levels of NH(2)-terminal probrain natriuretic peptide (NT-proBNP), a marker of acute heart failure, are associated with increased risk of cardiovascular disease (CVD) in the general population. However, there is little information on the potential role of NT-proBNP as a biomarker of vascular complications in type 1 diabetic patients. We investigated whether serum NT-proBNP levels were associated with micro- and macrovascular disease in type 1 diabetic subjects. RESEARCH DESIGN AND METHODS: A cross-sectional nested case-control study from the EURODIAB Prospective Complications Study of 507 type 1 diabetic patients was performed. Case subjects (n = 345) were defined as those with one or more complications of diabetes; control subjects (n = 162) were those with no evidence of any complication. We measured NT-proBNP levels by a two-site sandwich electrochemiluminescence immunoassay and investigated their associations with complications. RESULTS: Mean NT-proBNP levels were significantly higher in case than in control subjects. In logistic regression analyses, NT-proBNP values >26.46 pg/mL were independently associated with a 2.56-fold increased risk of all complications. Odds ratios of CVD (3.95 [95% CI 1.26-12.35]), nephropathy (4.38 [1.30-14.76]), and distal symmetrical polyneuropathy (4.32 [1.41-13.23]) were significantly increased in patients with NT-proBNP values in the highest quartile (>84.71 pg/mL), independently of renal function and known risk factors. These associations were no longer significant after inclusion of TNF-α into the model. CONCLUSIONS: In this large cohort of type 1 diabetic subjects, we found an association between NT-proBNP and diabetic micro- and macrovascular complications. Our results suggest that the inflammatory cytokine TNF-α may be involved in this association.