OBJECTIVE Adipose tissue insulin resistance is one of the pathophysiological components of type 2 diabetes. Herein we investigated: 1) adipose insulin resistance index (Adipose-IR) (calculated as fasting insulin × free fatty acids [FFAs]) in youth across the spectrum of adiposity from normal weight to obese and the spectrum from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to type 2 diabetes, 2) the relationship of Adipose-IR with physical and metabolic characteristics, and 3) the predictive power of Adipose-IR for determining dysglycemia in youth. RESEARCH DESIGN AND METHODS A total of 205 youth had fasting glucose, insulin, FFA, Adipose-IR, body composition, visceral adipose tissue (VAT), leptin, and adiponectin evaluated. RESULTS Adipose-IR was 2.2-fold higher in obese NGT, 4.3-fold higher in IGT, and 4.6-fold higher in type 2 diabetes compared with that in normal weight peers (all P < 0.05). Females with dysglycemia (IGT and type 2 diabetes) had higher Adipose-IR than their male counterparts (P < 0.001). Adipose-IR correlated positively with total body and visceral adiposity, fasting glucose, HOMA-IR, and leptin and negatively with adiponectin. Receiver operating characteristic curve analysis yielded an optimal cutoff for Adipose-IR of 9.3 μU/mL × mmol/L for determining dysglycemia with 80% predictive power. CONCLUSIONS Adipose-IR is a simple surrogate estimate that reflects pathophysiological alterations in adipose tissue insulin sensitivity in youth with progressive deterioration from normal weight to obese and from NGT to IGT to type 2 diabetes. Adipose-IR can be applied in large-scale epidemiological/observational studies of the natural history of youth-onset type 2 diabetes, and its progression or reversal with intervention strategies.

OBJECTIVE: The shape of the glucose response curve during an oral glucose tolerance test (OGTT), monophasic versus biphasic, identifies physiologically distinct groups of individuals with differences in insulin secretion and sensitivity. We aimed to verify the value of the OGTT-glucose response curve against more sensitive clamp-measured biomarkers of type 2 diabetes risk, and to examine incretin/pancreatic hormones and free fatty acid associations in these curve phenotypes in obese adolescents without diabetes. RESEARCH DESIGN AND METHODS: A total of 277 obese adolescents without diabetes completed a 2-h OGTT and were categorized to either a monophasic or a biphasic group. Body composition, abdominal adipose tissue, OGTT-based metabolic parameters, and incretin/pancreatic hormone levels were examined. A subset of 106 participants had both hyperinsulinemic-euglycemic and hyperglycemic clamps to measure in vivo insulin sensitivity, insulin secretion, and β-cell function relative to insulin sensitivity. RESULTS: Despite similar fasting and 2-h glucose and insulin concentrations, the monophasic group had significantly higher glucose, insulin, C-peptide, and free fatty acid OGTT areas under the curve compared with the biphasic group, with no differences in levels of glucagon, total glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, and pancreatic polypeptide. Furthermore, the monophasic group had significantly lower in vivo hepatic and peripheral insulin sensitivity, lack of compensatory first and second phase insulin secretion, and impaired β-cell function relative to insulin sensitivity. CONCLUSIONS: In obese youth without diabetes, the risk imparted by the monophasic glucose curve compared with biphasic glucose curve, independent of fasting and 2-h glucose and insulin concentrations, is reflected in lower insulin sensitivity and poorer β-cell function, which are two major pathophysiological biomarkers of type 2 diabetes in youth.

OBJECTIVE In adults, the shape of the glucose response during an oral glucose tolerance test (OGTT) prospectively and independently predicts type 2 diabetes. However, no reports have described the utility of this indicator in younger populations. The purpose of this study was to compare type 2 diabetes risk factors in Latino adolescents characterized by either a monophasic or biphasic glucose response during an OGTT. RESEARCH DESIGN AND METHODS A total of 156 nondiabetic Latino adolescents completed a 2-h OGTT. Monophasic and biphasic groups were compared for the following type 2 diabetes risk factors: fasting and 2-h glucose, HbA_1c, glucose area under the curve (AUC), insulin sensitivity (Matsuda index), insulin secretion (insulinogenic index), and β-cell function as measured by the disposition index (insulin sensitivity × insulin secretion). RESULTS Of the participants, 107 youth were categorized as monophasic and 49 were biphasic. Compared with the monophasic group, participants with a biphasic response exhibited lower HbA_1c (5.4 ± 0.3 vs. 5.6 ± 0.3%, P < 0.01) and lower glucose AUC (14,205 ± 2,382 vs. 16,230 ± 2,537 mg ⋅ dL⁻¹ ⋅ h⁻¹, P < 0.001) with higher insulin sensitivity (5.4 ± 3.2 vs. 4.6 ± 3.4, P ≤ 0.05), higher insulin secretion (2.1 ± 1.3 vs. 1.8 ± 1.3, P = 0.05), and better β-cell function (10.3 ± 7.8 vs. 6.0 ± 3.6, P < 0.001). Differences persisted after adjusting for age, sex, and BMI. CONCLUSIONS These data suggest that the glycemic response to an OGTT may differentiate risk for type 2 diabetes in youth. This response may be an early marker of type 2 diabetes risk among high-risk youth.

Despite evidence of insulin resistance and β-cell dysfunction in glucose metabolism in youth with prediabetes, the relationship between adipose tissue insulin sensitivity (ATIS) and β-cell function remains unknown. We investigated whole-body lipolysis, ATIS, and β-cell function relative to ATIS (adipose disposition index [DI]) in obese youth with impaired glucose tolerance (IGT) versus normal glucose tolerance (NGT). Whole-body lipolysis (glycerol appearance rate [GlyRa], [2H5]glycerol at baseline and during a hyperinsulinemic-euglycemic clamp), lipid oxidation (indirect calorimetry), insulin secretion (2-h hyperglycemic clamp), and body composition (dual-energy X-ray absorptiometry) were examined. Adipose DI was calculated as ATIS: (1/GlyRa × fasting insulin) × first-phase insulin secretion. Despite similar percent body fat, youth with IGT versus NGT had higher GlyRa, lower ATIS at baseline and during hyperinsulinemia, and higher lipid oxidation. Adipose DI was ∼43% lower in youth with IGT and correlated positively with glucose DI. The lower ATIS and diminished adipose DI in IGT versus NGT is in line with the compromised glucose metabolism reflected in impaired β-cell function relative to peripheral insulin resistance. We conclude that youth with IGT manifest a global decline in insulin sensitivity, including impaired insulin action in suppressing lipolysis and lipid oxidation, accompanied by β-cell dysfunction in fat and glucose metabolism, enhancing their risk of type 2 diabetes.

CONTEXT Metabolic flexibility reflects the ability to switch from lipid to carbohydrate oxidation during insulin stimulation manifested in increased respiratory quotient (RQ). Despite insulin resistance in glucose metabolism in PCOS women and adolescents, little is known about adipose tissue metabolism and metabolic flexibility. OBJECTIVE To investigate whole-body lipolysis, substrate oxidation and metabolic flexibility in obese PCOS vs. non-PCOS girls. PATIENTS/DESIGN Twenty-one obese (BMI 32.7 ± 1.0 kg/m²) PCOS and 21 obese (33.3 ± 1.2 kg/m²) non-PCOS adolescent girls were pair-matched for age and race. Body composition (DEXA), abdominal visceral adipose tissue [VAT] (CT), sex hormones, lipid profile and adiponectin were measured. Whole-body lipolysis ([²H₅]glycerol turnover), RQ, substrate oxidation (indirect calorimetry) were evaluated during fasting and during a 3-hr hyperinsulinemic (80 mu/m²/min)-euglycemic clamp together with assessment of insulin sensitivity (IS). RESULTS Despite similar BMI and percent body fat, PCOS vs. non-PCOS girls had significantly lower fasting lipolysis, lower fasting fat oxidation and less increase in RQ during hyperinsulinemia with impaired suppression in lipolysis and lipid oxidation, and diminished increase in glucose oxidation and lower IS. In multiple regression models the best predictors of metabolic flexibility were [using clinical parameters: adiponectin, fasting triglycerides and fasting insulin (R²=0.618, P<0.0001); using research parameters: IS, VAT, and baseline RQ (R²=0.756, P<0.0001)]. CONCLUSIONS Obese PCOS vs. non-PCOS girls have decreased lipid mobilization, diminished fat oxidation and metabolic inflexibility. Whether or not this metabolic phenotype of adipose tissue dysfunction, conducive to fat accretion, plays a role in induction/maintenance of obesity in PCOS adolescents remains to be determined.