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African-American (AA) children are hyperinsulinemic and insulin resistant compared with American White (AW) children. This study investigated 1) whether AA/AW differences in insulinemia are associated with differences in insulin clearance; 2) whether dietary patterns, mainly carbohydrate and fat intake, play a role; and 3) whether the quantitative relationship between insulin sensitivity and secretion is similar between AA and AW children. Forty-four prepubertal children (22 AA and 22 AW) with comparable body composition and visceral adiposity were studied. All underwent a 3-h hyperinsulinemic (40 mU ⅐ m ؊2 ⅐ min ؊1)-euglycemic clamp to calculate insulin sensitivity and insulin clearance and a 2-h hyperglycemic clamp (12.5 mmol/l) to assess first-and second-phase insulin responses. Twenty-four-hour food recalls were analyzed for macronutrient intake. Insulin clearance (19.5 ؎ 0.7 vs. 22.9 ؎ 1.1 ml ⅐ min ؊1 ⅐ kg ؊1 fat-free mass [FFM]; P ‫؍‬ 0.011) and insulin sensitivity were lower in AA versus AW children (14.8 ؎ 1.0 vs. 18.9 ؎ 1.4 mol ⅐ min ؊1 ⅐ kg ؊1 FFM; P ‫؍‬ 0.021). Both insulin clearance and insulin sensitivity correlated inversely with dietary fat/carbohydrate ratio, which was higher in AA than in white children. Fasting C-peptide and insulin were higher in AA children with no difference in proinsulin levels. First-and second-phase insulin concentrations and glucose disposition index (insulin sensitivity ؋ first-phase insulin) were higher in AA than in white children (12.8 ؎ 2.1 vs. 7.2 ؎ 0.6 mol ⅐ min ؊1 ⅐ kg ؊1 FFM; P ‫؍‬ 0.019). In conclusion, the hyperinsulinemia observed in AA children is due to both lower insulin clearance and higher insulin secretion compared with their white peers. The quantitative relationship between insulin secretion and sensitivity is upregulated in AA children. This suggests that increased insulin secretion in AA children is not merely a compensatory response to lower insulin sensitivity. Dietary factors may have a role. Additional studies are needed to determine whether metabolic/nutritional factors, possibly mediated through free fatty acids, may play a role in the hyperinsulinism observed in AA children. Diabetes 51:3014 -3019, 2002

The incidence of type 2 diabetes mellitus in children is increasing with the increasing prevalence of obesity, particularly in African-American children. We hypothesized that African-American obese adolescents are more insulin resistant than their white peers, but have lower insulin secretion, thus increasing their risk of type 2 diabetes mellitus. The present study investigated insulin sensitivity and secretion, visceral adiposity (VAT), and cardiovascular disease (CVD) risk profile in black obese adolescents (BOA) vs. white obese adolescents (WOA). Twenty-four BOA and 26 WOA underwent a hyperinsulinemic-euglycemic clamp to assess insulin sensitivity, a hyperglycemic clamp to determine insulin secretion, dual energy x-ray absorptiometry for body composition and computed tomography scan at L4-L5 to measure VAT and sc abdominal adipose tissue. Fasting lipid and automated blood pressure measurements were obtained. The WOA and BOA groups were divided into low VAT and high VAT groups. BOA compared with WOA of similar body mass index and percent body fat had less visceral adiposity, lower hepatic glucose production, and lower lipid levels. Visceral adiposity was associated with lower insulin sensitivity in both groups [low vs. high VAT; BOA, 2.9 +/- 0.4 vs. 1.7 +/- 0.2 micromol/kg x min per pmol/liter (P = 0.016); WOA, 2.6 +/- 0.5 vs. 1.5 +/- 0.1 (P = 0.032)]. However, this was compensated by higher insulin secretion in whites (low VAT, 934.8 +/- 121.8; high VAT, 1590.6 +/- 232.8 pmol/liter; P = 0.037), but not in blacks (low VAT, 1398.9 +/- 214.0; high VAT, 1423.7 +/- 108.7 pmol/liter). Glucose disposition index (insulin sensitivity x first phase insulin) was lower in high VAT vs. low VAT BOA, but not in WOA. In each racial group, high VAT groups had elevation of systolic and diastolic blood pressure, but dyslipidemia was worse in WOA with high VAT. In conclusion, a given level of body mass index confers different metabolic risks for WOA vs. BOA. Although differences in fat patterning may help explain the more atherogenic risk profile in whites, the cause of the more diabetogenic insulin sensitivity/secretion profile in blacks remains unknown and needs to be investigated further.

OBJECTIVE -Adiponectin is an adipose tissue protein that enhances insulin sensitivity and has antiatherogenic properties. The present study investigated the relationship of adiponectin levels in adolescents to 1) obesity and body fat distribution and 2) insulin sensitivity and the components of syndrome X.RESEARCH DESIGN AND METHODS -Twenty-three normal-weight and 26 obese adolescents had fasting adiponectin, lipid profile, and proinsulin measurements performed. Hepatic and peripheral insulin sensitivity were assessed with constant-rate [6,6-2 H 2 ]glucose infusion and a 3-h hyperinsulinemic-euglycemic clamp, respectively. Body composition was evaluated by dual-energy X-ray absorptiometry, and visceral adipose tissue (VAT) and subcutaneous adipose tissue were measured by computed tomography scan at the L 4 -L 5 level.RESULTS -Obese adolescents had ϳ50% lower adiponectin than normal-weight adolescents. Moreover, obese adolescents with high (111.8 Ϯ 9.3 cm 2 ) versus low (55.4 Ϯ 2.1 cm 2 ) VAT had lower adiponectin levels (6.2 Ϯ 0.9 vs. 9.0 Ϯ 1.0 g/ml, P ϭ 0.05). Plasma adiponectin correlated positively with peripheral and hepatic insulin sensitivity (r ϭ 0.67, P Ͻ 0.001 and r ϭ 0.54, P Ͻ 0.001, respectively) and HDL (r ϭ 0.52, P Ͻ 0.001) and negatively with fasting proinsulin and the proinsulin-to-insulin ratio (r ϭ Ϫ0.64, P Ͻ 0.001 and r ϭ Ϫ0.43, P ϭ 0.003, respectively). In a multiple regression analysis, adiponectin, independently and together with BMI, explained 73% (R 2 ϭ 0.73, P Ͻ 0.001) of the variance in insulin sensitivity. Adiponectin, but not adiposity, was the significant independent determinant of the proinsulin-to-insulin ratio (R 2 ϭ 0.18, P ϭ 0.008) and of HDL (R 2 ϭ 0.45, P Ͻ 0.001).CONCLUSIONS -In summary, hypoadiponectinemia in youth is a strong and independent correlate of insulin resistance, ␤-cell dysfunction, visceral adiposity, and syndrome X. The antidiabetogenic and antiatherogenic properties of adiponectin are evident early in life and compromised in youth-onset obesity.

OBJECTIVE -This study evaluates insulin sensitivity, pancreatic ␤-cell function (BCF), and the balance between the two in youth with type 2 diabetes and assesses the relationship of diabetes duration and HbA 1c to insulin sensitivity and BCF.RESEARCH DESIGN AND METHODS -The subjects were 14 adolescents with type 2 diabetes and 20 obese control subjects of comparable age, BMI, body composition, and puberty. Insulin sensitivity was evaluated with a 3-h hyperinsulinemic (80 mU ⅐ m -2 ⅐ min -1 ) euglycemic clamp. First-phase insulin secretion (FPIS) and second-phase insulin secretion (SPIS) were evaluated with a 2-h hyperglycemic (12.5 mmol/l) clamp. Fasting glucose rate of appearance was determined with the use of [6,6-2 H 2 ]glucose.RESULTS -Fasting glucose rate of appearance was higher in type 2 diabetic patients than in obese control subjects (16.5 Ϯ 1.1 vs. 12.3 Ϯ 0.5 mol ⅐ kg -1 ⅐ min -1 ; P ϭ 0.002). Insulin sensitivity was lower in type 2 diabetic patients than in obese control subjects (1.0 Ϯ 0.1 vs. 2.0 Ϯ 0.2 mol ⅐ kg -1 ⅐ min -1 per pmol/l; P ϭ 0.001). Fasting insulin was higher in type 2 diabetic patients than in obese control subjects (289.8 Ϯ 24.6 vs. 220.2 Ϯ 18.0 pmol/l; P ϭ 0.007), and FPIS and SPIS were lower (FPIS: 357.6 Ϯ 42.0 vs. 1,365.0 Ϯ 111.0 pmol/l; SPIS: 652.2 Ϯ 88.8 vs. 1,376.4 Ϯ 88.8 pmol/l; P Ͻ 0.001 for both). The glucose disposition index (GDI ϭ insulin sensitivity ϫ FPIS) was ϳ86% lower in type 2 diabetic patients than in obese control subjects. HbA 1c correlated with FPIS (r ϭ Ϫ0.61, P ϭ 0.025) with no relationship to insulin sensitivity.CONCLUSIONS -Despite the impairment in both insulin sensitivity and BCF in youth with type 2 diabetes, the magnitude of the derangement is greater in BCF than insulin sensitivity when compared with that in obese control subjects. The inverse relationship between BCF and HbA 1c may either reflect the impact of deteriorating BCF on glycemic control or be a manifestation of a glucotoxic phenomenon on BCF. Future studies in youth type 2 diabetes should target the natural course of ␤-cell failure and means of retarding and/or preventing it. Diabetes Care 28:638 -644, 2005D espite the increasing rate of type 2 diabetes in youth, the information on its pathophysiology is mostly derived from adult studies (1). Decreased insulin sensitivity and impaired ␤-cell function (BCF) are the two key components in type 2 diabetes pathogenesis (2-4). The development sequence of these abnormalities has been long debated. Several studies in adults proposed that insulin resistance with compensatory hyperinsulinemia is the initial step in type 2 diabetes pathogenesis (2,4). This is an implication of the hyperbolic relationship between insulin sensitivity and BCF, which calls for an increase in insulin secretion when insulin sensitivity decreases (4). The subsequent step in type 2 diabetes pathogenesis is impaired early insulin secretion, leading to postprandial and, later, fasting hyperglycemia (at which time clinical diabetes becomes evident). This sequence has also been do...

Functional adrenal hyperandrogenism occurs in women with polycystic ovary syndrome (PCOS). Insulin, similar to its ovarian effect, may impact the regulation of adrenal steroidogenesis by modulating the activity of P450c17alpha, the rate-limiting enzyme in androgen biosynthesis. We previously demonstrated that obese adolescents with PCOS are severely insulin resistant and are at heightened risk for impaired glucose tolerance and type 2 diabetes. In the present study we tested the hypothesis that metformin therapy in obese adolescents with PCOS will attenuate the adrenal steroidogenic response to ACTH, with reduction of insulin resistance/insulinemia. Fifteen adolescents with PCOS and impaired glucose tolerance received 3 months of metformin (850 mg, twice daily) therapy. Pre- and posttherapy they had oral glucose tolerance testing, ACTH stimulation test, a 3-h hyperinsulinemic (80 mU/m(2).min)-euglycemic clamp to assess insulin sensitivity and a hyperglycemic clamp to assess insulin secretion. After 3 months of metformin treatment, glucose intolerance improved, with eight subjects having normal glucose tolerance. Total and free T decreased [1.5 +/- 0.2 vs. 1.0 +/- 0.1 nmol/liter (P = 0.022) and 41.3 +/- 8.3 vs. 22.2 +/- 2.1 pmol/liter (P = 0.028), respectively]. Insulin-stimulated glucose disposal increased (21.5 +/- 2.2 vs. 25.0 +/- 2.2 micromol/kg.min; P = 0.041). Fasting insulin and oral glucose tolerance test insulin and glucose area under the curve decreased significantly. ACTH-stimulated increases in androstenedione, 17-hydroxyprogesterone, and 17-hydroxypregnenelone were lower after metformin treatment [2.8 +/- 0.4 vs. 1.7 +/- 0.3 nmol/liter (P = 0.014), 7.0 +/- 0.6 vs. 5.3 +/- 0.5 nmol/liter (P = 0.011), and 30.4 +/- 3.7 vs. 25.7 +/- 4.2 nmol/liter (P = 0.054)]. Fasting insulin correlated with the 17-hydroxypregnenelone response to ACTH stimulation (r = 0.52; P = 0.008). In summary, metformin treatment of obese adolescents with PCOS and impaired glucose tolerance is beneficial in improving glucose tolerance and insulin sensitivity, in lowering insulinemia, and in reducing elevated androgen levels. Moreover, metformin therapy is associated with attenuation of the adrenal steroidogenic response to ACTH. Metformin therapy was well tolerated. In conclusion, double blind, placebo-controlled studies will determine whether insulin-sensitizing therapy corrects not only ovarian hyperandrogenism but also functional adrenal hyperandrogenism in adolescents with PCOS.

OBJECTIVE -Obesity is often associated with insulin resistance and the components of the metabolic syndrome. However, wide variations in insulin sensitivity are noted in obese youth. It is not clear if greater insulin resistance confers a higher risk of cardiovascular comorbidities and risk for type 2 diabetes.RESEARCH DESIGN AND METHODS -We investigated physical and metabolic features of 54 obese adolescents. Subsequently, we pair matched 17 moderately insulin-resistant (MIR group) to 17 severely insulin-resistant (SIR group) youth based on cut points for insulin sensitivity (MIR group insulin sensitivity within 2 SDs and SIR group Ͻ2 SDs of normal-weight adolescent values). We evaluated differences in body composition (dual-energy X-ray absorptiometry), abdominal fat (computed tomography scan), cardiorespiratory fitness (CRF) (VO 2max on a treadmill), insulin sensitivity and secretion (hyperinsulinemic-euglycemic and hyperglycemic clamps), substrate utilization (indirect calorimetry), and fasting adiponectin and lipid profile.RESULTS -SIR youth had higher visceral adiposity (78.3 Ϯ 6.9 vs. 60.3 Ϯ 6.9 cm 2 , P ϭ 0.017) and waist-to-hip ratio (0.91 Ϯ 0.01 vs. 0.86 Ϯ 0.02, P ϭ 0.026) and lower HDL (1.0 Ϯ 0.03 vs. 1.16 Ϯ 0.06 mmol/l, P ϭ 0.015) than pair-matched MIR subjects. There was a tendency for adiponectin (6.1 Ϯ 0.5 vs. 8.6 Ϯ 1.1 g/ml, P ϭ 0.079) and CRF (49.9 Ϯ 3.2 vs. 55.2 Ϯ 3.5 ml ⅐ min Ϫ1 ⅐ kg Ϫ1 fat-free mass, P ϭ 0.09) to be lower in SIR subjects. SIR youth also had an impaired balance between insulin sensitivity and ␤-cell compensation with a lower glucose disposition index.CONCLUSIONS -Despite similar BMI, the degree of insulin resistance impacts the risk for obesity-related metabolic comorbidities. The SIR youth are at greater risk for type 2 diabetes and cardiovascular disease. Diabetes Care 29:1599 -1604, 2006A lthough obesity is often associated with insulin resistance and the components of the metabolic syndrome, there is a subgroup of obese individuals who do not fit this metabolic profile (1). With wide variations in insulin sensitivity, it is not clear what distinguishes obese moderately insulinresistant children from obese severely insulin-resistant peers and whether they are at lower risk of obesity-related comorbidities. With the current obesity epidemic in children (2), it is important to be able to identify these individuals so that therapeutic efforts can be concentrated on the more at-risk category.In adults, obese and nonobese insulin-sensitive versus insulin-resistant individuals have higher HDL and adiponectin levels, lower fasting insulin and triglycerides, but no significant difference in blood pressure (3). Similarly, obese metabolically normal postmenopausal women have 49% less visceral fat, lower fasting and post-oral glucose tolerance test insulin levels, lower triglycerides, and higher HDL levels than their insulin-resistant counterparts (4). In a recent study (5), obese insulin-sensitive adolescents were found to have lower visceral and intramyocellular fat. Because physica...

OBJECTIVE -Family history of type 2 diabetes is a major risk factor for type 2 diabetes in youth, which is increasing. This investigation aimed to evaluate the impact of family history of type 2 diabetes on insulin secretion relative to insulin sensitivity in healthy children. ␤-Cell compensation for insulin sensitivity was calculated as the product of insulin sensitivity ϫ firstphase insulin secretion, termed glucose disposition index (GDI). RESEARCH DESIGN AND METHODS-A total of 28 healthy white children (12 boys and 16 girls; 12.1 Ϯ 0.5 years of age) with a positive family history of type 2 diabetes and 26 healthy white children (13 boys and 13 girls; 11.5 Ϯ 0.4 years of age) with a negative family history of type 2 diabetes underwent a 3-h 40 mU ⅐ m Ϫ2 ⅐ min Ϫ1 hyperinsulinemic-euglycemic clamp to assess insulin sensitivity and clearance and a 2-h hyperglycemic clamp to assess insulin secretion. Body composition and visceral adiposity were evaluated with dual-energy X-ray absorptiometry and computed tomography at the L 4 -L 5 intervertebral space.RESULTS -Insulin sensitivity was lower in children with a family history of type 2 diabetes versus children without a family history (8.8 Ϯ 0.9 vs. 12.2 Ϯ 1.1 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 per pmol/l, P ϭ 0.02). Similarly, insulin clearance was lower. First-and second-phase insulin levels were not different between groups with and without a positive family history. The GDI was lower in youth with versus youth without a positive family history (4.1 Ϯ 0.3 vs. 5.2 Ϯ 0.5 mmol ⅐ kg Ϫ1 ⅐ min Ϫ1 , P ϭ 0.039). IGF binding protein-1 (IGFBP-1) was 60% lower in youth with versus youth without the positive family history.CONCLUSIONS -These results demonstrate that family history of type 2 diabetes in white children is associated with decreased insulin sensitivity and clearance, decreased IGFBP-1, and an impaired relationship between insulin action and ␤-cell compensation. Detection of these alterations in hormonal and metabolic parameters in children with a positive family history suggests that at least some of the determinants of GDI are genetic/heritable. Diabetes Care 28:127-131, 2005T ype 2 diabetes is increasing in children (1,2). Both obesity and family history of type 2 diabetes are associated with increased risk of type 2 diabetes in youth, irrespective of the ethnic background (3,4). Insulin resistance and ␤-cell failure are prerequisites for development of type 2 diabetes. However, the relative role of each remains controversial because adult studies of at-risk firstdegree relatives of patients with type 2 diabetes have yielded conflicting results. Some studies have shown that the familial nature of type 2 diabetes is manifest by the presence of insulin resistance in nondiabetic first-degree relatives (5-8), whereas others have shown ␤-cell dysfunction (9 -13). Despite the abundance of adult data, only few pediatric published studies have investigated the impact of family history of type 2 diabetes on parameters of glucose metabolism (14 -17). We previously demonstrated that b...