The platelet to high density lipoprotein -cholesterol ratio is a valid biomarker of nascent metabolic syndrome.

AIMS: The metabolic syndrome (MetS) is a major global problem, and inflammation and insulin resistance appear to be key underpinnings in this cardio-metabolic cluster. MetS predisposes to an increased risk of diabetes and atherosclerotic cardiovascular disease (ASCVD). It has a procoagulant diathesis which included increased platelet activity and impaired fibrinolysis. High density lipoprotein (HDL) appears to be anti-thrombotic. Accordingly, we examined the ratios between platelets to HDL-cholesterol(C) and adiponectin (Adipo) in patients with nascent MetS without the confounding of diabetes, ASCVD and smoking to determine their validity as biomarkers of MetS. METHODS: Patients with nascent MetS (n = 58) and matched controls (n = 44) were recruited. Fasting blood samples were obtained for complete blood counts, basic metabolic panel, lipids, insulin, and Adipo. Ratios of platelets to HDL-C and Adipo were calculated. RESULTS: Following adjustment for adiposity, only the platelet: HDL ratio was significantly increased in MetS and increased with severity of MetS. Receiver operating characteristic curve analysis showed that the platelet: HDL-C area under the curve (AUC) significantly added to both platelets and platelet lymphocyte ratio AUCs. Also the platelet: HDL-C ratio correlated with all cardio-metabolic features of MetS, high sensitivity C-reactive protein, insulin resistance chemerin, and leptin. CONCLUSIONS: The ratio of platelets: HDL-C is significantly increased in patients with nascent MetS and appear to be a valid biomarker of MetS. It could also emerge as a biomarker for athero-thrombotic risk. However, these preliminary findings need confirmation in large prospective studies.

Increased inflammasome activity in subcutaneous adipose tissue of patients with metabolic syndrome.

AIMS: The metabolic syndrome (MetS) is an inflammatory disorder associated with an increased risk for diabetes and atherosclerotic cardiovascular disease (ASCVD). Studies in patients and animal models of obesity and diabetes have shown increased NOD-like receptor family pyrin domain containing 3 (NLPR3) inflammasome activity. However, there is scanty data on the activity of the NLRP3 inflammasome in patients with nascent MetS. The aim of this study was to determine the status of the inflammasome in subcutaneous adipose tissue (SAT) of patients with nascent MetS without concomitant diabetes, ASCVD and smoking. MATERIALS AND METHODS: Patients with nascent MetS and controls were recruited from Sacramento County. Fasting blood samples were collected for biomediators of inflammation and SAT was obtained by biopsy for immunohistochemical (IHC) staining for caspase 1, IL-1ß and IL-18. RESULTS: Caspase1, a marker of inflammasome activity and its downstream mediators IL-1ß and IL-18 were significantly increased in SAT of patients with MetS compared to controls. Significant positive correlations of caspase 1 were obtained with certain cardio-metabolic features, biomediators of inflammation and markers of angiogenesis and fibrosis in SAT. Both mast cell and eosinophil abundance but not macrophage density correlated with caspase1. CONCLUSIONS: We make the novel observation that the SAT of patients with nascent MetS displays increased NLRP3 inflammasome activity manifest by increased caspase 1 in SAT and this may contribute to increased insulin resistance, inflammation and SAT fibrosis in these patients.

The Ratios of Triglycerides and C-reactive protein to High density-lipoprotein -cholesterol as valid biochemical markers of the Nascent Metabolic Syndrome.

Aims: Metabolic syndrome (MetS), a cardiometabolic cluster, is a major global problem. The ratio of triglycerides (TG) to high-density lipoprotein cholesterol (HDL-C) is a good biomarker of MetS in certain populations  C-reactive protein (CRP) has also been also shown to be a biomarker of MetS. Since CRP captures inflammation, we compared the ratios of TG to HDL-C and CRP to HDL-C in patients with nascent MetS.Methods: Patients with MetS (n = 58) and matched controls (n = 44) were recruited. Fasting blood samples were obtained for routine laboratories, insulin, and adipokines. TG and CRP ratios to HDL-C were calculated. Data were analyzed statistically.Results: Both the TG to HDL-C and CRP to HDL-C ratios were significantly increased in MetS and both increased with increasing severity of MetS. Whilst both correlated with cardiometabolic features and insulin resistance, only the CRP to HDL-C ratio correlated significantly with adiponectin and leptin. Receiver operating characteristic curve analysis showed that both ratios showed excellent discrimination for MetS with no significant differences between ratios.Conclusions: Thus both the TG to HDL-C and CRP to HDL-C ratios are significantly increased in patients with nascent MetS and appear to be valid biomarkers of MetS. However, these preliminary findings with CRP: HDL-C need confirmation in large prospective studies and could have important implications for assessing cardiometabolic risk in African Americans, an under-served population.

Chemerin Ratios to HDL-cholesterol and Adiponectin as Biomarkers of Metabolic Syndrome.

AIMS: Metabolic Syndrome (MetS) a global problem, which comprises a cardio-metabolic cluster of risk factors, increases the risk for type-2 diabetes (T2DM) and atherosclerotic cardiovascular diseases (ASCVD). To date, the best laboratory-based biomarker for MetS appears to be high-sensitivity C-reactive protein (hsCRP). Chemerin, a novel adipokine is increased in MetS and appears to contribute to both insulin resistance and inflammation. In this pilot study, we tested if the chemerin:HDL-C or chemerin:adiponectin ratios are better biomarkers for predicting MetS than hsCRP. PATIENTS AND METHODS: We enrolled patients and controls with nascent MetS, uncomplicated by diabetes, ASCVD, macro-inflammation, and smoking using rigorous criteria. Fasting blood samples were obtained in order to calculate insulin resistance in the liver (HOMA-IR) and adipose tissue (ADIPO-IR) and for measurement of chemerin and adiponectin levels. Statistical analyses including receiver operating characteristic (ROC) curves were used to evaluate data. RESULTS: We observed the chemerin:HDL-C ratio is significantly increased in MetS and increases with severity of MetS (p < .001). The chemerin: adiponectin ratio was not significantly increased following adjustment for age and waist circumference. The chemerin:HDL-C ratio correlated with BMI, WC, triglycerides, plasma glucose, HDL-C, and both HOMA-IR and ADIPO-IR. ROC curve analysis showed that the chemerin:HDL-C ratio area under the curve (AUC) was greater than the AUC for hsCRP. CONCLUSION: In this preliminary report, we demonstrate that the ratio of chemerin to HDL-C is a valid biomarker of MetS and appears to be a better predictor than hsCRP. These findings need to be confirmed in larger studies.

Increased mast cell abundance in adipose tissue of metabolic syndrome: relevance to the proinflammatory state and increased adipose tissue fibrosis.

Metabolic Syndrome (MetS) affects 35% of American adults > 40 yr and portends an increased risk for both atherosclerotic cardiovascular disease (ASCVD) and diabetes. The role of mast cells in the proinflammatory state of MetS is not well elucidated. We propose that mast cells in subcutaneous adipose tissue (SAT) of MetS patients without diabetes or clinical ASCVD contribute to insulin resistance and inflammation. Matched controls ( n = 15) and MetS ( n = 19) subjects were recruited from Sacramento, CA, and selected based on Adult Treatment Panel III criteria. SAT biopsy was performed on all subjects and processed for immunohistochemistry. The SAT sections were stained using Astra Blue stain and tryptase stain for mast cells. Fasting blood was obtained for chemistries and biomarkers. Abundance of mast cells (Astra Blue stain) in SAT of MetS subjects compared with controls was increased 2.5-fold ( P < 0.0001). Mast cells correlated positively and significantly with waist circumference, glucose, triglycerides, homeostatic model of assessment-insulin resistance (HOMA-IR), AT insulin resistance, leptin, interleukin (IL)-1ß, IL-6, chemerin, p38 MAPK activity, and nuclear factor κB activity in circulating monocytes. Mast cells also correlated significantly with markers of fibrosis and angiogenesis. Tryptase staining of mast cells in AT revealed a significant increase ( P = 0.008) with similar correlations. We make the novel observation that there are increased mast cells in SAT of MetS, and these mast cells correlate with insulin resistance (hepatic and adipose tissue), inflammation, and AT fibrosis. Hence, these immune cells appear to occupy a pivotal role in the pathogenesis of MetS.

Correction to: Statin Therapy in Metabolic Syndrome and Hypertension Post-JUPITER: What is the Value of CRP?

A portion of this article was previously published as part of an article titled "Human C-reactive protein and the metabolic syndrome" in the following journal: Curr Opin Lipidol. 2009 Jun;20(3):182-9.

Correction to: Role of C-Reactive Protein in Contributing to Increased Cardiovascular Risk in Metabolic Syndrome.

A portion of this article was previously published as part of an article titled "Human C-reactive protein and the metabolic syndrome" in the following journal: Curr Opin Lipidol. 2009 Jun;20(3):182-9. doi: 10.1097/MOL.0b013e32832ac03e. https://insights.ovid.com/crossref?an=00041433-200906000-00007.

Fetuin-A is also an adipokine.

Fetuin-A (FetA), which impairs insulin action is considered classically as a hepatokine. In patients with Metabolic Syndrome without the confounding of diabetes or cardiovascular diseases, we showed significant increases in both circulating and subcutaneous adipose tissue secreted Fet-A. Furthermore we showed in mice models increase mRNA and protein following a high fat diet and in a model of metabolic syndrome. This work was recently confirmed by another group of investigators. Hence we propose that Fet-A be considered also as an adipokine.

Secretory tumors of the pituitary gland: a clinical biochemistry perspective.

The pituitary gland is responsible for the production and/or secretion of various hormones that play a vital role in regulating endocrine function within the body. Secretory tumors of the anterior pituitary predominantly, pituitary adenomas, collectively account for 10%-25% of central nervous system tumors requiring surgical treatment. The most common secretory tumors are prolactinomas, which can be diagnosed by basal prolactin levels. Acromegaly can be diagnosed by basal insulin growth-like factor 1 levels and the failure of growth hormone (GH) to suppress during an oral glucose tolerance test. Cushing disease can be diagnosed by demonstrating hypercortisolemia evidenced by increased salivary cortisol levels in the evening, increased urine free cortisol excretion and failure of plasma cortisol to suppress following oral dexamethasone given overnight (1.0 mg). We also discuss the diagnosis of the rarer thyroid-stimulating hormone and gonadotrophin secretory tumors. Morbidity is associated with tumor occurrence, clinical sequelae as well as the related medical, surgical and radiological management. This review focuses on the pathogenesis of secretory tumors of the anterior pituitary with emphasis on molecular mechanisms associated with tumorigenesis and the major role of the clinical chemistry laboratory in diagnosis and management of these tumors.

Potential anti-atherosclerotic effects of dipeptidyl peptidase-4 inhibitors in type 2 diabetes mellitus.

Cardiovascular disease (CVD) is the leading cause of mortality in patients with diabetes. Pharmacotherapy that can reduce hyperglycemia and also exhibit pleiotropic effects that can result in a reduction in cardiovascular disease will be a major advance. Recently, the dipeptidyl-peptidase-4 inhibitors were introduced as ant-hyperglycemic therapy. Studies from numerous groups have reported effects that could potentially result in a reduction in CVD. Some of the drugs in this class, especially vildagliptin and sitagliptin, have been shown to reduce postprandial hyperlipidemia following a fat load, improve endothelial function as evidenced by increased forearm blood flow, and also display anti-inflammatory effects. Their effects on platelet function, blood pressure, and oxidative stress are very preliminary and need to be confirmed. Finally, they have been shown to reduce subclinical atherosclerosis by reducing carotid intimal-medial thickness. However, the final arbiter with respect to a reduction in CVD will be the ongoing clinical trials.

An Increasing Triglyceride-Glucose Index Is Associated with a Pro-Inflammatory and Pro-Oxidant Phenotype.

Background/Objectives: Insulin resistance is crucial in the pathogenesis of Metabolic Syndrome (MetS), type 2 diabetes mellitus (T2DM) and premature atherosclerotic cardiovascular disease (ASCVD). The triglyceride-glucose index (TyG index), a validated measure of insulin resistance, also predicts MetS, T2DM, the severity of albuminuria and ASCVD. There are scant data providing mechanistic insights into these sequalae. Accordingly, we investigated the relationship between the TyG index and biomarkers of inflammation, oxidative stress, free fatty acid (FFA) levels and adipokine dysregulation in a cohort comprising both controls and patients with nascent MetS. Methods: Participants (n = 102) included 59 patients with MetS and 43 controls. People with diabetes, ASCVD, smoking and macro-inflammation were excluded. Fasting blood was obtained for both plasma and monocyte isolation. Results: Receiver Operating Characteristic (ROC) curve analysis revealed that the TyG index was an excellent predictor of MetS with an area under the curve of 0.87, and it correlated with both hepatic and adipose tissue insulin resistance. Both serum RBP-4 levels and non-HDL cholesterol increased significantly over tertiles of the TyG index. Based on the TyG index tertiles and/or correlations, oxidized LDL, nitrotyrosine, C-reactive protein, endotoxin, chemerin, interleukin-6 levels and monocyte toll-like receptor (TLR)-4 and TLR-2 and their cellular signaling were significantly associated with the TyG index. Conclusions: Increased non-HDL-C and, most importantly, a pro-inflammatory and pro-oxidant state could be advanced as potential mechanisms explaining the increased risk for T2DM and ASCVD with an increasing TyG index.

The triglyceride-glucose index is superior to homeostasis model assessment of insulin resistance in predicting metabolic syndrome in an adult population in the United States.

BACKGROUND: Metabolic Syndrome (MetS) is a cluster of cardio-metabolic features portending an increased risk for both type 2 diabetes mellitus (T2DM) and premature atherosclerotic cardiovascular disease (ASCVD). Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) is a widely used surrogate measure of insulin resistance. The triglyceride-glucose (TyG) index is another validated measure of insulin resistance that predicts both diabetes and cardiovascular disease in low and medium-income countries, but only diabetes in high income countries. OBJECTIVE: Due to the paucity of data on the TyG index in the US population, we compared the validity of the TyG index and HOMA-IR in predicting MetS. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) between 2005 and 2018 on Non-Hispanic White(NHW), Hispanic American(HA), and African American(AA) individuals(n = 5380) aged 20-80 years were used for analysis. Individuals were classified as having MetS based on three or more of its components. HOMA-IR and the TyG index were determined from fasting samples. RESULTS: Both the TyG index and HOMA-IR were significantly increased in MetS and increased significantly with increasing severity of the syndrome. Also both indices correlated significantly with all 5 features of MetS, hsCRP and non-HDL-C. ROC-AUC analysis for TyG index was significantly greater than that of HOMA-IR in predicting MetS: 0.87(95 % CI 0.85-0.88) versus 0.82(95 % CI 0.81-0.83) respectively, p < 0.0001. This was not evident for the small AA subgroup. CONCLUSION: The TyG index outperformed HOMA-IR in predicting MetS, a proxy for both T2DM and ASCVD, in a general US population and is a valuable biomarker.

Bempedoic Acid, an Inhibitor of Cholesterol Biosynthesis, Reduces Cardiovascular Events.

An elevated low-density lipoprotein cholesterol (LDL-C) is a major risk factor for premature atherosclerotic cardiovascular diseases (ASCVD) [...].

Correlates of Insulin Resistance in Nascent Metabolic Syndrome.

Background: Metabolic Syndrome (MetS), a major global problem, is a cluster of cardio-metabolic risk factors that predisposes to both type 2 diabetes mellitus (T2DM) and premature atherosclerotic cardiovascular disease (ASCVD). Insulin resistance is a major underpinning of MetS. Objectives: We investigated the relationship between insulin resistance and biomarkers of inflammation, oxidative stress, free fatty acids (FFA) levels and adipokine dysregulation in a cohort of nascent MetS. Design: This was a cross-sectional study comparing patients with MetS with matched controls. Patients and Methods: Participants included 47 patients with MetS and 41 controls. Persons with diabetes, ASCVD, smoking and macro-inflammation were excluded. Fasting blood was obtained for both plasma and monocyte isolation. Homeostasis model assessment insulin resistance index (HOMA-IR) was calculated from fasting glucose and insulin levels. Results: The patients were insulin resistant as determined by a valid measure, HOMA-IR. HOMA-IR increased with increasing severity of MetS and correlated with cardio-metabolic features, hsCRP, FFA levels, and adipose tissue insulin resistance. Insulin resistance also correlated with biomarkers of oxidative stress and both circulating and cellular biomarkers of inflammation. Receiver operating Characteristic (ROC) curve analysis revealed that HOMA-IR was an excellent predictor of MetS with an area under the curve of 0.80. Conclusion: In our patients with nascent MetS we show that they have significant insulin resistance. Based on our findings, elevated FFA levels, oxidative stress and inflammation could contribute to the insulin resistance.

The triglyceride-waist circumference index is a valid biomarker of metabolic syndrome in African Americans.

BACKGROUND: The hypertriglyceridemia waist (HTGW) phenotype is associated with visceral adiposity, metabolic syndrome, type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD). Since the cut points for abdominal obesity and hypertriglyceridemia, differ for different race groups, investigators have developed the product of triglycerides (TG) and waist circumference (WC) as the TG.WC index. We compared this TG.WC index to the TG:HDL-C ratio in the National Health and Nutrition Examination Survey (NHANES) study to predict metabolic syndrome (MetS) in African Americans (AAs). METHODS: Participants included 950 AAs and 2651 non-Hispanic Whites (NHWs) for comparison from the NHANES data set. Persons with diabetes, ASCVD and macro-inflammation were excluded. Fasting blood was obtained for lipids, insulin and CRP. RESULTS: In AAs and NHWs, both the TG.WC index and TG:HDL-C ratio were significantly increased in MetS patients. Also, both increased with increasing severity of MetS and correlated with all features of MetS, insulin resistance and inflammation. Receiver operating characteristic (ROC) curve analysis showed that discrimination with TG.WC for MetS was superior to the TG:HDL-C ratio especially in AAs. CONCLUSIONS: TG.WC index is a superior biomarker to TG:HDL-C for predicting MetS in AAs despite their lower TG levels.

Increased Adipocyte Hypertrophy in Patients with Nascent Metabolic Syndrome.

Background and Aims: Metabolic Syndrome (MetS), a global problem, predisposes to an increased risk for type 2 diabetes and premature cardiovascular disease. While MetS is associated with central obesity, there is scanty data on adipocyte hypertrophy, increased fat cell size (FCS), in MetS. The aim of this study was to investigate FCS status in adipose tissue (AT) biopsy of patients with nascent MetS without the confounding of diabetes, cardiovascular disease, smoking, or lipid therapy. Methods and Results: Fasting blood and subcutaneous gluteal AT biopsies were obtained in MetS (n = 20) and controls (n = 19). Cardio-metabolic features, FFA levels, hsCRP, and HOMA-IR were significantly increased in patients with MetS. Waist-circumference (WC) adjusted-FCS was significantly increased in patients with MetS and increased with increasing severity of MetS. Furthermore, there were significant correlations between FCS with glucose, HDL-C, and the ratio of TG: HDL-C. There were significant correlations between FCS and FFA, as well as endotoxin and monocyte TLR4 abundance. Additionally, FCS correlated with readouts of NLRP3 Inflammasome activity. Most importantly, FCS correlated with markers of fibrosis and angiogenesis. Conclusions: In conclusion, in patients with nascent MetS, we demonstrate WC-adjusted increase in FCS from gluteal adipose tissue which correlated with cellular inflammation, fibrosis, and angiogenesis. While these preliminary observations were in gluteal fat, future studies are warranted to confirm these findings in visceral and other fat depots.

Use of Apolipoprotein B in the Era of Precision Medicine: Time for a Paradigm Change?

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide and the risk of a major cardiovascular event is highest among those with established disease. Ongoing management of these patients relies on the accurate assessment of their response to any prescribed therapy, and their residual risk, in order to optimize treatment. Recent international guidelines and position statements concur that the plasma concentration of apolipoprotein B (apoB) is the most accurate measure of lipoprotein associated ASCVD risk. This is especially true for the growing number of individuals with diabetes, obesity, or the metabolic syndrome, and those on statin therapy. Most guidelines, however, continue to promote LDL-C as the primary risk marker due to uncertainty as to whether the greater accuracy of apoB is sufficient to warrant a paradigm shift. Recommendations regarding apoB measurement vary, and the information provided on how to interpret apoB results is sometimes insufficient, particularly for non-lipid specialists. Misinformation regarding the reliability of the assays is also frequently repeated despite its equivalent or better standardization than many other diagnostic assays. Thus, demand for apoB testing is relatively low, which means there is little incentive to increase its availability or reduce its cost. In this review, we examine the results of recent clinical outcomes studies and meta-analyses on the relative values of apoB, LDL-C, and non-HDL-C as markers of ASCVD risk. Although there is seemingly minimal difference among these markers when only population-based metrics are considered, it is evident from our analysis that, from a personalized or precision medicine standpoint, many individuals would benefit, at a negligible total cost, if apoB measurement were better integrated into the diagnosis and treatment of ASCVD.

Hyperglycemia induces Toll like receptor 4 expression and activity in mouse mesangial cells: relevance to diabetic nephropathy.

Diabetes is a proinflammatory state. The pattern recognition receptors, Toll-like receptors (TLRs), are increased in diabetic patients and have been suggested to play a role in diabetic nephropathy (DN). Progression of DN involves altered mesangial cell (MC) function with an expansion of the mesangial matrix. There is a paucity of data examining the role of TLR and its expression in MC. We hypothesize the expression of TLRs in the mesangium might be an important factor contributing to mesangium expansion and nephropathy. Thus we evaluated the effect of high glucose on TLR2 and TLR4 expression in mouse mesangial cells (MMC) in vitro. Exposure of MMC to 25 mM glucose for 24 h resulted in increased TLR4 mRNA and cell surface receptor expression compared with 5.5 mM glucose (P < 0.05). Interestingly, we were not able to detect expression of TLR2 in MMC. Furthermore, expression of a TLR4 downstream signaling cascade including myeloid differentiation factor 88 (MyD88), interferon regulatory factor 3 (IRF3), and Toll interleukin receptor domain containing adaptor inducing interferon-ß (TRIF)-related adaptor molecule (TRAM) were significantly increased in cells exposed to 25 mM glucose (P < 0.05). There was also a significant increase in NF-κB activation along with increased secretion of inflammatory cytokines IL-6 and monocyte chemotactic protein-1. Levels of transforming growth factor-ß were also significantly increased in the presence of 25 mM glucose (P < 0.05). Collectively, these data suggest that hyperglycemia activates TLR4 expression and activity in MC and could contribute to DN.