Outcome of lifestyle intervention in relation to duration of pre-diabetes: the Pathobiology and Reversibility of Prediabetes in a Biracial Cohort (PROP-ABC) study.

INTRODUCTION: In studies that enrolled people with prevalent pre-diabetes of unknown duration, lifestyle intervention (LI) delayed progression to type 2 diabetes (T2D) but did not reverse pre-diabetes in most participants. Here, we assessed the effects of LI among individuals with pre-diabetes of known duration to determine whether outcomes are related to duration of pre-diabetes. RESEARCH DESIGN AND METHODS: The Pathobiology and Reversibility of Prediabetes in a Biracial Cohort study initiated LI in subjects with incident pre-diabetes during follow-up of initially normoglycemic African Americans and European Americans with parental T2D. Participants were stratified into those initiating LI after <3, 3-5, or >5 years of pre-diabetes diagnosis. Assessments included anthropometry, body fat, fasting and 2-hour plasma glucose (FPG, 2hPG), and insulin sensitivity and secretion. The outcomes were normal glucose regulation (NGR; ie, normal FPG and 2hPG), persistent pre-diabetes, or T2D. Participants who maintained normal FPG and normal 2hPG levels during follow-up served as the control. The control subjects did not receive lifestyle or other intervention to alter the course of glycemia or body weight. RESULTS: Of 223 participants (age 53.3±9.28 years, body mass index 30.6±6.70 kg/m2), 72 (control) maintained normoglycemia during follow-up and 138 subjects with incident pre-diabetes initiated LI after 4.08±2.02 years (range 3 months-8.3 years) of diagnosis. Compared with control, LI participants showed decrease in glucose, weight, and body fat; 42.8% reverted to NGR, 50% had persistent pre-diabetes, and 7.2% developed T2D after 5 years. These outcomes were similar across race and pre-diabetes duration strata, but greater glycemic decrease occurred when LI was initiated within 5 years of pre-diabetes diagnosis. CONCLUSIONS: Ninety-three per cent of adults with parental T2D who initiated LI within 3 months to 8.3 years of developing pre-diabetes did not progress to T2D; nearly half reverted to NGR.Trial registration number NCT02027571.

Plasma FGF-21 and Sclerostin Levels, Glycemia, Adiposity, and Insulin Sensitivity in Normoglycemic Black and White Adults.

Increased circulating fibroblast growth factor (FGF)-21 and sclerostin levels have been reported in patients with type 2 diabetes (T2D). We assessed the association of FGF-21 and sclerostin with adiposity, glycemia, and glucoregulatory measures in healthy subjects. We studied 20 normoglycemic Black and White offspring of parents with T2D. Assessments included oral glucose tolerance test, insulin sensitivity (Si-clamp), insulin secretion (homeostasis model assessment index of b-cell function [HOMA-B]), and body fat (dual-energy X-ray absorptiometry). Fasting plasma FGF-21 and sclerostin levels were measured with enzyme-linked immunosorbent assays. The participants' mean (+SD) age was 50.4 ± 5.97 years; body mass index (BMI) 32.5 ± 5.86 kg/m2; fasting plasma glucose (FPG) 96.1 ± 5.21 mg/dL, and 2-hour postload glucose 116 ± 5.45 mg/dL. FGF-21 levels were similar in Black people vs White people (0.36 ± 0.15 ng/mL vs 0.39 ± 0.25 ng/mL), men vs women (0.45 ± 0.14 vs 0.44 ± 0.07 ng/mL), correlated positively with BMI (r = 0.23, P = .05) and waist circumference (r = 0.27, P = .04), and inversely with FPG (r = -0.26, P = .05). Sclerostin levels also were similar in Black people (33.5 ± 17.1 pmol/L) vs White people (34.2 ± 6.41 pmol/L), men vs women (35.3 ± 9.01 pmol/L vs 32.3 ± 15.8 pmol/L), and correlated inversely with FPG (r = -0.11 to -0.44) but not adiposity measures. The correlation coefficient between Si-clamp values and FGF-21 levels was -0.31 (P = .09) compared with 0.04 (P = .89) for sclerostin levels. FGF-21 and sclerostin levels were not correlated with each other or HOMA-B. Among healthy Black and White subjects, plasma FGF-21 and sclerostin showed differential associations with adiposity but concordant association with FPG levels.

Association of plasma acylcarnitines with insulin sensitivity, insulin secretion, and prediabetes in a biracial cohort.

The ability to predict prediabetes, which affects ∼90 million adults in the US and ∼400 million adults worldwide, would be valuable to public health. Acylcarnitines, fatty acid metabolites, have been associated with type 2 diabetes risk in cross-sectional studies of mostly Caucasian subjects, but prospective studies on their link to prediabetes in diverse populations are lacking. Here, we determined the association of plasma acylcarnitines with incident prediabetes in African Americans and European Americans enrolled in a prospective study. We analyzed 45 acylcarnitines in baseline plasma samples from 70 adults (35 African-American, 35 European-American) with incident prediabetes (progressors) and 70 matched controls (non-progressors) during 5.5-year (mean 2.6 years) follow-up in the Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) study. Incident prediabetes (impaired fasting glucose/impaired glucose tolerance) was confirmed with OGTT. We measured acylcarnitines using tandem mass spectrometry, insulin sensitivity by hyperinsulinemic euglycemic clamp, and insulin secretion using intravenous glucose tolerance test. The results showed that progressors and non-progressors during POP-ABC study follow-up were concordant for 36 acylcarnitines and discordant for nine others. In logistic regression models, beta-hydroxy butyryl carnitine (C4-OH), 3-hydroxy-isovaleryl carnitine/malonyl carnitine (C5-OH/C3-DC), and octenoyl carnitine (C8:1) were the only significant predictors of incident prediabetes. The combined cut-off plasma levels of <0.03 micromol/L for C4-OH, <0.03 micromol/L for C5-OH/C3-DC, and >0.25 micromol/L for C8:1 acylcarnitines predicted incident prediabetes with 81.9% sensitivity and 65.2% specificity. Thus, circulating levels of one medium-chain and two short-chain acylcarnitines may be sensitive biomarkers for the risk of incident prediabetes among initially normoglycemic individuals with parental history of type 2 diabetes.

Pathobiology and Reversibility of Prediabetes in a Biracial Cohort (PROP-ABC) Study: design of lifestyle intervention.

INTRODUCTION: Intensive lifestyle intervention (ILI) prevents progression from prediabetes to type 2 diabetes (T2D) but reversal of prediabetes is less well studied. RESEARCH DESIGN AND METHODS: The overall objectives of the Pathobiology and Reversibility of Prediabetes in a Biracial Cohort (PROP-ABC) Study (ClinicalTrials.gov ID: NCT02027571) are to determine the natural history and reversibility of prediabetes. The study tests specific hypotheses on the patterns of progression to prediabetes among normoglycemic African-American (AA) and European-American (EA) offspring of parents with T2D; emergence of microvascular and macrovascular complications during transition from normal to impaired glucose regulation; significance of the 'metabolically healthy' obese phenotype; and effect of duration of the prediabetic state on its reversibility with lifestyle intervention. Participants who developed incident prediabetes were offered ILI and evaluated quarterly for 5 years. The primary outcome was restoration of normal glucose regulation (fasting plasma glucose <100 mg/dL and two-hour plasma glucose (2hrPG)<140 mg/dL). RESULTS: Of the 223 subjects enrolled in the PROP-ABC Study, 158 participants with incident prediabetes started ILI. The mean age was 53.3±9.28 years; body mass index 30.6±6.70 kg/m2; 70% were female, 52.4% AA and 47.6% EA. The ILI program used goal setting, weight-based calorie restriction, physical activity (180 min/week), self-monitoring, and meal replacement. Monthly face-to-face (F2F) counseling sessions during the initial 6 months, and quarterly visits thereafter, were supplemented with electronic and postal contacts. Attendance at F2F sessions was highly correlated with weight loss (r=0.98, p<0.0001). Meal replacement induced ~5 kg weight loss within 3 months in participants with recrudescent weight pattern. Self-reported exercise minutes correlated with pedometer step counts (r=0.47, p<0.0001). CONCLUSION: The PROP-ABC Study has demonstrated the feasibility of executing an ILI program designed to test reversibility of incident prediabetes in a biracial cohort.

Amino acid signature predictive of incident prediabetes: A case-control study nested within the longitudinal pathobiology of prediabetes in a biracial cohort.

OBJECTIVE: Circulating branched-chain amino acids (BCAAs, isoleucine, leucine, valine) and aromatic amino acids (AAAs, tyrosine and phenylalanine) predicted type 2 diabetes mellitus (T2DM) risk in a Caucasian population. Here, we assessed amino acid levels in relation to incident prediabetes among initially normoglycemic African Americans (AA) and European Americans (EA). RESEARCH DESIGN AND METHODS: Using a nested case-control design, we studied 70 adults (35 AA, 35 EA) who developed prediabetes (progressors) and 70 matched participants who maintained normoglycemia (nonprogressors) during 5.5 years of follow-up in the Pathobiology of Prediabetes in a Biracial Cohort study. Assessments included plasma amino acid levels, insulin sensitivity, and beta-cell function. RESULTS: The total level of all 18 amino acid assayed was significantly associated with lean mass (r = 0.36, P < 0.0001), waist circumference (r = 0.27, P = 0.001), fasting plasma glucose (r = 0.24, P = 0.005), HOMA-IR (r = 0.22, P = 0.01) and HDL cholesterol (r = -0.18, P = 0.03). Individual amino acid levels were significantly associated with insulin sensitivity and insulin secretion. Compared with nonprogressors, progressors had higher baseline levels of asparagine and aspartic acid (P <0.0001), glutamine/glutamic acid (P = 0.005) and phenylalanine (P = 0.02), and lower histidine (P = 0.02) levels. In fully-adjusted logistic regression models, aspartic acid/asparagine (OR 2.72 [95% CI 1.91-3.87]) and histidine (OR 0.90 [95% CI 0.85-0.96]) were the only amino acids that significantly predicted incident prediabetes. CONCLUSIONS: Baseline plasma aspartic acid and asparagine levels predicted progression to prediabetes, whereas histidine levels were protective of prediabetes risk. Thus, the amino acid signature associated with prediabetes in a diverse population may be distinct from that previously linked to T2DM in Caucasians.

Awareness of Prediabetes Status and Subsequent Health Behavior, Body Weight, and Blood Glucose Levels.

BACKGROUND: Lifestyle intervention decreases diabetes risk in prediabetic subjects, but the impact of passive notification of prediabetes status on glycemia or health behavior is unclear. METHODS: The Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) study followed normoglycemic African American (AA) and European American (EA) offspring of parents with type 2 diabetes mellitus for incident prediabetes. During 5.5 years of follow-up (mean, 2.62 years), 101 of 343 subjects developed prediabetes and were notified, without any interventions. Participants were recalled 18 months poststudy. Here, we compared data from participants with incident prediabetes or normoglycemia (control) during POP-ABC who underwent retesting 18-months poststudy. RESULTS: There were 73 subjects (46 female, 27 male; 36 AA, 37 EA) in the prediabetes group and 73 subjects (48 female, 25 male; 35 AA, 38 EA) in the control group. The mean (± SEM) enrollment age was 48.7 ± 0.96 years versus 48.3 ± 1.06 years (P = .37) and body mass index (BMI) was 31.1 ± 0.70 kg/m2 versus 29.2 ± 0.69 kg/m2 (P = .04) for prediabetes versus control groups, respectively. The 18-month changes (prediabetes vs control) were the following: fasting plasma glucose (FPG), -8.01 ± 1.11 vs 2.02 ± 0.64 mg/dL; 2-hour plasma glucose (2hrPG), -8.21 ± 3.34 vs 8.53 ± 3.17 mg/dL; weight, -0.54 ± 0.72 vs 2.77 ± 1.25 kg; and waist circumference -1.07 ± 0.78 vs 1.78 ± 0.85 (P = .03-<0.0001). The interval changes in FPG were significantly correlated with changes in weight and waist circumference (r = 0.2, P = .01). The prediabetes group reported improved dietary and exercise habits compared with control. CONCLUSION: Communication of prediabetes status is associated with improvements in glucose tolerance, glycemia, and adiposity, probably via self-directed lifestyle modification.

Physiology of Glycemic Recovery and Stabilization After Hyperinsulinemic Euglycemic Clamp in Healthy Subjects.

Background: The hyperinsulinemic euglycemic clamp (HEC) is the gold standard for measuring insulin sensitivity, but glycemic recovery and stabilization after the procedure have not been well studied. Here, we assessed the physiological determinants of postclamp recovery. Methods: We analyzed data from 207 healthy subjects [102 African American (AA) and 105 European American (EA)] who underwent HEC in the Pathobiology of Prediabetes in a Biracial Cohort study. At the end of HEC, insulin infusion was stopped, and dextrose (20%) infusion was tapered and stopped when plasma glucose stabilized ≥20 mg/dL above the preclamp value (∼100 mg/dL). Glucose recovery time (GRT) was defined as the interval from cessation of insulin infusion to discontinuation of dextrose infusion. Insulin clearance was calculated under basal and clamp conditions. Results: The mean (± SD) age and body mass index were 46.3 ± 9.96 years and 30.7 ± 8.43 kg/m2, respectively. Plasma glucose (mg/dL) was 92.2 ± 6.26 preclamp and 124.2 ± 26.9 postclamp. The median GRT (minutes) was 65 (range, 30 to 270); mean GRT was 77.1 ± 42.7 (men: 82.9 ± 45.5; women: 74.4 ± 42.3; AA, 82.0 ± 49.6; EA, 72.3 ± 34.2; P > 0.1 for sex or race). The 90th percentile for GRT was 119 minutes. In regression models, significant predictors of GRT were age (P = 0.03), weight (P = 0.009), 2-hour plasma glucose (P = 0.0002), insulin sensitivity (P = 0.03), disposition index (P = 0.017), and basal insulin clearance (P = 0.02). Conclusions: In our biracial cohort, glycemic recovery after hyperinsulinemic clamp was independent of sex or race but was significantly predicted by age, weight, and glucose tolerance and by insulin sensitivity, secretion, and clearance. We recommend that monitoring be maintained for ∼2 hours postclamp to ensure adequate glycemic stabilization.

Parental history of type 2 diabetes is associated with lower resting energy expenditure in normoglycemic subjects.

OBJECTIVE: Resting energy expenditure (REE) is linked to obesity, insulin resistance and type 2 diabetes (T2DM). REE and T2DM are inherited traits. Therefore, we investigated the effect of parental T2DM on REE in normoglycemic subjects. METHODS: Eighty-seven subjects with parental T2DM and 83 subjects without parental T2DM were matched in age, gender, race, BMI, weight and waist circumference. Subjects underwent a 75 g oral glucose tolerance test; REE was determined by indirect calorimetry and body composition was assessed by dual energy X-ray absorptiometry. Statistical analysis was performed using Student's t-test, analysis of variance and regression analysis. RESULTS: The mean age was 38.8±11.3 years, 57% were females and 53% were African-Americans. The mean BMI was 28.5±6.1 kg/m2, waist circumference 91.8±15.1 cm, weight 83.9±20.3 kg, fat mass 31.0%±10.0%, mean fat-free mass (FFM) 54.4±12.9 kg. REE was significantly lower in subjects with parental diabetes, normalized REE 1364.4±263.4Kcal/day vs 1489.4±323.2 Kcal/day, p=0.006 and 29.2±5.3Kcal/kg FFM/day vs 31.9±6.0 Kcal/kg FFM/day, p=0.002. African-Americans had a lower REE compared with Caucasians 28.6±5.4Kcal/kg FFM/day vs 32.6±5.5 Kcal/kg FFM/day, p<0.0001. In a multiple regression model, ethnicity (p<0.0001), parental history of T2DM (p=0.006) and FFM (p=0.021) were independent predictors of REE. CONCLUSION: Compared with subjects without parental diabetes, offspring with parental T2DM had lower REE, which was more pronounced in African-Americans. This metabolic alteration could increase the risk of obesity, insulin resistance and dysglycemia.

Ethnic Disparities in Endothelial Function and Its Cardiometabolic Correlates: The Pathobiology of Prediabetes in A Biracial Cohort Study.

BACKGROUND: Endothelial function (EF) reflects the balance between vasodilatory and vasoconstrictive factors produced by (or acting on) the innermost lining of blood vessels. Endothelial dysfunction, an imbalance between these factors that favors vasoconstriction, has been associated with increased risk for cardiovascular disease. However, the influence of race/ethnicity and glycemic status on association between EF and cardiovascular risk factors remain to be clarified. SUBJECTS AND METHODS: We assessed EF in relation to glycemia and cardiometabolic profile in African-American (AA) and European-American (EA) offspring of parents with type 2 diabetes (T2D), who are participants in the prospective pathobiology and reversibility of prediabetes in a biracial cohort (PROP-ABC) study. Assessments at enrollment included a 75 g oral glucose tolerance test (OGTT), blood pressure, anthropometry, body composition (DEXA), and lipid profile. Other assessments were insulin sensitivity and resting energy expenditure. EF was measured using flow-mediated vasodilation (EndoPAT 2000) and expressed as reactive hyperemia index (RHI). RESULTS: We studied 190 subjects (100 AA, 90 C), mean age (±SD) 53.1 ± 9.1 years, and body mass index 30.6 ± 6.8 kg/m2. Based on OGTT data, 96 subjects (52 AA, 44 EA) had prediabetes and 94 subjects were normoglycemic (48 AA and 46 EA). The RHI was lower in AA than EA (2.17 ± 0.55 vs. 2.36 ± 0.72, P = 0.05) and in prediabetic than normoglycemic subjects (2.14 ± 0.62 vs. 2.38 ± 0.65, P = 0.013). Using RHI ≤ 1.68 as diagnostic cut-off, 19% of participants with prediabetes and 10% of normoglycemic participants had endothelial dysfunction (P = 0.04). In univariate models, RHI was positively associated with age and HDL cholesterol levels, and inversely associated with adiposity, diastolic blood pressure, and 2hr plasma glucose. The association between RHI and adiposity was stronger in men than women. The association between RHI and age, glucose and HDL cholesterol displayed marked ethnic disparities. CONCLUSION: In our biracial cohort comprising offspring of parents with T2D, prediabetes increased the risk of endothelial dysfunction. However, the association between EF and cardiometabolic risk factors was significantly modified by ethnicity and gender. Our findings support current understanding of endothelial dysfunction as an early sensitive indicator of cardiometabolic risk.

Basal and Dynamic Leptin Secretion: Association with Cardiometabolic Risk and Body Weight Trajectories in African-Americans and European-Americans.

BACKGROUND: Fasting plasma leptin levels reflect fat mass, but dynamic leptin responses to secretagogues, and the influence of race/ethnicity, have not been well studied. Here, we compared basal and stimulated leptin levels in relation to cardiometabolic risk and weight trajectories in black and white subjects. SUBJECTS AND METHODS: We studied 254 (127 black and 127 white) normoglycemic adults enrolled in the Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) study. At baseline and annually, POP-ABC participants underwent physical examination, oral glucose tolerance test, and measurements of body fat (dual energy X-ray absorptiometry), fasting plasma leptin, insulin, cortisol, lipids, and leptin secretory response to single-dose (2 mg) dexamethasone (dex). The interactions among basal and stimulated leptin and changes in adiposity/cardiometabolic measures during the ensuing year were then analyzed. RESULTS: The mean (±SD) fasting leptin level (50.6 ± 47.7 vs. 39.5 ± 37.6 ng/mL, P = 0.004) and body mass index (BMI) (31.9 ± 7.14 vs. 29.0 ± 7.66 kg/m2, P = 0.0043) were higher in black women vs. white women, but similar in black men vs. white men (leptin: 12.4 ± 2.07 vs. 11.1 ± 1.40 ng/mL; BMI: 29.4 ± 7.68 vs. 28.1 ± 4.23 kg/m2). The peak leptin response to dex (~200% baseline) did not differ significantly by gender or race. Total body fat correlated positively with fasting leptin (r = 0.81, P < 0.0001) and inversely stimulated leptin levels (r = -0.26, P < 0.0001). Fasting leptin was unrelated to 1-year change in weight or fat mass, whereas stimulated leptin levels were significantly associated with 1-year trajectories in weight (P = 0.0016) and total fat mass (P = 0.0035). Stimulated leptin levels also had significant interactions with insulin sensitivity (homeostasis model of insulin resistance, P = 0.01), triglycerides (P = 0.0078), fasting glucose (P = 0.027), systolic blood pressure (P = 0.037), and high-sensitivity C-reactive protein (P = 0.027). CONCLUSION: We found no significant ethnic disparities in basal or dynamic leptin secretion in relation to adiposity. Fasting leptin levels were not associated with 1-year weight change, while stimulated levels showed weak though significant association with 1-year weight change.

Parental History of Type 2 Diabetes Abrogates Ethnic Disparities in Key Glucoregulatory Indices.

Context: There are ethnic differences in glucoregulation and prevalence of type 2 diabetes, but studies on the role of genetics in modifying ethnic effects in normoglycemic African-Americans and Caucasians are limited. Therefore, we investigated glucoregulation in normoglycemic African-Americans and Caucasians with or without parental diabetes. Design: Fifty subjects with parental diabetes (from the Pathobiology of Prediabetes in a Biracial Cohort Study) and 50 subjects without parental diabetes were matched in age, sex, ethnicity, and body mass index (BMI). Subjects underwent a 75-g oral glucose tolerance test (OGTT), physical examination, anthropometry, biochemistries, indirect calorimetry and assessment of body composition, insulin sensitivity by euglycemic clamp (Si-clamp), and ß-cell function by Disposition index. Results: The mean age was 40.5 ± 11.6 years, BMI 28.7 ± 5.9 kg/m2, fasting plasma glucose 90.2 ± 5.9 mg/dL, and 2-hour postglucose 120.0 ± 26.8 mg/dL. Offspring with parental diabetes showed higher glycemic excursion during OGTT-area under the curve-glucose (16,005.6 ± 2324.7 vs 14,973.8 ± 1819.9, P < 0.005), lower Si-clamp (0.132 ± 0.068 vs 0.162 ± 0.081 µmol/kg fat-free mass/min/pmol/L, P < 0.05), and lower Disposition index (8.74 ± 5.72 vs 11.83 ± 7.49, P < 0.05). Compared with lean subjects without parental diabetes, ß cell function was lower by ∼30% in lean subjects with parental diabetes, ∼40% in obese subjects without parental diabetes, and ∼50% in obese individuals with parental diabetes (P < 0.0001). African-Americans without parental diabetes had ∼40% lower insulin sensitivity (P < 0.001), twofold higher acute insulin secretion (P < 0.001), but ∼30% lower Disposition index (P < 0.01) compared with Caucasians without parental diabetes. Remarkably, there were no significant differences by ethnicity in these glucoregulatory measures among subjects with parental diabetes. Conclusion: Offspring with parental diabetes harbor substantial impairments in glucoregulation compared with individuals without parental diabetes. Ethnic disparities in glucoregulation were abrogated by parental diabetes.

Insulin-sensitive and insulin-resistant obese and non-obese phenotypes: role in prediction of incident pre-diabetes in a longitudinal biracial cohort.

OBJECTIVE: We measured insulin sensitivity with euglycemic clamp (Si-clamp) in initially normoglycemic African Americans (AA) and European Americans (EA), to probe the existence of subphenotypes of obesity and leanness, and their impact on incident dysglycemia during longitudinal follow-up. RESEARCH DESIGN AND METHODS: 320 healthy subjects (176 AA, 144 EA; mean age 44.2±10.6 years) underwent baseline assessments, including Si-clamp and homeostasis model of insulin resistance (HOMA-IR) and were stratified into: insulin-resistant obese (IRO) (body mass index (BMI) >30 kg/m2, Si-clamp <0.1, HOMA-IR >2.5); insulin-sensitive obesity (ISO) (BMI >30 kg/m2, Si-clamp >0.1, HOMA-IR <2.5); insulin-resistant non-obese (IRN) (BMI <28 kg/m2, Si-clamp <0.1, HOMA-IR >2.5); insulin-sensitive non-obese (ISN) (BMI <28 kg/m2, Si-clamp >0.1, HOMA-IR <2.5). Outcome measures were cardiometabolic risks and incident pre-diabetes/type 2 diabetes (T2D) during 5.5 years. RESULTS: Compared with IRO, subjects with ISO had lower abdominal fat, triglycerides and high-sensitivity C reactive protein and higher adiponectin (p=0.015 to <0.0001). IRN subjects had higher cardiometabolic risk markers than ISN (p=0.03 to <0.0001). During 5.5-year follow-up, incident pre-diabetes/T2D was lower in ISO (31.3% vs 48.7%) among obese subjects and higher in IRN (47.1% vs. 26.0%) among non-obese subjects (p=0.0024). Kaplan-Meier analysis showed significantly different pre-diabetes/T2D survival probabilities across insulin sensitivity/adiposity phenotypes (p=0.0001). CONCLUSIONS: Insulin sensitivity predicts ~40% decrease in the relative risk of incident pre-diabetes/T2D among obese persons, whereas insulin resistance predicts ~80% increased risk among non-obese persons. This is the first documentation of healthy and unhealthy phenotypes of obesity and leanness in a prospective biracial cohort, using rigorous measurement of insulin sensitivity.

Relationships between blood pressure and blood glucose among offspring of parents with type 2 diabetes: Prediction of incident dysglycemia in a biracial cohort.

AIMS: We assessed blood pressure (BP) and blood glucose (BG) values in healthy subjects, and examined baseline BP as a predictor of incident prediabetes during follow-up. METHODS: Participants in the Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) study underwent screening assessments (anthropometry, BP, OGTT) and were stratified into normal BP (NBP), prehypertension, or hypertension, and normal glucose regulation (NGR), prediabetes (IFG/IGT), or type 2 diabetes (T2D) status. NGR subjects who met all inclusion criteria were enrolled in a 5-yr prospective study, with the primary outcome of incident prediabetes. RESULTS: We screened 602 adults (341 black, 261 white) and enrolled 343 (193 black, 150 white) for prospective follow-up. Systolic and diastolic BP correlated significantly with fasting and nonfasting BG (P=0.003-<0.0001). Compared to NGR group, more prediabetic subjects had prehypertension (42.5% vs. 36.2%) and fewer had NBP (35.9% vs. 48.6%) (P=0.009). During ~5years of follow-up, 26.3% of NBP and 35.7% of prehypertensive subjects developed prediabetes (P=0.02). Kaplan-Meier analysis showed higher probability of incident prediabetes among participants with prehypertension compared to NBP during ~5years of follow-up (P=0.0012). CONCLUSIONS: In our biracial cohort, BP and BG values were significantly correlated, and BP status predicted incident prediabetes among initially normoglycemic individuals. These findings suggest co-evolution of factors involved in the dysregulation of BP and BG.

Plasma lipid levels predict dysglycemia in a biracial cohort of nondiabetic subjects: Potential mechanisms.

Dyslipidemia and dysglycemia are etiologically associated, but the direction, chronology, and mechanisms of the association are not fully understood. We, therefore, analyzed data from 335 healthy adults (184 black, 151 white) enrolled in the Pathobiology of Prediabetes in A Biracial Cohort study. Subjects underwent oral glucose tolerance test (OGTT) and were enrolled if they had normal fasting and 2-h plasma glucose levels. Assessments during year 1 included anthropometry, fasting lipid profile, insulin sensitivity, and insulin secretion. Thereafter, OGTT was assessed annually for 5.5 years. The primary outcome was occurrence of prediabetes (impaired fasting glucose or impaired glucose tolerance) or diabetes. During a mean follow-up of 2.62 years, 110 participants (32.8%) developed prediabetes (N = 100) or diabetes (N = 10). In multivariate logistic regression models, higher baseline low-density lipoprotein (LDL) cholesterol and triglyceride levels and lower HDL cholesterol levels significantly increased the risk of incident prediabetes. The combined relative risk (95% confidence interval [CI]) of prediabetes for participants with lower baseline HDL cholesterol (10th vs. 90th percentile), higher LDL cholesterol (90th vs. 10th percentile) and high triglycerides levels (90th vs. 10th percentile) was 4.12 (95% CI 1.61-10.56), P = 0.0032. At baseline, lipid values showed significant associations with measures of adiposity, glycemia, insulin sensitivity, and secretion. In both ethnic groups, waist circumference correlated positively with triglycerides and inversely with HDL cholesterol levels (P = 0.0004-<0.0001); fasting plasma glucose correlated positively with triglycerides and LDL cholesterol levels and inversely with HDL cholesterol levels (P = 0.006-<0.0001); insulin sensitivity correlated positively with HDL cholesterol and inversely with triglyceride levels (P < 0.0001), and insulin secretion correlated positively with triglycerides (P = 0.01) and inversely with HDL cholesterol (P < 0.0001). We conclude that a baseline lipidemic signature identifies normoglycemic individuals at high risk for future glycemic progression, via congruent associations with adiposity and glucoregulatory mechanisms. These findings suggest that early lifestyle intervention could ameliorate progressive dyslipidemia and dysglycemia.

Adiponectin levels predict prediabetes risk: the Pathobiology of Prediabetes in A Biracial Cohort (POP-ABC) study.

BACKGROUND: Adiponectin levels display ethnic disparities, and are inversely associated with the risk of type 2 diabetes (T2DM). However, the association of adiponectin with prediabetes risk in diverse populations has not been well-studied. Here, we assessed baseline adiponectin levels in relation to incident prediabetes in a longitudinal biracial cohort. RESEARCH DESIGN AND METHODS: The Pathobiology of Prediabetes in A Biracial Cohort study followed non-diabetic offspring of parents with T2DM for the occurrence of prediabetes, defined as impaired fasting glucose and/or impaired glucose tolerance. Assessments at enrollment and during follow-up included a 75 g oral glucose tolerance test, anthropometry, biochemistries (including fasting insulin and adiponectin levels), insulin sensitivity and insulin secretion. Logistic regression was used to evaluate the contribution of adiponectin to risk of progression to prediabetes. RESULTS: Among the 333 study participants (mean (SD) age 44.2 (10.6) year), 151(45.3%) were white and 182 (54.8%) were black. During approximately 5.5 (mean 2.62) years of follow-up, 110 participants (33%) progressed to prediabetes (N=100) or T2DM (N=10), and 223 participants (67%) were non-progressors. The mean cohort adiponectin level was 9.41+5.30 µg/mL (range 3.1-45.8 µg/mL); values were higher in women than men (10.3+5.67 µg/mL vs 7.27+3.41 µg/mL, p<0.0001) and in white than black offspring (10.7+5.44 µg/mL vs 8.34+4.95 µg/mL, p<0.0001). Adiponectin levels correlated inversely with adiposity and glycemia, and positively with insulin sensitivity and high-density lipoprotein cholesterol levels. Baseline adiponectin strongly predicted incident prediabetes: the HR for prediabetes per 1 SD (approximately 5 µg/mL) higher baseline adiponectin was 0.48 (95% CI 0.27 to 0.86, p=0.013). CONCLUSIONS: Among healthy white and black adults with parental history of T2DM, adiponectin level is a powerful risk marker of incident prediabetes. Thus, the well-known association of adiponectin with diabetes risk is evident at a much earlier stage in pathogenesis, during transition from normoglycemia to prediabetes.

Dietary habits and leisure-time physical activity in relation to adiposity, dyslipidemia, and incident dysglycemia in the pathobiology of prediabetes in a biracial cohort study.

BACKGROUND: Dietary and exercise data are frequently recorded in clinical research, but their correlation with metabolic measures needs further evaluation. OBJECTIVE: We examined the association of food and exercise habits with body size, lipid profile, and glycemia in a prospective biracial cohort. METHODS: The Pathobiology of Prediabetes in A Biracial Cohort study followed initially normoglycemic offspring of parents with type 2 diabetes (T2DM) for the occurrence of incident prediabetes, defined as impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). At enrollment, participants underwent a 75-gram OGTT, anthropometry, measurement of fasting lipids, insulin, and body fat (DEXA), and completed the Food Habits Questionnaire (FHQ), and Modifiable Activity Questionnaire (MAQ). We assessed the relationship between FHQ and MAQ scores and adiposity, cardiometabolic measures, and incident dysglycemia. RESULTS: Among our cohort of 338 subjects (188 black, 150 white; mean age {±SD} 45.2±10.2 years, BMI 30.3±7.2 kg/m(2)), FHQ and MAQ scores were individually correlated with BMI (r=0.14, -0.12; P=0.01, 0.03) and waist circumference (r=0.19, -0.11; P=0.004, 0.05). Diet-adjusted leisure activity (MAQ/FHQ) was significantly correlated with total body fat (r=-0.20, P=0.0007), trunk fat (r=-0.20, P=0.0006), and serum triglycerides (r=-0.17, P=0.003) and HDL cholesterol (r=0.11, P=0.04) levels. During 5.5 years of follow-up, 111 subjects (Progressors) developed prediabetes (n=101) or diabetes (n=10) and 227 remained normoglycemic (Non-progressors). Age, BMI, MAQ and MAQ/FHQ values were significant predictors of incident prediabetes/diabetes. Progressors reported similar dietary habits (FHQ score 2.57±0.49 vs. 2.57±0.53) but 30% lower physical activity (MAQ score 15.2±20.5 vs. 22.3±30.5 MET-hr/wk, P=0.015) compared with non-progressors. CONCLUSIONS: Among African-American and Caucasian offspring of parents with T2DM, self-reported dietary and exercise habits correlated with measures of adiposity and dyslipidemia; however, physical activity, but not dietary recall, significantly predicted incident dysglycemia during 5.5 years of follow-up.