ß-cell function, incretin response, and insulin sensitivity of glucose and fat metabolism in obese youth: Relationship to OGTT-time-to-glucose-peak.

BACKGROUND: In adults, the time-to-glucose-peak at or after 30 minutes during an oral glucose tolerance test (OGTT) identifies physiologically distinct groups with differences in insulin sensitivity, ß-cell function and risk for type 2 diabetes. In obese non-diabetic adolescents, we investigated if the OGTT-time-to-glucose-peak also reflects incretin and free fatty acid (FFA) responses besides insulin sensitivity and ß-cell function, measured by the clamp. METHODS: Obese adolescents (n = 278) were categorized according to their OGTT-time-to-glucose-peak by Early-peak (at 30 minutes) vs Late-peak (>30 minutes) groups. Body composition, visceral adipose tissue, oral disposition index and OGTT-area under the curve (AUC) were examined. A subset of 102 participants had both hyperinsulinemic-euglycemic and hyperglycemic clamps to measure in vivo insulin sensitivity, insulin secretion, and ß-cell function relative to insulin sensitivity. RESULTS: Compared with the Early-peak group, the Late-peak group had impaired ß-cell function relative to insulin sensitivity, lower glucose-dependent insulinotropic polypeptide-AUC, and higher FFA-AUC despite higher insulin- and C-peptide-AUC. They also had lower hepatic and peripheral insulin sensitivity despite similar percent body fat and visceral adipose tissue, and had higher prevalence of impaired glucose tolerance (all P < .05). CONCLUSIONS: In obese non-diabetic youth, those with a Late-peak vs an Early-peak glucose during an OGTT showed diminished ß-cell function, blunted incretin secretion, and lower insulin sensitivity of glucose and FFA metabolism. It remains to be determined if Late-peak glucose predicts the future development of type 2 diabetes in these high-risk youth.

Elementary school classroom physical activity breaks: student, teacher, and facilitator perspectives.

Current physical activity (PA) guidelines recommend that children accumulate at least 60 min of PA each day, and that adults should collaborate across sectors to increase opportunities for PA. Implementing brief classroom PA breaks (CPABs) is one way to help increase daily PA. The primary purpose of this study was to determine perceptions of a 14-wk CPAB program among elementary school children, in the first through fourth grades ( n = 254), at a suburban elementary school, and their teachers ( n = 18). The CPAB program was implemented by university exercise science students, and student and teacher perceptions were assessed through surveys. The children reported that the CPABs were very fun (86%), provided them with a nice break during the school day (88%), were very good for their health (94%), helped them feel more ready to learn (71%), and learn better (50%). The teachers reported that the students really enjoyed the CPABs (100%), that encouraging students to be physically active was either very important (83%) or important (17%), and that they were either very confident (72%) or confident (28%) that they themselves could lead the CPABs. No teacher reported that the CPABs hindered classroom learning. CPABs appear to be enjoyable to both students and teachers, easy to administer, and supportive of learning. Recommendations for improvements within the present collaboration were minimal and could be easily addressed with firmer entrenchment of the program. This collaboration was beneficial and fun for the vast majority involved, and others are urged to implement similar programs.

Adipose Tissue Insulin Resistance in Youth on the Spectrum From Normal Weight to Obese and From Normal Glucose Tolerance to Impaired Glucose Tolerance to Type 2 Diabetes.

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.

Patterns of Physical Activity Adherence by Adolescents With Diabetes or Obesity Enrolled in a Personalized Community-Based Intervention.

PURPOSE: The purpose of this study was to determine the feasibility of a personalized, 16-week community-based physical activity intervention for adolescents with diabetes or obesity and examine the weekly patterns of adherence to the intervention. METHODS: Physical activity adherence was evaluated throughout the intervention using accelerometers in 46 adolescents with type 1 diabetes (N = 22), type 2 diabetes (N = 12), or obesity (N = 12) (age, 14.4 ± 1.5 years; 56.5% female; 61% Hispanic). Of these, 39 completed the intervention, and 7 did not. RESULTS: There were no differences in baseline anthropometric characteristics or fitness between the completers versus noncompleters. Completers began above 1060 metabolic equivalent (MET) min/wk-1and stayed above 900 MET min/wk-1 for ~4 weeks and declined 39 MET min/wk-1 until end of study. Noncompleters began at 924 MET min/wk-1 yet dropped below 800 MET min/wk-1 by end of week 1 and declined an average of 151 MET min/wk-1. Interestingly, self-report of barriers to activity were higher in completers versus noncompleters. CONCLUSIONS: Findings highlight that adolescents completing the intervention could sustain a prescribed level of personalized activity for at least 1 month but had steadfast declines in weekly activity. Even with individualized programs, factors other than barriers to activity need to be considered when designing approaches to physical activity adherence for adolescents with diabetes or obesity.

Impaired Lipolysis, Diminished Fat Oxidation, and Metabolic Inflexibility in Obese Girls With Polycystic Ovary Syndrome.

Context: Metabolic flexibility reflects the ability to switch from lipid to carbohydrate oxidation during insulin stimulation manifested in increased respiratory quotient (RQ). Little is known about adipose tissue metabolism and metabolic flexibility in adolescent girls with polycystic ovary syndrome (PCOS). Objective: We investigated whole-body lipolysis, substrate oxidation, and metabolic flexibility in obese girls with PCOS vs obese girls without PCOS. Patients/Design: Twenty-one obese girls with PCOS and 21 obese girls without PCOS were pair-matched for age and race. Body composition, abdominal visceral adipose tissue (VAT), sex hormones, lipid profile, and adiponectin were measured. Whole-body lipolysis ([2H5]glycerol turnover), RQ, and substrate oxidation (indirect calorimetry) were evaluated during fasting and a hyperinsulinemic-euglycemic clamp together with assessment of insulin sensitivity (IS). Results: Despite similar body mass index and percent body fat, girls with PCOS vs girls without PCOS had lower fasting lipolysis and fat oxidation, less increase in RQ during hyperinsulinemia with impaired suppression in lipolysis and lipid oxidation, and lower IS. In multiple regression, the best predictors of metabolic flexibility were [using clinical parameters: adiponectin, fasting triglycerides, and insulin (R2 = 0.618, P < 0.0001); using research parameters: IS, VAT, and baseline RQ (R2 = 0.756, P < 0.0001)]. Conclusions: Obese girls with PCOS vs obese girls without PCOS have decreased lipid mobilization, diminished fat oxidation, and metabolic inflexibility. Whether this metabolic phenotype of adipose tissue dysfunction, which is conducive to fat accretion, plays a role in the induction and maintenance of obesity in adolescent girls with PCOS remains to be determined.

Increased Lipolysis, Diminished Adipose Tissue Insulin Sensitivity, and Impaired ß-Cell Function Relative to Adipose Tissue Insulin Sensitivity in Obese Youth With Impaired Glucose Tolerance.

Despite evidence of insulin resistance and ß-cell dysfunction in glucose metabolism in youth with prediabetes, the relationship between adipose tissue insulin sensitivity (ATIS) and ß-cell function remains unknown. We investigated whole-body lipolysis, ATIS, and ß-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 ß-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 ß-cell dysfunction in fat and glucose metabolism, enhancing their risk of type 2 diabetes.

Differences in ß-cell function and insulin secretion in Black vs. White obese adolescents: do incretin hormones play a role?

Black youth are at higher risk for type 2 diabetes (T2D) than their White peers. Previously we demonstrated that for the same degree of insulin sensitivity, Black youth have an upregulated ß-cell function and insulin hypersecretion, in response to intravenous (iv) glucose, compared with Whites. To investigate if the same holds true during an oral glucose challenge and because of the important role of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in augmenting insulin secretion, we examined ß-cell function and incretin hormones in 85 Black and 78 White obese adolescents, with normal glucose tolerance (NGT), during a 2-h oral glucose tolerance test (OGTT) with mathematical modeling of plasma glucose and C-peptide concentrations to assess ß-cell glucose sensitivity (ßCGS), rate sensitivity, potentiation factor, and insulin sensitivity. Incretin, pancreatic polypeptide, and glucagon concentrations were measured during the OGTT. Black obese youth had a heightened early insulin secretion together with significantly greater ßCGS, rate sensitivity, and potentiation factor compared with Whites, with no differences in incretin and glucagon concentrations. Basal and stimulated insulin clearance was lower (p = 0.001) in Black vs. White youth. In conclusion, during an OGTT Black obese youth with NGT demonstrate a pronounced early insulin secretion jointly with heightened ß-cell glucose sensitivity, rate sensitivity, and potentiation factor. These racial disparities in ß-cell function and the pathophysiological components of T2D are unlikely to be attributed to incretin hormones and remain to be investigated further to explain the metabolic basis for the enhanced risk of T2D in back youth.

Anti-Müllerian Hormone in Obese Adolescent Girls With Polycystic Ovary Syndrome.

PURPOSE: Anti-Müllerian hormone (AMH) is proposed as a biomarker of polycystic ovary syndrome (PCOS). This study investigated: (1) AMH concentrations in obese adolescents with PCOS versus without PCOS; (2) the relationship of AMH to sex steroid hormones, adiposity, and insulin resistance; and (3) the optimal AMH value and the multivariable prediction model to determine PCOS in obese adolescents. METHODS: AMH levels were measured in 46 obese PCOS girls and 43 obese non-PCOS girls. Sex steroid hormones, clamp-measured insulin sensitivity and secretion, body composition, and abdominal adiposity were evaluated. Logistic regression and receiver-operating characteristic curve analyses were used, and multivariate prediction models were developed to test the utility of AMH for the diagnosis of PCOS. RESULTS: AMH levels were higher in obese PCOS versus non-PCOS girls (8.3 ± .6 vs. 4.3 ± .4 ng/mL, p < .0001), of comparable age and puberty. AMH concentrations correlated positively with age in both groups, total and free testosterone in PCOS girls only, abdominal adipose tissue in non-PCOS girls, with no correlation to in vivo insulin sensitivity and secretion in either groups. A multivariate model including AMH (cutoff 6.26 ng/mL, area under the curve .788) together with sex hormone-binding globulin and total testosterone exhibited 93.4% predictive power for diagnosing PCOS. CONCLUSIONS: AMH may be a useful biomarker for the diagnosis of PCOS in obese adolescent girls.

Maternal excess gestational weight gain and infant waist circumference: a 2-y observational study.

BACKGROUND: The purpose of this study was to examine the effects of gestational weight gain (GWG) and infant feeding practices on infant growth parameters in infants from 6 to 24 mo of age. METHODS: Forty mother-infant pairs were recruited after delivery and followed up to 24 mo postpartum. GWG was calculated as prepregnancy weight subtracted from weight at delivery. Infant weight velocity was calculated as the change in weight between consecutive visits divided by the intervening time. Infant feeding practices were measured by interview and infant growth and waist circumference by standard anthropometry. RESULTS: Infants born to mothers with excess GWG were heavier at birth (3,521 ± 91 vs. 3,196 ± 97 g, P = 0.02) and had an average 2.16 ± 1.1 cm (P = 0.03) larger waist circumference throughout the 24 mo compared with infants born to mothers with appropriate GWG. Waist circumference increased by 0.12 and 2.0 cm for every 1 unit increase in GWG and infant birth weight. CONCLUSION: Infants born to women who exceeded the Institute of Medicine (IOM)-recommended guidelines for GWG were heavier at birth and had a significantly higher waist circumference up to 2 y of age. Strategies to control maternal excess GWG and thus the outcome on infant birth weight and waist circumference should be pursued.

The Shape of the Glucose Response Curve During an Oral Glucose Tolerance Test Heralds Biomarkers of Type 2 Diabetes Risk in Obese Youth.

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 ß-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 ß-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 ß-cell function, which are two major pathophysiological biomarkers of type 2 diabetes in youth.

Distinguishing characteristics of metabolically healthy versus metabolically unhealthy obese adolescent girls with polycystic ovary syndrome.

OBJECTIVE: To investigate the key physical, metabolic, hormonal and cardiovascular characteristics of metabolically healthy obese (MHO) versus unhealthy obese (MUHO) girls with polycystic ovary syndrome (PCOS). DESIGN: Cross-sectional study. SETTING: Research center. PATIENT(S): Seventy obese girls with PCOS were divided into 19 MHO and 51 MUHO based on cutoff points for in vivo insulin sensitivity (within and < 2 SDs of the mean of the insulin sensitivity of the normal-weight girls, respectively). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Body composition, abdominal fat, in vivo insulin sensitivity and secretion (hyperinsulinemic-euglycemic and hyperglycemic clamps respectively), hormonal profile, and cardiovascular disease risk markers. RESULT(S): MUHO-PCOS girls had higher waist circumference, visceral adipose tissue, leptin, and free testosterone, lower SHBG and E2, higher non-high-density lipoprotein (HDL) cholesterol and atherogenic lipoprotein particle concentrations, smaller HDL particle size, and higher high-sensitivity C-reactive protein compared with MHO-PCOS girls. Hepatic and peripheral insulin sensitivity were lower with higher first- and second-phase insulin secretion, but ß-cell function relative to insulin sensitivity was lower in MUHO versus MHO. Pair matching of MHO and MUHO regarding age and body mass index revealed similar findings. MUHO-PCOS girls had larger visceral adiposity, lower insulin sensitivity and ß-cell function, worse hormonal profile, and severely atherogenic lipoprotein concentrations compared with MHO-PCOS girls. CONCLUSION(S): MHO-PCOS girls have favorable physical, metabolic, hormonal, and cardiovascular disease (CVD) characteristics and lower risk biomarkers for type 2 diabetes compared with their MUHO-PCOS peers. A greater understanding of the contrast in this risk phenotype in obese girls with PCOS may have important implications for therapeutic interventions, their outcomes, and their durability.

ß-cell function, incretin effect, and incretin hormones in obese youth along the span of glucose tolerance from normal to prediabetes to type 2 diabetes.

Using the hyperglycemic and euglycemic clamp, we demonstrated impaired ß-cell function in obese youth with increasing dysglycemia. Herein we describe oral glucose tolerance test (OGTT)-modeled ß-cell function and incretin effect in obese adolescents spanning the range of glucose tolerance. ß-Cell function parameters were derived from established mathematical models yielding ß-cell glucose sensitivity (ßCGS), rate sensitivity, and insulin sensitivity in 255 obese adolescents (173 with normal glucose tolerance [NGT], 48 with impaired glucose tolerance [IGT], and 34 with type 2 diabetes [T2D]). The incretin effect was calculated as the ratio of the OGTT-ßCGS to the 2-h hyperglycemic clamp-ßCGS. Incretin and glucagon concentrations were measured during the OGTT. Compared with NGT, ßCGS was 30 and 65% lower in youth with IGT and T2D, respectively; rate sensitivity was 40% lower in T2D. Youth with IGT or T2D had 32 and 38% reduced incretin effect compared with NGT in the face of similar changes in GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) in response to oral glucose. We conclude that glucose sensitivity deteriorates progressively in obese youth across the spectrum of glucose tolerance in association with impairment in incretin effect without reduction in GLP-1 or GIP, similar to that seen in adult dysglycemia.

Polycystic ovary syndrome and nonalcoholic fatty liver in obese adolescents: association with metabolic risk profile.

OBJECTIVE: To investigate the relationship between liver fat and in vivo insulin sensitivity, body composition, abdominal adiposity, and lipid metabolism in obese adolescent girls with polycystic ovary syndrome (PCOS). DESIGN: Cross-sectional case-control study. SETTING: Research center. PATIENT(S): Thirty Tanner stage V obese girls with PCOS. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Liver fat, abdominal adiposity, in vivo insulin-stimulated glucose disposal, whole-body lipolysis, fat oxidation, lipoprotein particle size and concentration, and liver enzymes (alanine aminotransferase and aspartate aminotransferase). Fatty liver index <1 is indicative of fatty liver. RESULT(S): Fatty liver was present in 6.7% of the individuals (6.7%). Levels of alanine aminotransferase and aspartate aminotransferase were not different between those with fatty liver vs. without. Fatty liver index was associated with age (r = -0.53), body mass index (r = -0.41), total (r = -0.43) and subcutaneous (r = -0.41) abdominal adiposity, insulin-stimulated glucose disposal (r = 0.36), and small, medium small, and very small low-density lipoprotein concentrations (r ≥ -0.43). In a multiple regression analysis, age, total T, race, and insulin-stimulated glucose disposal explained 43% of the variance (R(2) = 0.43) in fatty liver index, with age (R(2) = 0.28) and total T (R(2) = 0.11) being independent contributors. CONCLUSION(S): Liver fat is associated with increasing age, even in the narrow adolescent age range, increasing abdominal adiposity, worsening insulin sensitivity, and dyslipoproteinemia in obese adolescent girls with PCOS. Targeting these abnormalities early in the course of PCOS may halt future nonalcoholic fatty liver disease in adulthood.

ß-Cell lipotoxicity in response to free fatty acid elevation in prepubertal youth: African American versus Caucasian contrast.

Prepubertal African American (AA) youth compared with their Caucasian (C) peers have higher insulin secretion, which correlates positively with free fatty acid (FFA) concentration. In our continued efforts to explain the racial disparity in insulinemia, and because FFAs modulate insulin secretion, we hypothesized that AA youth would have a greater response to FFA-induced ß-cell insulin secretion than C youth. We compared the short-term effects of FFA elevation on fasting and glucose-stimulated C-peptide-modeled insulin secretion in prepubertal normal-weight AA versus C peers during a 2-h hyperglycemic clamp (12.5 mmol/L) on two occasions: 1) infusion of normal saline and 2) infusion of 20% intralipid (IL). During IL infusion, insulin sensitivity (IS) declined comparably in AA and C youth. Glucose sensitivity of first- and second-phase insulin secretion showed a significant condition × race interaction being higher in AA youth. Disposition index, ß-cell function relative to IS, declined with IL infusion in AA and C youth, with a significantly greater decrease in Cs compared with AAs. In conclusion, AA and C prepubertal youth both demonstrated a decline in ß-cell function relative to IS during IL infusion, indicative of acute lipotoxicity. The greater decline in C youth compared with AAs may suggest that C youth are more susceptible to ß-cell lipotoxicity than AA youth, or alternatively, that AA youth are hypersensitive to FFA stimulation of ß-cell insulin secretion, consistent with our theory.

ß-Cell lipotoxicity after an overnight intravenous lipid challenge and free fatty acid elevation in African American versus American white overweight/obese adolescents.

OBJECTIVE: Overweight/obese (OW/OB) African American (AA) adolescents have a more diabetogenic insulin secretion/sensitivity pattern compared with their American white (AW) peers. The present study investigated ß-cell lipotoxicity to test whether increased free fatty acid (FFA) levels result in greater ß-cell dysfunction in AA vs AW OW/OB adolescents. RESEARCH DESIGN AND METHODS: Glucose-stimulated insulin secretion was modeled, from glucose and C-peptide concentrations during a 2-hour hyperglycemic (225 mg/dL) clamp in 22 AA and 24 AW OW/OB adolescents, on 2 occasions after a 12-hour overnight infusion of either normal saline or intralipid (IL) in a random sequence. ß-Cell function relative to insulin sensitivity, the disposition index (DI), was examined during normal saline and IL conditions. Substrate oxidation was evaluated with indirect calorimetry and body composition and abdominal adiposity with dual-energy X-ray absorptiometry and magnetic resonance imaging at L4-L5, respectively. RESULTS: Age, sex, body mass index, total and sc adiposity were similar between racial groups, but visceral adiposity was significantly lower in AAs. During IL infusion, FFAs and fat oxidation increased and insulin sensitivity decreased similarly in AAs and AWs. ß-Cell glucose sensitivity of first- and second-phase insulin secretion did not change significantly during IL infusion in either group, but DI in each phase decreased significantly and similarly in AAs and AWs. CONCLUSIONS: Overweight/obese AA and AW adolescents respond to an overnight fat infusion with significant declines in insulin sensitivity, DI, and ß-cell function relative to insulin sensitivity, suggestive of ß-cell lipotoxicity. However, contrary to our hypothesis, there does not seem to be a race differential in ß-cell lipotoxicity. Longer durations of FFA elevation may unravel such race-related contrasts.

Metabolomic profiling of amino acids and ß-cell function relative to insulin sensitivity in youth.

CONTEXT: In longitudinal studies of adults, elevated amino acid (AA) concentrations predicted future type 2 diabetes mellitus (T2DM). OBJECTIVE: The aim of the present investigation was to examine whether increased plasma AA concentrations are associated with impaired ß-cell function relative to insulin sensitivity [i.e. disposition index (DI)], a predictor of T2DM development. DESIGN, SETTING, AND PARTICIPANTS: Metabolomic analysis for fasting plasma AAs was performed by tandem mass spectrometry in 139 normal-weight and obese adolescents with and without dysglycemia. First-phase insulin secretion was evaluated by a hyperglycemic (∼225 mg/dl) clamp and insulin sensitivity by a hyperinsulinemic-euglycemic clamp. DI was calculated as the product of first-phase insulin and insulin sensitivity. RESULTS: DI was positively associated with branched-chain AAs (leucine/isoleucine and valine; r = 0.27 and 0.29, P = 0.001), neutrally transported AAs (phenylalanine and methionine; r = 0.30 and 0.35, P < 0.001), basic AAs (histidine and arginine; r = 0.28 and 0.23, P ≤ 0.007), serine (r = 0.35, P < 0.001), glycine (r = 0.26, P = 0.002), and branched-chain AAs-derived intermediates C3, C4, and C5 acylcarnitine (range r = 0.18-0.19, P ≤ 0.04). CONCLUSION: In youth, increased plasma AA concentrations are not associated with a heightened metabolic risk profile for T2DM; rather, they are positively associated with ß-cell function relative to insulin sensitivity. These contrasting observations between adults and youth may be a reflection of developmental differences along the lifespan dependent on the combined impact of the aging process together with the impact of progressive obesity.

HbA(1c) diagnostic categories and ß-cell function relative to insulin sensitivity in overweight/obese adolescents.

OBJECTIVE: The recommended HbA(1c) diagnostic categories remain controversial and their utility in doubt in pediatrics. We hypothesized that alterations in the pathophysiologic mechanisms of type 2 diabetes may be evident in the American Diabetes Association recommended at-risk/prediabetes category (HbA(1c) 5.7 to <6.5%). RESEARCH DESIGN AND METHODS: We compared in vivo hepatic and peripheral insulin sensitivity by [6,6-(2)H(2)] glucose and a 3-h hyperinsulinemic-euglycemic clamp and ß-cell function by a 2-h hyperglycemic clamp (∼225 mg/dL) in overweight/obese (BMI ≥85th percentile) adolescents with prediabetes (HbA(1c) 5.7 to <6.5%) (n = 160) to those with normal HbA(1c) (<5.7%) (n = 44). ß-Cell function was expressed relative to insulin sensitivity (i.e., the disposition index = insulin sensitivity × first-phase insulin). RESULTS: In the prediabetes versus normal HbA(1c) category, fasting glucose, insulin, and oral glucose tolerance test (OGTT) area under the curve for glucose and insulin were significantly higher; hepatic and peripheral insulin sensitivity were lower; and ß-cell function relative to insulin sensitivity was lower (366 ± 48 vs. 524 ± 25 mg/kg/min; P = 0.005). A total of 27% of youth in the normal HbA(1c) category and 41% in the prediabetes HbA(1c) category had dysglycemia (impaired fasting glucose and/or impaired glucose tolerance) by a 2-h OGTT. CONCLUSIONS: Overweight/obese adolescents with HbA(1c) in the at-risk/prediabetes category demonstrate impaired ß-cell function relative to insulin sensitivity, a metabolic marker for heightened risk of type 2 diabetes. Thus, HbA(1c) may be a suitable screening tool in large-scale epidemiological observational and/or interventional studies examining the progression or reversal of type 2 diabetes risk.

Metabolomic profiling of fatty acid and amino acid metabolism in youth with obesity and type 2 diabetes: evidence for enhanced mitochondrial oxidation.

OBJECTIVE: We compared acylcarnitine (AcylCN) species, common amino acid and fat oxidation (FOX) byproducts, and plasma amino acids in normal weight (NW; n = 39), obese (OB; n = 64), and type 2 diabetic (n = 17) adolescents. RESEARCH DESIGN AND METHODS: Fasting plasma was analyzed by tandem mass spectrometry, body composition by dual energy X-ray absorptiometry and computed tomography, and total-body lipolysis and substrate oxidation by [(2)H(5)]glycerol and indirect calorimetry, respectively. In vivo insulin sensitivity (IS) was assessed with a 3-h hyperinsulinemic-euglycemic clamp. RESULTS: Long-chain AcylCNs (C18:2-CN to C14:0-CN) were similar among the three groups. Medium- to short-chain AcylCNs (except C8 and C10) were significantly lower in type 2 diabetes compared with NW, and when compared with OB, C2-, C6-, and C10-CN were lower. Amino acid concentrations were lower in type 2 diabetes compared with NW. Fasting lipolysis and FOX were higher in OB and type 2 diabetes compared with NW, and the negative association of FOX to C10:1 disappeared after controlling for adiposity, Tanner stage, and sex. IS was lower in OB and type 2 diabetes with positive associations between IS and arginine, histidine, and serine after adjusting for adiposity, Tanner stage, and sex. CONCLUSIONS: These metabolomics results, together with the increased rates of in vivo FOX, are not supportive of defective fatty acid or amino acid metabolism in obesity and type 2 diabetes in youth. Such observations are consistent with early adaptive metabolic plasticity in youth, which over time-with continued obesity and aging-may become dysfunctional, as observed in adults.