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.

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.

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.

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.

A comparison of the ratios of C-reactive protein and triglycerides to high-density lipoprotein-cholesterol as biomarkers of metabolic syndrome in African Americans and non-Hispanic Whites.

AIMS: The ratio of triglycerides (TG) to high density lipoprotein-cholesterol (HDL-C) is a validated biomarker of insulin resistance and metabolic syndrome (MetS). In African-Americans (AA) there is concern about this ratio because their mean TG level is lower than the general population. As an alternative approach, we examined the CRP:HDL-C ratio in both AA and non-Hispanic whites (NHW) in the NHANES study for its association with MetS. METHODS: A total of n = 3541 individuals were studied from the NHANES data. Fasting blood samples were obtained for lipids, insulin, and CRP. TG and CRP ratios to HDL-C were calculated. RESULTS: The TG:HDL-C ratio was significantly increased in NHW compared to AA, but the CRP:HDL-C ratio did not differ between NHW and AA groups. Both ratios were significantly increased in MetS patients versus controls (both races) and increased with greater severity of MetS. Receiver Operating Characteristic (ROC) curve analysis showed that the TG:HDL-C area under the curve was superior to CRP:HDL-C in predicting MetS in both AA and NHW patients. CONCLUSION: In this large NHANES study, the TG:HDL-C ratio is a superior predictor of MetS in both AA and NHW persons despite the lower TG levels in AA persons.

Bempedoic acid: a novel oral LDL-cholesterol lowering agent.

An elevated LDL-cholesterol is a potent risk factor for atherosclerotic cardiovascular disease (ASCVD). Invariably, pharmacotherapy is required to get high risk patients to goal. The cornerstone of such therapy is the statin class of drugs. Recently Bempedoic Acid (BA), a first in class ATP-citrate lyase inhibitor was approved for LDL-C reduction based on the CLEAR trials in which BA was superior to Placebo. In addition to lowering LDL-C it also lowers apoB and hsCRP levels. BA appears to be very efficacious in combination with ezetimibe especially in statin intolerant patients. However the reduction in LDL-C is modest, it lowers HDL-C levels, causes hyperuricemia and an elevated creatinine. The ongoing Outcomes trial examining ASCVD events with BA will firmly establish the role of BA in our arsenal for the management of ASCVD if positive.

Practical Clinical Applications of Islet Autoantibody Testing in Type 1 Diabetes.

BACKGROUND: The distinction between type 1 diabetes (T1D) and type 2 diabetes (T2D) is extremely important for the choice of therapy, body weight and dietary management, screening for coexistent autoimmune diseases and comorbidities, anticipated prognosis, and risk assessment in relatives. Not uncommonly, the presentation of the patient may not allow an unambiguous discrimination between T1D and T2D. To help resolve this challenge, the detection of islet autoantibodies can support the diagnosis of T1D. CONTENT: The presence of islet autoantibodies in a person with diabetes indicates an autoimmune etiology therefore establishing the diagnosis of T1D. Presently 5 islet autoantibodies are available for routine clinical use: islet cell cytoplasmic autoantibodies (ICA), insulin autoantibodies (IAA), glutamic acid decarboxylase autoantibodies (GADA), insulinoma associated-2 autoantibodies (IA-2A), and zinc transporter-8 autoantibodies (ZnT8A). There are caveats to the selection of which islet autoantibodies should be measured. Islet autoantibodies can also predict the development of T1D. Therefore, once safe and effective therapies are available to prevent T1D, islet autoantibody testing is expected to become a routine part of medical practice. A very rare cause of autoimmune diabetes is the type B insulin resistance syndrome resulting from antagonistic autoantibodies to the insulin receptor. Rarely hypoglycemia can result from agonistic insulin receptor autoantibodies, or high-titer IAA causing the autoimmune insulin syndrome (i.e., Hirata disease). SUMMARY: In summary, autoimmune causes of dysglycemia are increasing in clinical importance requiring the scrutiny of laboratorians. The determination of islet autoantibodies can greatly aid in the diagnosis and the prediction of T1D.

Chylomicronemia Due to the Rare Hyperlipoproteinemia Type 3 Complicated by a Circulating Monoclonal Protein.

The polygenic variety of chylomicronemia occurs in adults in whom factors such as obesity, diabetes, alcoholism, renal disease, and certain drugs can precipitate chylomicronemia. A rare cause of polygenic chylomicronemia is hyperlipoproteinemia type 3 (HLP3). We report on a 54-year-old male who presented with chylomicronemia with triglycerides (TG) >2000 mg/dL. From admission, the ratio of total cholesterol to total triglycerides was not below 0.2 but was closer to 0.5, suggesting that his condition was not classic chylomicronemia. We confirmed that the patient had HLP3 based on his very-low-density lipoprotein cholesterol (VLDL-C)/TG ratio, which was ≥0.3, and lipoprotein electrophoresis showing a broad beta band. Because he was not responsive to initial therapy, we considered an interferent impairing lipolysis and TG reduction. The interferent was an M-protein that may also have falsely elevated both apolipoprotein-B and direct-LDL-C levels. In this case study, we report on a patient with chylomicronemia resulting from HLP3 complicated by a circulating M-protein.

An African American Male Patient with Rare Type B Insulin Resistance Syndrome.

Syndromes of severe insulin resistance can result from mutations in the insulin receptor gene or autoantibodies to the insulin receptor. The type B syndrome of insulin resistance results from autoantibodies to the insulin receptor and occurs predominantly in women under age 50 years. Here we report on a 64 year old African American man with systemic lupus erythematosus (SLE) and acanthosis nigricans who had severe insulin resistance requiring up to 5000 units of insulin per day. He was diagnosed with type B insulin resistance syndrome based on his clinical presentation and demonstration of autoantibodies to the insulin receptor in his serum. This case study underscores the importance of assaying for autoantibodies to the insulin receptors especially in African American patients with severe insulin resistance and diabetes requiring excessive doses of insulin, in the setting of an autoimmune disease like SLE. It also behooves reference laboratories to develop and offer this assay because these patients have a very high mortality.

Comparison of the triglyceride-waist circumference and the C-reactive protein-waist circumference indices in nascent metabolic syndrome.

The Hypertriglyceridemia waist (HTGW) appears to be a valid measure of visceral adiposity, metabolic syndrome (MetS), type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD). Since the cut points differ for different race groups recent studies have instead used the simplified product of triglycerides and waist circumference (TG.WC). In our patients with nascent MetS (without the confounding of T2DM, ASCVD, smoking and macro-inflammation) we found that only 41% had an increased HTGW. Since MetS is a pro-inflammatory disorder we compared the product of CRP to WC (CRP.WC) to TG.WC in our patients with nascent MetS as biomarkers. Patients with MetS (n=58) and matched controls (n=44) were recruited. Fasting blood samples were obtained for routine laboratories including the lipid profile, insulin, and adipokines. Both the TG.WC and CRP.WC indices were significantly increased in MetS and both increased with increasing severity of MetS. Whilst both correlated with cardio-metabolic features and insulin resistance, only the CRP.WC correlated significantly with adiponectin, an adipokine largely deriving from visceral adipose tissue. The TG.WC correlated with LDL-cholesterol which was not increased in this group. Receiver Operating Characteristic (ROC) curve analysis showed that both ratios showed good discrimination for MetS with no significant differences between ratios. Thus both the TG.WC and CRP.WC indices are significantly increased in patients with nascent MetS and appear to be valid biomarkers of MetS.