Alternate glycemic markers reflect glycemic variability in continuous glucose monitoring in youth with prediabetes and type 2 diabetes.

OBJECTIVE: To determine whether the alternate glycemic markers, fructosamine (FA), glycated albumin (GA), and 1,5-anhydroglucitol (1,5AG), predict glycemic variability captured by continuous glucose monitoring (CGM) in obese youth with prediabetes and type 2 diabetes (T2D). STUDY DESIGN: Youth with BMI ≥85th%ile, 10-18 years, had collection of fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), FA, GA, and 1,5AG and 72 hours of CGM. Participants with HbA1c ≥5.7% were included. Relationships between glycemic markers and CGM variables were determined with Spearman correlation coefficients. Linear models were used to examine the association between alternate markers and CGM measures of glycemic variability-standard deviation (SD) and mean amplitude of glycemic excursions (MAGE)-after controlling for HbA1c. RESULTS: Total n = 56; Median (25th%ile, 75th%ile) age = 14.3 years (12.5, 15.9), 32% male, 64% Hispanic, 20% black, 13% white, HbA1c = 5.9% (5.8, 6.3), FA=211 mmol/L (200, 226), GA= 12% (11%, 12%), and 1,5AG = 22mcg/mL (19, 26). HbA1c correlated with average sensor glucose, AUC, SD, MAGE, and %time > 140 mg/dL. FA and GA correlated with average and peak sensor glucose, %time >140 and >200 mg/dL, and MAGE. GA also correlated with SD and AUC180. 1,5AG correlated with peak glucose, AUC180, SD, and MAGE. After adjusting for HbA1c, all 3 markers independently predicted MAGE; FA and GA independently predicted SD. CONCLUSIONS: Alternate glycemic markers predict glycemic variability as measured by CGM in youth with prediabetes and T2D. After adjusting for HbA1c, these alternate markers continued to predict components of glycemic variability detected by CGM.

Screening for type 2 diabetes and prediabetes in obese youth: evaluating alternate markers of glycemia - 1,5-anhydroglucitol, fructosamine, and glycated albumin.

Hemoglobin A1c (HbA1c) is increasingly performed over the oral glucose tolerance test (OGTT) as the initial screening test for type 2 diabetes in youth. However, the optimal strategy for identifying type 2 diabetes in youth remains controversial. Alternate glycemic markers have been proposed as potentially useful tools for diabetes screening. We examined the relationships among fructosamine (FA), glycated albumin (GA), and 1,5-anhydroglucitol (1,5-AG) with traditional screening tests, HbA1c and OGTT. Youth 10-18 yrs, BMI ≥85th‰, and HbA1c <7.5% had a single visit with measurement of HbA1c, 1,5-AG, FA, GA, and a standard OGTT. Distributions of FA, GA, and 1,5-AG by HbA1c and 2-hour glucose (2hG) categories were compared. Receiver operating characteristic (ROC)-curves were generated to determine the cut points at which alternate markers maximized sensitivity and specificity for predicting prediabetes and diabetes. One hundred and seventeen, 62% female, 59% Hispanic, 22% White, 17% black, median 14.1 yr, and body mass index (BMI) z-score 2.3 participated. Median values of each alternate marker differed significantly between prediabetes and diabetes HbA1c and 2hG categories (p < 0.017). Only GA medians differed (p = 0.006) between normal and prediabetes HbA1c. Area under the receiver operating characteristic curves (ROC-AUCs) for alternate markers as predictors of prediabetes (0.5-0.66) were low; however, alternate marker ROC-AUCs for identifying diabetes (0.82-0.98) were excellent. Although the alternate markers were poor predictors of prediabetes, they all performed well predicting diabetes by 2hG and HbA1c. Whereas the usefulness of these markers for identifying prediabetes is limited, they may be useful in certain scenarios as second line screening tools for diabetes in overweight/obese youth.

Peripheral insulin resistance in obese girls with hyperandrogenism is related to oxidative phosphorylation and elevated serum free fatty acids.

Hyperandrogenic syndrome (HAS) is associated with insulin resistance (IR) and type 2 diabetes. Muscle IR in type 2 diabetes is linked with defects in mitochondrial oxidative capacity. In vivo muscle mitochondrial function has not been studied in HAS, especially in youth, who are early in the disease process. Our goal was to measure muscle mitochondrial oxidative function and peripheral IR in obese youth with HAS. Obese girls without HAS [n = 22, age 15(13,17) yr, BMI Z-score 2.05 ± 0.37] and with HAS [n = 35, age 15(14,16) yr, BMI Z-score 2.18 ± 0.30] were enrolled. Mitochondrial function was assessed with (31)phosphorus MR spectroscopy before, during, and after near-maximal isometric calf exercise, and peripheral IR was assessed with an 80 mU·m(-2)·min(-1) hyperinsulinemic euglycemic clamp. Girls with HAS had higher androgens [free androgen index 7.9(6.6,15.5) vs. 3.5(3.0,4.0), P < 0.01] and more IR [glucose infusion rate 9.4(7.0, 12,2) vs. 14.5(13.2,15.8) mg·kg lean(-1)·min(-1), P < 0.01]. HAS girls also had increased markers of inflammation including CRP, platelets, and white blood cell count and higher serum free fatty acids during hyperinsulinemia. Mitochondrial oxidative phosphorylation was lower in HAS [0.11(0.06,0.19) vs. 0.18(0.12,0.23) mmol/s, P < 0.05], although other spectroscopy markers of mitochondrial function were similar between groups. In multivariate analysis of the entire cohort, IR related to androgens, oxidative phosphorylation, and free fatty acid concentrations during hyperinsulinemia. These relationships were present in just the HAS cohort as well. Obese girls with HAS have significant peripheral IR, which is related to elevated androgens and free fatty acids and decreased mitochondrial oxidative phosphorylation. These may provide future options as targets for therapeutic intervention.

Hemoglobin A1c assay variations and implications for diabetes screening in obese youth.

BACKGROUND: Standardization of the hemoglobin A1c (A1c) assay has led to its increasing utilization as a screening tool for the diagnosis of prediabetes and type 2 diabetes in youth. However, significant A1c assay variability remains and has implications for clinical management. OBJECTIVE: To describe our center's experiences with A1c results in youth and to evaluate inter-method differences and their clinical implications. SUBJECTS: Seventy-five youth (aged 10-18 yr old), body mass index (BMI) ≥85th‰ participated. METHODS: Seventy-two participants had two A1c values performed on the same sample, one via immunoassay (DCA Vantage Analyzer, A1c1 ) and the other via high performance liquid chromatography (Bio-Rad Variant II, A1c2 ). Nineteen had A1c run on two immunoassay devices (A1c1 and Dimensions Vista, A1c3 ). RESULTS: Mean age of participants was 13.9 years, BMI% 97.89%, 33% male, 16% white, 21% black, and 61% Hispanic (H). Mean A1c1 was 5.68% ± 0.38 vs. a mean A1c2 of 5.73% ± 0.39, p = 0.049. Concordance in diabetes status between methods was achieved in 79% of subjects. Nineteen subjects with A1c3 results had testing performed an average of 22 ± 9 days prior to A1c1 . Mean A1c3 was 6.24% ± 0.4, compared to a mean A1c1 of 5.74% ± 0.31, (p < 0.0001). A1c1 was on average systematically -0.5 ± 0.28 lower compared to A1c3 . There was poor agreement in diabetes classification between A1c1 and A1c3 , with a concordance in classification between methods of only 36.8%. CONCLUSIONS: Clinically significant inter-method A1c variability exists that impacts patient classification and treatment recommendations. In the screening of obese youth for diabetes, A1c results should be interpreted with caution.

Insulin Resistance, Hyperinsulinemia, and Mitochondria Dysfunction in Nonobese Girls With Polycystic Ovarian Syndrome.

OBJECTIVE: Obese girls with polycystic ovarian syndrome (PCOS) have decreased insulin sensitivity (IS), muscle mitochondrial dysfunction and increased liver fat, which may contribute to their increased risk for type 2 diabetes. Less is known regarding normal-weight girls with PCOS. METHODS: Normal-weight girls with PCOS [n =18, age 15.9 ± 1.8 years, body mass index (BMI) percentile 68 ± 18] and normal-weight controls (NWC; n = 20; age 15.0 ± 2.1 years, BMI percentile 60 ± 21) were studied. Tissue-specific IS was assessed with a four-phase hyperinsulinemic-euglycemic clamp with isotope tracers and a 2-hour oral glucose tolerance test (OGTT). Hepatic fat was determined using magnetic resonance imaging. Postexercise muscle mitochondrial function was assessed with 31P MR spectroscopy. RESULTS: Both groups had similar demographics, anthropomorphics, physical attributes, habitual physical activity levels and fasting laboratory values, except for increased total testosterone and DHEAS in PCOS. Clamp-assessed peripheral IS was lower in PCOS (10.4 ± 2.4 mg/kg/min vs 12.7 ± 2.1; P = 0.024). The 120-minute OGTT insulin and glucose concentrations were higher in PCOS (114 IU/mL ± 26 vs 41 ± 25, P = <0.001 and 119 ± 22 mg/dL vs 85 ± 23, P = 0.01, respectively). Muscle mitochondrial ADP and phosphocreatine time constants were slower in PCOS. Despite a higher percentage liver fat in PCOS, hepatic IS was similar between groups, as was adipose IS. CONCLUSIONS: Normal-weight girls with PCOS have decreased peripheral IS and muscle mitochondrial dysfunction, abnormal glucose disposal, relative postprandial hyperinsulinemia, and increased hepatic fat compared to NWC. Despite a normal BMI, multiple aspects of metabolism appear altered in normal-weight girls with PCOS.

Hepatic Steatosis is Common in Adolescents with Obesity and PCOS and Relates to De Novo Lipogenesis but not Insulin Resistance.

OBJECTIVE: Increased liver fat and type 2 diabetes are prevalent in women with polycystic ovarian syndrome (PCOS) and cause excess mortality, yet little is known about their development during adolescence. The objective of this study was to measure hepatic steatosis and related metabolic contributors in girls with obesity, with and without PCOS. METHODS: Nondiabetic adolescents with obesity, 41 with PCOS (PCOS; age 15.0 [13.0-16.0] years, BMI 35.2 ± 0.61 kg/m2 ) and 30 without PCOS (OB; age 14.5 [13.0-17.0], BMI 33.2 ± 1.8), were studied. Visceral and liver fat were assessed with MRI. Serum measures included androgens and 16:1 and 18:1 N7 fatty acids specific to de novo lipogenesis. Adipose, hepatic, and peripheral insulin sensitivity (IS) were assessed with a four-phase hyperinsulinemic-euglycemic clamp with isotope tracers. RESULTS: Forty-nine percent of the PCOS group had hepatic steatosis versus fourteen percent of the OB group (P = 0.02), and the PCOS group had higher N7 (43 ± 4 vs. 29 ± 5 nmol/g; P = 0.02). Peripheral IS was lower in PCOS (9.4 [7.2-12.3] vs. 14.5 [13.1-18.05 mg/lean kg/min]; P < 0.001) as was hepatic (P = 0.006) and adipose IS (P = 0.005). Percent liver fat correlated with N7 (R = 0.46, P = 0.02) and visceral fat (R = 0.42, P < 0.001), not androgens or peripheral IS. CONCLUSIONS: Nearly 50% of nondiabetic girls with PCOS and obesity have hepatic steatosis, which relates to visceral fat and lipogenesis, but not to IS or androgens.

Continuous glucose monitoring and its relationship to hemoglobin A1c and oral glucose tolerance testing in obese and prediabetic youth.

CONTEXT: The optimal screening test for diabetes and prediabetes in obese youth is controversial. OBJECTIVE: We examined whether glycosylated hemoglobin (HbA1c) or the oral glucose tolerance test (OGTT) is a better predictor of free-living glycemia as measured by continuous glucose monitoring (CGM). DESIGN: This was a cross-sectional study of youth 10-18 years old, body mass index (BMI) 85th percentile or greater, with diabetes risk factors. SETTING AND PARTICIPANTS: Participants (n = 118) with BMI 85th percentile or greater, not on medications for glucose management, were recruited from primary care and pediatric endocrinology clinics around Denver, Colorado. INTERVENTION: HbA1c, fasting plasma glucose, and 2-hour glucose were collected and all participants wore a blinded CGM for 72 hours. MAIN OUTCOME MEASURES: CGM outcomes were determined and descriptive statistics calculated. Performance characteristics at current American Diabetes Association cutpoints were compared with CGM outcomes. RESULTS: CGM data were successfully collected on 98 obese youth. Those with prediabetes had significantly higher average glucose, area under the curve (AUC), peak glucose, and time greater than 120 and greater than 140 mg/dL (P < .01) on CGM than youth with normal HbA1c or OGTT. HbA1c had a greater magnitude of correlation to CGM average glucose, AUC, and minimum glucose; 2-hour glucose had a greater magnitude of correlation to CGM SD, peak glucose, and time greater than 140 and greater than 200 mg/dL. However, there were no overall differences in the strength comparisons between 2-hour glucose and HbA1c correlations to CGM outcomes. CONCLUSIONS: In obese youth, HbA1c and 2-hour glucose performed equally well at predicting free-living glycemia on CGM, suggesting that both are valid tests for dysglycemia screening.