Neslihan Gungor

Comparison of Different Definitions of Pediatric Metabolic Syndrome: Relation to Abdominal Adiposity, Insulin Resistance, Adiponectin, and Inflammatory Biomarkers

OBJECTIVES To examine the prevalence of the metabolic syndrome using different pediatric definitions reported in the literature and its relationship to abdominal adipose tissue (AT), in vivo insulin resistance, and inflammatory biomarkers in children and adolescents, as well as the utility of fasting insulin and adiponectin as predictors of the metabolic syndrome. STUDY DESIGN Cross-sectional measurements were obtained from 122 African Americans and 129 Caucasians age 8 to 19 years. Insulin sensitivity (IS) was measured by a 3-h hyperinsulinemic-euglycemic clamp. Blood pressure, fasting lipids, adiponectin, interleukin (IL)-6, adhesion molecules (intercellular adhesion molecule [ICAM]-1, vascular cell adhesion molecule [VCAM]-1, and E-selectin), and abdominal AT were measured. RESULTS Regardless of the metabolic syndrome criteria used, the prevalence of the metabolic syndrome was higher in overweight (24% approximately 51%) compared with non-overweight youths (1% approximately 3%) in both African Americans and Caucasians (P <.01). Youths with the metabolic syndrome had higher visceral AT and fasting insulin and lower IS and adiponetin independent of race (P < .01). In Caucasians, youths with the metabolic syndrome had higher levels of inflammatory biomarkers (IL-6, ICAM-1, and E-selectin). The area under the receiver operating curve (AUC) for insulin was 0.86 approximately 0.89 in African Americans and 0.86 approximately 0.89 in Caucasians, depending on the metabolic syndrome criteria used. For adiponetin, the AUC was 0.73 approximately 0.78 in African Americans and 0.81 approximately 0.86 in Caucasians. CONCLUSIONS The prevalence of metabolic syndrome varies depending on the definition used in the literature. Thus, there is a need for a unified definition of this syndrome in children and adolescents to streamline the research in this area. Independent of race, visceral obesity, insulin resistance, hyperinsulinemia, and hypoadiponectinemia are the common characteristics of youths with the metabolic syndrome. In Caucasians but not in African Americans, the metabolic syndrome is associated with increased inflammatory markers; however, the translation of such findings remains to be determined based on long-term longitudinal outcome studies in different racial groups.

Insulin Resistance: Link to the components of the metabolic syndrome and biomarkers of endothelial dysfunction in youth

OBJECTIVE—We examined the relationship of in vivo insulin sensitivity to the components of the metabolic syndrome and biomarkers of endothelial dysfunction in youth. RESEARCH DESIGN AND METHODS—Subjects included 216 youths (8–19 years of age) who participated in a 3-h hyperinsulinemic-euglycemic clamp. RESULTS—Independent of race, the frequencies of central obesity, high triglycerides, low HDL, high blood pressure, impaired fasting glucose, and impaired glucose tolerance were significantly higher (P < 0.05) in the lowest versus highest quartile of insulin sensitivity. BMI, abdominal adiposity, systolic blood pressure, and triglycerides increased and adiponectin and HDL decreased significantly (P for trend for all <0.05), with decreasing insulin sensitivity in both races. After controlling for BMI, insulin resistance remained associated (P < 0.05) with visceral adipose tissue in both races (P for trend = 0.01 in blacks and 0.08 in whites). In whites but not blacks, lower insulin sensitivity was associated (P < 0.05) with higher intercellular adhesion molecule-1 (ICAM-1) and E-selectin levels; however, these relationships did not remain significant (P > 0.05) once visceral adipose tissue was controlled for. CONCLUSIONS—The prevalence of the individual components of metabolic syndrome increases with decreasing insulin sensitivity in black and white youth. In whites but not blacks, insulin resistance is associated with increased circulating endothelial biomarkers. It remains to be determined if lower abdominal adiposity and triglycerides in blacks underlies the racial differences in risk translation.

From Pre-Diabetes to Type 2 Diabetes in Obese Youth: Pathophysiological characteristics along the spectrum of glucose dysregulation

OBJECTIVE Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are considered pre-diabetes states. There are limited data in pediatrics in regard to their pathophysiology. We investigated differences in insulin sensitivity and secretion among youth with IFG, IGT, and coexistent IFG/IGT compared with those with normal glucose tolerance (NGT) and type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 24 obese adolescents with NGT, 13 with IFG, 29 with IGT, 11 with combined IFG/IGT, and 30 with type 2 diabetes underwent evaluation of hepatic glucose production ([6,6-2H2]glucose), insulin-stimulated glucose disposal (Rd, euglycemic clamp), first- and second-phase insulin secretion (hyperglycemic clamp), body composition (dual-energy X-ray absorptiometry), abdominal adiposity (computed tomography), and substrate oxidation (indirect calorimetry). RESULTS Adolescents with NGT, pre-diabetes, and type 2 diabetes had similar body composition and abdominal fat distribution. Rd was lower (P = 0.009) in adolescents with type 2 diabetes than in those with NGT. Compared with adolescents with NGT, first-phase insulin was lower in those with IFG, IGT, and IFG/IGT with further deterioration in those with type 2 diabetes (P < 0.001), and β-cell function relative to insulin sensitivity (glucose disposition index [GDI]) was also lower in those with IFG, IGT, and IFG/IGT (40, 47, and 47%, respectively), with a further decrease (80%) in those with type 2 diabetes (P < 0.001). GDI was the major determinant of fasting and 2-h glucose levels. CONCLUSIONS Obese adolescents who show signs of glucose dysregulation, including abnormal fasting glucose, glucose intolerance or both, are more likely to have impaired insulin secretion rather than reduced insulin sensitivity. Given the impairment in insulin secretion, they are at high risk for progression to type 2 diabetes. Further deterioration in insulin sensitivity or secretion may enhance the risk for this progression.

Phenotypic Type 2 Diabetes in Obese Youth Insulin Sensitivity and Secretion in Islet Cell Antibody-Negative Versus -Positive Patients

OBJECTIVE— Some obese youth with a clinical diagnosis of type 2 diabetes have evidence of islet cell autoimmunity with positive autoantibodies. In this study, we investigated the differences in insulin sensitivity and secretion between autoantibody-negative (Ab−) and -positive (Ab+) youth with clinically diagnosed type 2 diabetes in comparison with control subjects. RESEARCH DESIGN AND METHODS— Sixteen Ab− and 26 Ab+ clinically diagnosed type 2 diabetic patients and 39 obese control youth underwent evaluation of insulin sensitivity (3-h hyperinsulinemic-euglycemic clamp), substrate oxidation (indirect calorimetry), first- and second-phase insulin secretion (2-h hyperglycemic clamp), body composition and abdominal adiposity (dual energy X-ray absorptiometry and computed tomography scan, respectively), and glucose disposition index (first-phase insulin secretion × insulin sensitivity). RESULTS— Insulin-stimulated total, oxidative, and nonoxidative glucose disposal, and suppression of fat oxidation during hyperinsulinemia were significantly lower in Ab− compared with Ab+ clinically diagnosed type 2 diabetic and control subjects with no difference between the latter two. First- and second-phase insulin secretion and C-peptide were lower in Ab+ compared with Ab− type 2 diabetes. Glucose disposition index was not different between the Ab− and Ab+ clinically diagnosed type 2 diabetic patients, but both were significantly lower than that in control subjects. Systolic blood pressure and alanine aminotransferase were higher in Ab− versus Ab+ clinically diagnosed type 2 diabetic patients, whereas the frequency of ketonuria at diagnosis was higher in Ab+ versus Ab− patients. CONCLUSIONS— Islet-cell Ab− clinically diagnosed type 2 diabetic youth are characterized by severe insulin resistance and relative insulin deficiency, whereas Ab+ youth have severe insulin deficiency and β-cell failure. The former group has additional features of insulin resistance. These important metabolic differences could influence the natural history of hyperglycemia, insulin dependence, and clinical outcomes in these youth.

In Vivo Insulin Sensitivity and Secretion in Obese Youth What are the differences between normal glucose tolerance, impaired glucose tolerance, and type 2 diabetes?

OBJECTIVE—Impaired glucose tolerance (IGT) represents a pre-diabetic state. Controversy continues in regards to its pathophysiology. The aim of this study was to investigate the differences in insulin sensitivity (IS) and secretion in obese adolescents with IGT compared with those with normal glucose tolerance (NGT) and type 2 diabetes. RESEARCH DESIGN AND METHODS—A total of 12 obese adolescents with NGT, 19 with IGT, and 17 with type 2 diabetes underwent evaluation of insulin sensitivity (3-h hyperinsulinemic [80mu/m2/min]–euglycemic clamp), first-phase insulin and second-phase insulin secretion (2-h hyperglycemic clamp), body composition, and abdominal adiposity. Glucose disposition index (GDI) was calculated as the product of first-phase insulin × insulin sensitivity. RESULTS—Insulin-stimulated glucose disposal was significantly lower in subjects with type 2 diabetes compared with subjects with NGT and IGT, with no difference between the latter two. However, compared with youth with NGT, youth with IGT have significantly lower first-phase insulin and C-peptide levels and GDI (P = 0.012), whereas youth with type 2 diabetes have an additional defect in second-phase insulin. Fasting and 2-h glucose correlated with GDI (r = −0.68, P < 0.001 and r = −0.73, P < 0.001, respectively) and first-phase insulin but not with insulin sensitivity. CONCLUSIONS—Compared with youth with NGT, obese adolescents with IGT have evidence of a β-cell defect manifested in impaired first-phase insulin secretion, with a more profound defect in type 2 diabetes involving both first- and second-phase insulin. GDI shows a significantly declining pattern: it is highest in NGT, intermediate in IGT, and lowest in type 2 diabetes. Such data suggest that measures to prevent progression or conversion from pre-diabetes to type 2 diabetes should target improvement in β-cell function.

In Vivo Insulin Sensitivity and Secretion in Obese Youth: What are the Differences between NGT, IGT and Type 2 Diabetes?

OBJECTIVE—Impaired glucose tolerance (IGT) represents a pre-diabetic state. Controversy continues in regards to its pathophysiology. The aim of this study was to investigate the differences in insulin sensitivity (IS) and secretion in obese adolescents with IGT compared with those with normal glucose tolerance (NGT) and type 2 diabetes. RESEARCH DESIGN AND METHODS—A total of 12 obese adolescents with NGT, 19 with IGT, and 17 with type 2 diabetes underwent evaluation of insulin sensitivity (3-h hyperinsulinemic [80mu/m2/min]–euglycemic clamp), first-phase insulin and second-phase insulin secretion (2-h hyperglycemic clamp), body composition, and abdominal adiposity. Glucose disposition index (GDI) was calculated as the product of first-phase insulin × insulin sensitivity. RESULTS—Insulin-stimulated glucose disposal was significantly lower in subjects with type 2 diabetes compared with subjects with NGT and IGT, with no difference between the latter two. However, compared with youth with NGT, youth with IGT have significantly lower first-phase insulin and C-peptide levels and GDI (P = 0.012), whereas youth with type 2 diabetes have an additional defect in second-phase insulin. Fasting and 2-h glucose correlated with GDI (r = −0.68, P < 0.001 and r = −0.73, P < 0.001, respectively) and first-phase insulin but not with insulin sensitivity. CONCLUSIONS—Compared with youth with NGT, obese adolescents with IGT have evidence of a β-cell defect manifested in impaired first-phase insulin secretion, with a more profound defect in type 2 diabetes involving both first- and second-phase insulin. GDI shows a significantly declining pattern: it is highest in NGT, intermediate in IGT, and lowest in type 2 diabetes. Such data suggest that measures to prevent progression or conversion from pre-diabetes to type 2 diabetes should target improvement in β-cell function.

Progression from normal glucose tolerance to type 2 diabetes in a young girl: longitudinal changes in insulin sensitivity and secretion assessed by the clamp technique and surrogate estimates

Abstract:  The pathophysiology of type 2 diabetes (T2DM) involves insulin resistance and relative insulin deficiency in at‐risk youth. We‐report longitudinal changes in insulin sensitivity and secretion in a high‐risk African‐American youth with obesity and polycystic ovary syndrome who progressed from normal glucose tolerance to impaired glucose tolerance to T2DM within 5 yr. This report demonstrates that in our patient: (i) insulin resistance was the pre‐existing abnormality, but it was the marked decline in insulin secretion which led to T2DM and (ii) surrogate estimates of insulin sensitivity using fasting glucose and insulin concentrations were not reliable indices in reflecting the changes in in vivo insulin sensitivity in this case.

Declining β-cell function relative to insulin sensitivity with escalating OGTT 2-h glucose concentrations in the nondiabetic through the diabetic range in overweight youth.

OBJECTIVE Overweight in youth is associated with the risk of developing type 2 diabetes. We hypothesized that β-cell function relative to insulin sensitivity decreases with increasing 2-h glucose levels based on an oral glucose tolerance test (OGTT) in overweight youth. RESEARCH DESIGN AND METHODS A total of 147 overweight (BMI ≥85th percentile for age and sex) youth, aged 8 to <20 years, undertook three tests: 1) a 3-h hyperinsulinemic-euglycemic clamp; 2) a 2-h hyperglycemic clamp; and 3) a 2-h OGTT. Participants were categorically assigned to five groups according to their OGTT 2-h plasma glucose level, ranging from <120 to ≥200 mg/dL. β-Cell function relative to insulin sensitivity, assessed by clamp disposition index (DI) and oral disposition index (DIO), were compared among groups. RESULTS Insulin sensitivity, first-phase insulin, and DI declined significantly as 2-h glucose concentrations increased. The highest DI was found in youth with 2-h plasma glucose concentrations <120 mg/dL, with a significant decline of ~40% in those with glucose concentrations between 120 and <140 mg/dL, and an ~75% decline, the lowest DI, in youth with glucose concentrations ≥200 mg/dL. Data were similar with regard to the OGTT DIO. CONCLUSIONS These data in overweight youth demonstrate that impairment in insulin secretion relative to insulin sensitivity is apparent even with normal glucose tolerance. Below the current cutoff of 140 mg/dL for impaired glucose tolerance, there is a >30% decline in β-cell function relative to insulin sensitivity. Against this back drop of metabolically heightened risk for type 2 diabetes, preventive measures should target the β-cell alongside insulin sensitization.

Measures of β-Cell Function during the Oral Glucose Tolerance Test, Liquid Mixed-Meal Test, and Hyperglycemic Clamp Test

OBJECTIVE To evaluate clinically useful measures of beta-cell function derived from the oral glucose tolerance test (OGTT) or mixed-meal (ie, Boost) tolerance test to assess insulin secretion in comparison with the gold standard, the hyperglycemic clamp (Hyper-C) test. STUDY DESIGN We hypothesized that OGTT/Boost-derived measures are useful estimates of beta-cell function and correlate well with insulin secretion measured by the Hyper-C test. This study was designed to assess the correlation between the ratio of the early incremental insulin/glucose responses at 15 and 30 minutes (DeltaI(15)/DeltaG(15) and DeltaI(30)/DeltaG(30)) of the OGTT and the Boost test with insulin secretion measured during the Hyper-C test (225 mg/dL). The same indices were evaluated using C-peptide. A total of 26 children (14 males, 12 females; mean age, 9.9 +/- 0.2 years; mean body mass index = 22.1 +/- 1.2 kg/m(2)) underwent a 2-hour Hyper-C test (225 mg/dL) and 3-hour OGTT and Boost tests with measurements of glucose, insulin, and C-peptide. RESULTS Correlations between Hyper-C- and OGTT-derived measures of insulin secretion were stronger for the 15-minute index than for the 30-minute index of insulin secretion and stronger for C-peptide levels than for insulin levels (r = .7, P < .001 for first-phase C-peptide vs both OGTT and Boost, DeltaC(15)/DeltaG(15)). CONCLUSIONS In children with normal glucose tolerance, C-peptide rather than insulin level measured after 15 minutes of the OGTT or Boost test provides a reliable estimate of beta-cell function that correlates well with Hyper-C-derived insulin secretion.

Cardiorespiratory Fitness in Youth: Relationship to Insulin Sensitivity and β-Cell Function

Objective: We examined whether the relationship between cardiorespiratory fitness (CRF) and insulin sensitivity (IS)/secretion is independent of adiposity in healthy African‐American (n = 65) and white (n = 57) youth.