Inappropriate Use of Homeostasis Model Assessment Cutoff Values for Diagnosing Insulin Resistance in Pediatric Studies.

BACKGROUND: Assessing pediatric patients for insulin resistance is one way to identify those who are at a high risk of developing type 2 diabetes mellitus. The homoeostasis model assessment (HOMA) is a measure of insulin resistance based on fasting blood glucose and insulin levels. Although this measure is widely used in research, cutoff values for pediatric populations have not been established. OBJECTIVE: To assess the validity of HOMA cutoff values used in pediatric studies published in peer-reviewed journals. METHODS: Studies published from January 2010 to December 2015 were identified through MEDLINE. Initial screening of abstracts was done to select studies that were conducted in pediatric populations and used HOMA to assess insulin resistance. Subsequent full-text review narrowed the list to only those studies that used a specific HOMA score to diagnose insulin resistance. Each study was classified as using a predetermined fixed HOMA cutoff value or a cutoff that was a percentile specific to that population. For studies that used a predetermined cutoff value, the references cited to provide evidence in support of that cutoff were evaluated. RESULTS: In the 298 articles analyzed, 51 different HOMA cutoff values were used to classify patients as having insulin resistance. Two hundred fifty-five studies (85.6%) used a predetermined fixed cutoff value, but only 72 (28.2%) of those studies provided a reference that supported its use. One hundred ten studies (43%) that used a fixed cutoff either cited a study that did not mention HOMA or provided no reference at all. Tracing of citation history indicated that the most commonly used cutoff values were ultimately based on studies that did not validate their use for defining insulin resistance. CONCLUSION: Little evidence exists to support HOMA cutoff values commonly used to define insulin resistance in pediatric studies. These findings highlight the importance of validating study design elements when training medical students and novice investigators. Using available data to generate population ranges for HOMA would improve its clinical utility.

Use of the triglyceride to HDL cholesterol ratio for assessing insulin sensitivity in overweight and obese children in rural Appalachia.

BACKGROUND: Studies have suggested that triglyceride to HDL-cholesterol ratio (TRG/HDL) is a surrogate marker of insulin resistance (IR), but information regarding its use in pediatric patients is limited. This study investigated the ability of TRG/HDL ratio to assess IR in obese and overweight children. METHODS: The sample consisted of de-identified electronic medical records of patients aged 10-17 years (n=223). Logistic regression was performed using TRG/HDL ratio as a predictor of hyperinsulinemia or IR defined using homeostasis model assessment score. RESULTS: TRG/HDL ratio had limited ability to predict hyperinsulinemia (AUROC 0.71) or IR (AUROC 0.72). Although females had higher insulin levels, male patients were significantly more likely to have hypertriglyceridemia and impaired fasting glucose. CONCLUSIONS: TRG/HDL ratio was not adequate for predicting IR in this population. Gender differences in the development of obesity-related metabolic abnormalities may impact the choice of screening studies in pediatric patients.

Salivary uric acid as a noninvasive biomarker of metabolic syndrome.

BACKGROUND: Elevated serum uric acid is associated with obesity, hypertension and metabolic syndrome. Because a linear relationship exists between serum and salivary uric acid (SUA) concentration, saliva testing may be a useful noninvasive approach for monitoring cardiometabolic risk. The goal of this pilot study was to determine if SUA is increased in patients with metabolic syndrome and to investigate correlations between SUA and individual cardiometabolic risk factors. FINDINGS: Volunteers between the ages of 18 and 65 without conditions known to affect serum uric acid levels were recruited. Height, weight, blood pressure and waist circumference were measured and a full lipid panel along with fasting blood glucose was obtained. Saliva samples were collected and uric acid levels were determined. 78 volunteers, 35% of whom had metabolic syndrome, completed the study. SUA was significantly elevated in patients with metabolic syndrome (p=.002). The incidence of metabolic syndrome in the 4th quartile for SUA was 67% compared to 25% in quartiles1-3 combined. Significant correlations were seen between SUA and systolic blood pressure (r=.440, p=.000), diastolic blood pressure ( r=.304, p=.007), waist circumference (r=.332, p=.003), BMI ( r=.269, p=.018), fasting blood glucose ( r=.341, p=.002), triglycerides (r=.410, p=.000), HDL ( r=.237, p=.036) and the number of cardiometabolic risk factors present (r=0.257, p=.023). CONCLUSIONS: These results suggest that SUA may be a useful biomarker for noninvasive monitoring of cardiometabolic risk. Larger studies are needed to validate this approach.

Detection of homocysteine and C-reactive protein in the saliva of healthy adults: comparison with blood levels.

Inflammation and cardiovascular disease are associated with elevated serum levels of C-Reactive Protein (CRP) and homocysteine. The presence of both molecules in saliva provides an opportunity for development of non-invasive assessments of disease risk. However, salivary CRP and homocysteine reference ranges and their correlation with serum levels are unknown. This study investigated if CRP and homocysteine could be routinely detected in the saliva of healthy adults and the relationship between salivary and blood levels. CRP and homocysteine concentrations were determined using ELISA and enzymatic assays respectively. Homocysteine was detected in only two saliva samples (n = 55). CRP was measurable in all saliva samples (range: 0.05 to 64.3 mug/L; median = 1.2 mug/L) and plasma samples (range: 0.14 to 31.1 mg/L; median = 2.0 mg/L). Regression analysis demonstrated no relationship between CRP concentration in saliva and plasma (R(2) = 0.001). Generalized linear models including variables such as saliva flow rate and time since eating or drinking also did not pass lack of fit testing. Therefore, a relationship between CRP concentration in saliva and blood could not be established in this group of subjects. More sensitive detection methods are needed to determine if a correlation between salivary and serum homocysteine levels exists.

Effects of rib raising on the autonomic nervous system: a pilot study using noninvasive biomarkers.

CONTEXT: Rib raising is an osteopathic manipulative treatment technique used to address restricted excursion of the rib cage and modulate sympathetic nervous system (SNS) activity. However, the physiologic effects of this technique have not been well documented. OBJECTIVE: To investigate the effects of rib raising on the autonomic nervous system and the hypothalamic-pituitary-adrenal axis using noninvasive biomarkers. METHODS: Changes in salivary biomarkers after rib raising were investigated using a pretest-posttest, placebo-controlled design. Healthy adult participants were recruited and randomly assigned to rib raising or placebo (light touch) groups. All participants provided baseline saliva samples and samples immediately and 10 minutes after receiving the rib raising or placebo procedure. Salivary flow rate, alpha-amylase activity, and cortisol levels were measured for each sample. RESULTS: Twenty-three participants were recruited, of whom 14 completed the study (7 in each group). Subjects who received rib raising had a statistically significant decrease in alpha-amylase activity both immediately after (P=.014) and 10 minutes after (P=.008) the procedure. A statistically significant change in alpha-amylase activity was not seen in the placebo group at either time point. Changes in salivary cortisol levels and flow rate were not statistically significant in either group. CONCLUSIONS: The results of the present pilot study suggest that SNS activity may decrease immediately after rib raising, but the hypothalamic-pituitary-adrenal axis and parasympathetic activity are not altered by this technique. Salivary alpha-amylase may be a useful biomarker for investigating manipulative treatments targeting the SNS. Additional studies with a greater number of subjects are needed to expand on these results.

A novel approach to identifying beta-secretase inhibitors: bis-statine peptide mimetics discovered using structure and spot synthesis.

Beta-secretase 1 (BACE1) is an aspartic protease believed to play a critical role in Alzheimer's disease. Inhibitors of this enzyme have been designed by incorporating the non-cleavable hydroxyethylene and statine isosteres into peptides corresponding to BACE1 substrate sequences. We sought to develop new methods to quickly characterize and optimize inhibitors based on the statine core. Minimal sequence requirements for binding were first established using both crystallography and peptide spot synthesis. These shortened peptide inhibitors were then optimized by using spot synthesis to perform iterative cycles of substitution and deletion. The present study resulted in the identification of novel "bis-statine" inhibitors shown by crystallography to have a unique binding mode. Our results demonstrate the application of peptide spot synthesis as an effective method for enhancing peptidomimetic drug discovery.