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1.
Pediatr Diabetes ; 2020 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-32064729

RESUMO

OBJECTIVE: In treatment options for type 2 diabetes in adolescents and youth (TODAY), 4.5% of obese youth clinically diagnosed with type 2 diabetes (T2D) had genetic variants consistent with maturity onset diabetes of youth (MODY) diagnosis. The course of IS and ß-cell function in obese youth with MODY remains unknown. In this secondary analysis, we examined IS and ß-cell function in MODY vs. non-MODY obese youth at randomization and over time. METHODS: Genetic data in TODAY included 426 non-MODY (T2D) and 22 MODY youth (7 glucokinase MODY mutation positive [GCK-MODY], 12 hepatocyte nuclear factor MODY mutation positive [HNF-MODY], 2 Insulin gene mutation [insulin (INS)-MODY], and 1 Kruppel-like factor 11 [KLF11-MODY]). Oral glucose tolerance test (OGTT)-derived IS, C-peptide index, and ß-cell function relative to IS oral disposition index (oDI) was measured at randomization, and over 24 months in addition to total and high-molecular-weight adiponectin (HMWA). RESULTS: At randomization, IS, total adiponectin, and HMWA were significantly higher in the two MODY groups than in non-MODY. ß-cell function measured by C-peptide oDI was 3-fold higher in GCK-MODY than in HNF-MODY and 1.5-fold higher than non-MODY (P for both <.05). Glycemic failure rate was 75.0% in HNF-MODY, 46.9% in non-MODY, and zero in GCK-MODY youth. While the changes in IS and oDI were not different among the three groups in the first 6 months, IS improved from 6 to 24 months in HNF-MODY vs GCK-MODY youth. CONCLUSIONS: In TODAY, ß-cell function at randomization was worse in obese HNF-MODY youth compared with GCK-MODY youth, while insulin sensitivity was worse in non-MODY compared with the other two MODY groups. Over time, IS showed the greatest improvement in HNF-MODY youth. This raises the possibility that TODAY therapeutic modalities of insulin sensitization in these obese HNF-MODY youth may have played a beneficial role.

2.
Am J Clin Nutr ; 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31950134

RESUMO

BACKGROUND: Obese children are vulnerable to vitamin D deficiency and impaired cardiovascular health; vitamin D replenishment might improve their cardiovascular health. OBJECTIVES: The aims were to determine, in vitamin D-deficient overweight and obese children, whether supplementation with vitamin D3 1000 or 2000 IU/d is more effective than 600 IU/d in improving arterial endothelial function, arterial stiffness, central and systemic blood pressure (BP), insulin sensitivity (1/fasting insulin concentration), fasting glucose concentration, and lipid profile and to explore whether downregulation of adipocytokines and markers of systemic inflammation underlies vitamin D effects. METHODS: We conducted a randomized, double-masked, controlled clinical trial in 225 10- to 18-y-old eligible children. Change in endothelial function at 6 mo was the primary outcome. RESULTS: Dose-response increases in serum 25-hydroxyvitamin D concentrations were significant and tolerated without developing hypercalcemia. Changes at 3 and 6 mo in endothelial function, arterial stiffness, systemic-systolic BP, lipids, and inflammatory markers did not differ between children receiving 1000 or 2000 IU vitamin D and children receiving 600 IU. Some secondary outcomes differed between groups. Compared with the 600-IU group, central-systolic, central-diastolic, and systemic-diastolic BP was lower at 6 mo in the 1000-IU group [-2.66 (95% CI: -5.27, -0.046), -3.57 (-5.97, -1.17), and -3.28 (-5.55, -1.00) mm Hg, respectively]; insulin sensitivity increased at 3 and 6 mo and fasting glucose concentration declined at 6 mo (-2.67; 95% CI: -4.88, -0.46 mg/dL) in the 2000-IU group. CONCLUSIONS: Correction of vitamin D deficiency in overweight and obese children by vitamin D3 supplementation with 1000 or 2000 IU/d versus 600 IU/d did not affect measures of arterial endothelial function or stiffness, systemic inflammation, or lipid profile, but resulted in reductions in BP and fasting glucose concentration and in improvements in insulin sensitivity. Optimization of children's vitamin D status may improve their cardiovascular health. This trial was registered at clinicaltrials.gov as NCT01797302.

3.
Pediatr Diabetes ; 21(1): 18-27, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31677208

RESUMO

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.

4.
Pediatr Diabetes ; 20(7): 871-879, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31418516

RESUMO

OBJECTIVE: To understand the factors associated with glycemic control after starting insulin in youth with type 2 diabetes following glycemic failure (persistent HbA1c ≥8%) with metformin alone, metformin + rosiglitazone or metformin + lifestyle in the TODAY study. METHODS: Change in HbA1c after add-on insulin therapy and the factors predictive of glycemic response were evaluated. At 1-year postinsulin initiation, 253 youth had a mean of 3.9 ± 1.0 visits since the time of insulin initiation. Participants were divided into three groups according to glycemic control: consistent decrease in HbA1c by ≥0.5%, change <0.5%, or consistent increase in HbA1c ≥0.5%, at 75% or more of the visits. RESULTS: Within 1-year postinsulin initiation, 33.2% of participants had a consistent HbA1c decrease of ≥0.5%, 46.2% changed HbA1c <0.5%, and 20.6% had an increase ≥0.5%. At randomization into TODAY and at time of insulin initiation, the three glycemia groups were similar in age, sex, race-ethnicity, pubertal stage, BMI z-score, diabetes duration, and insulin secretion indices. Consistent HbA1c improvement was associated with higher insulin sensitivity (1/fasting insulin) at randomization and at time of failure, higher adiponectin at randomization, and was not associated with indices of ß-cell function. CONCLUSIONS: Response to add-on insulin was highly variable among youth in TODAY. Greater insulin sensitivity and higher adiponectin concentrations at randomization were associated with improved glycemic control after initiation of insulin. Due to limited information on adherence to insulin injections, the roles of adherence to the prescribed insulin regimen or psychosocial factors are unknown.

5.
Diabetes Care ; 42(1): 164-172, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30455329

RESUMO

OBJECTIVE: Obese youth without diabetes with monophasic oral glucose tolerance test (OGTT) glucose response curves have lower insulin sensitivity and impaired ß-cell function compared with those with biphasic curves. The OGTT glucose response curve has not been studied in youth-onset type 2 diabetes. Here we test the hypothesis that the OGTT glucose response curve at randomization in youth in the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study forecasts heightened glycemic failure rates and accelerated decline in ß-cell function. RESEARCH DESIGN AND METHODS: OGTTs (n = 662) performed at randomization were categorized as monophasic, biphasic, or incessant increase. Demographics, insulin sensitivity (1/fasting insulin), C-peptide index (△C30/△G30), and ß-cell function relative to insulin sensitivity (oral disposition index [oDI]) were compared among the three groups. RESULTS: At randomization, 21.7% had incessant increase, 68.6% monophasic, and 9.7% biphasic glucose response curves. The incessant increase group had similar insulin sensitivity but significantly lower C-peptide index and lower oDI, despite similar diabetes duration, compared with the other two groups. Glycemic failure rates were higher in the incessant increase group (58.3%) versus the monophasic group (42.3%) versus the biphasic group (39.1%) (P < 0.0001). The 6-month decline in C-peptide index (32.8% vs. 18.1% vs. 13.2%) and oDI (32.2% vs. 11.6% vs. 9.1%) was greatest in incessant increase versus monophasic and biphasic with no difference in insulin sensitivity. CONCLUSIONS: In the TODAY study cohort, an incessant increase in the OGTT glucose response curve at randomization reflects reduced ß-cell function and foretells increased glycemic failure rates with accelerated deterioration in ß-cell function independent of diabetes duration and treatment assignment compared with monophasic and biphasic curves. The shape of the OGTT glucose response curve could be a metabolic biomarker prognosticating the response to therapy in youth with type 2 diabetes.


Assuntos
Glicemia/metabolismo , Teste de Tolerância a Glucose , Células Secretoras de Insulina/metabolismo , Adolescente , Peptídeo C/sangue , Criança , Diabetes Mellitus Tipo 2/sangue , Jejum , Feminino , Humanos , Insulina/sangue , Resistência à Insulina , Estudos Longitudinais , Masculino , Obesidade/sangue
6.
Diabetes Care ; 42(2): 265-272, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30455334

RESUMO

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.


Assuntos
Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Intolerância à Glucose/metabolismo , Glucose/metabolismo , Peso Corporal Ideal/fisiologia , Resistência à Insulina , Obesidade Pediátrica/metabolismo , Adiposidade/fisiologia , Adolescente , Glicemia/metabolismo , Criança , Estudos de Coortes , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Intolerância à Glucose/complicações , Intolerância à Glucose/epidemiologia , Teste de Tolerância a Glucose , Humanos , Insulina/metabolismo , Resistência à Insulina/fisiologia , Masculino , Obesidade Pediátrica/complicações , Obesidade Pediátrica/epidemiologia , Adulto Jovem
7.
J Adolesc Health ; 64(3): 327-332, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30389203

RESUMO

PURPOSE: We compared body composition and cardiorespiratory fitness (CRF) between metabolically healthy overweight/obese (MHO) versus metabolically unhealthy overweight/obese (MUO) adolescents in 189 black and white adolescents (BMI ≥ 85th percentile, 12-18 years of age). METHODS: Participants were defined as MHO or MUO if their insulin-stimulated glucose disposal, measured by a 3-hour hyperinsulinemic-euglycemic clamp, was in the upper quartile or in the lower three quartiles. Total fat was measured by dual-energy X-ray absorptiometry, and visceral adiposity and liver fat were measured by magnetic resonance imaging and proton magnetic resonance spectroscopy, respectively. CRF was measured by a graded maximal treadmill test. RESULTS: Black MHO adolescents had lower (p < .05) 2-hour oral glucose tolerance test glucose, triglycerides, very-low-density lipoprotein cholesterol, and higher high-density lipoprotein cholesterol, with a lower prevalence of impaired fasting glucose and impaired glucose tolerance compared with black MUO adolescents. White MHO adolescents had lower (p < .05) triglycerides and very-low-density lipoprotein cholesterol, with a lower prevalence of impaired fasting glucose compared with white MUO adolescents. Independent of race, CRF was higher in MHO versus MUO adolescents. After accounting for gender, Tanner stage, and BMI, there were no differences in total fat (kg, %) between MHO versus MUO in both races. MHO adolescents had significantly lower trunk fat, waist circumference, and visceral fat compared with MUO adolescents in both races. In whites, MHO adolescents had lower (p = .055) liver fat compared with MUO adolescents. CONCLUSIONS: Independent of race, the MHO phenotype is characterized by high CRF, lower waist circumference and visceral fat, and lower rates of dysglycemia in youth.

8.
J Pediatr ; 206: 91-98.e1, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30554789

RESUMO

OBJECTIVE: To examine whether a combined aerobic exercise and resistance exercise is more effective than either aerobic exercise or resistance exercise alone in improving insulin sensitivity and reducing total adiposity and ectopic fat in adolescents. STUDY DESIGN: A total of 118 sedentary adolescents with overweight/obesity (body mass index >85th percentile, 12-17 years) were recruited from October 2013 through April 2017 at Children's Hospital of Pittsburgh. Participants were randomized to 1 of the following 6-month exercise groups (3 d/wk, 180 min/wk): aerobic exercise (n = 38), resistance exercise (n = 40), and combined aerobic exercise and resistance exercise (n = 40). The primary outcome was the change in insulin-stimulated glucose disposal by a 3-hour hyperinsulinemic-euglycemic clamp. The secondary outcomes were changes in liver fat by proton magnetic resonance spectroscopy and intermuscular adipose tissue by computed tomography. RESULTS: Of the 118 participants randomized, 85 participants (72%) completed the study with 90% exercise attendance. Total adiposity reduced similarly in all groups (-2%, P < .05). After adjusting for age and sex, insulin-stimulated glucose disposal increased (P < .05) in all groups, with the increase in the aerobic exercise group being greater than the resistance exercise group (1.7 ± 0.1 vs 0.7 ± 0.1 mg/kg/min, P < .05) but not different from the combined group (1.2 ± 0.1 mg/kg/min). Liver fat was reduced (P < .05) in the aerobic exercise (-0.6%) and combined (-0.6%) groups but not in the resistance exercise group (-0.3%, P > .05). Intermuscular adipose tissue decreased (P < .05) similarly in all groups. CONCLUSION: Combined aerobic exercise and resistance exercise and aerobic exercise alone are similarly beneficial in improving insulin sensitivity and reducing ectopic fat in adolescents with obesity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01938950.


Assuntos
Exercício , Resistência à Insulina , Sobrepeso/sangue , Sobrepeso/terapia , Obesidade Pediátrica/sangue , Obesidade Pediátrica/terapia , Tecido Adiposo/patologia , Adiposidade , Adolescente , Antropometria , Índice de Massa Corporal , Criança , Dieta , Terapia por Exercício , Fígado Gorduroso/metabolismo , Feminino , Teste de Tolerância a Glucose , Humanos , Insulina/metabolismo , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Comportamento Sedentário
9.
JCI Insight ; 3(24)2018 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-30568042

RESUMO

BACKGROUND: Excessive insulin secretion may lead to glucose dysregulation. Our aim was to identify primary (independent of insulin resistance) insulin hypersecretion in subjects with normal glucose tolerance and its role in the progression of dysglycemia. METHODS: In 1,168 adults, insulin secretion rate (ISR) and ß cell function were estimated by C-peptide modeling during an oral glucose tolerance test (OGTT) and an i.v. glucose tolerance test. Whole-body insulin sensitivity was measured by a hyperinsulinemic-euglycemic clamp. After regressing ISR on insulin sensitivity, subjects in the upper tertile of the distribution of residuals were defined as primary hypersecretors. This approach was applied to a biethnic cohort of 182 obese adolescents, who received an OGTT, a hyperglycemic, and a euglycemic clamp. RESULTS: Adult hypersecretors showed older age, more familial diabetes, sedentary lifestyle, increased fat mass, and worse lipid profile compared with the rest of the cohort, despite virtually identical BMI and insulin sensitivity. Insulin secretion was increased by 53% due to enhanced (+23%) ß cell glucose sensitivity. Despite the resulting hyperinsulinemia, glucose tolerance was worse in hypersecretors among both adults and adolescents, coupled with higher indices of liver insulin resistance and increased availability of gluconeogenic substrates. At the 3-year follow-up, adult hypersecretors had increased incidence of impaired glucose tolerance/type 2 diabetes. CONCLUSION: Primary insulin hypersecretion, independent of insulin resistance, is associated with a worse clinical and metabolic phenotype in adults and adolescents and predicts deterioration of glucose control over time. FUNDING: The relationship between insulin sensitivity and cardiovascular disease (RISC) Study was partly supported by EU grant QLG1-CT-2001-01252.


Assuntos
Secreção de Insulina/fisiologia , Insulina/metabolismo , Obesidade/fisiopatologia , Adolescente , Adulto , Índice de Massa Corporal , Criança , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Técnica Clamp de Glucose , Intolerância à Glucose , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Resistência à Insulina/fisiologia , Células Secretoras de Insulina/metabolismo , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
12.
Artigo em Inglês | MEDLINE | ID: mdl-29910773

RESUMO

Background: It is not known if dysglycemia and sleep-disordered breathing are linked in adolescents, as in adults. Objective: To perform a pilot study evaluating measures of sleep-disordered breathing across the spectrum of glucose tolerance in obese adolescents. We hypothesized that dysglycemia would be associated with sleep-disordered breathing. Participants/methods: This was a prospective, cross-sectional clinical pilot study that included 57 adolescents [body mass index (BMI) 38.9 ± 8.4 kg/m2] aged 12-18 years (14.5 ± 1.6) with normal glucose tolerance (NGT), or dysglycemia [impaired glucose tolerance (IGT) or type 2 diabetes (T2D)]. Measures: Anthropometrics, overnight polysomnogram, and oral glucose tolerance tests were performed. Participant characteristics and outcome measures were compared by glucose tolerance status. Correlational analyses were conducted to assess the associations between variables of interest. Results: Participants with dysglycemia (n = 21) were not different from those with NGT (n = 36) for BMI, waist circumference, body fat, or sleep characteristics. Nocturnal oxygen desaturation was associated with higher BMI (r = -0.334, p = 0.012). The apnea-hypopnea index (AHI) was not associated with physical and metabolic parameters. Although participants with dysglycemia tended to have higher AHIs (median 3.2, 2.2, and 1.6 events/h for T2D, IGT, and NGT, respectively), there was not a linear relationship between measures of glycemia and AHI. Conclusion: Further study with a larger proportion of youth with prediabetes and T2D is necessary to determine whether evaluation for sleep-disordered breathing is uniformly warranted.

14.
J Clin Endocrinol Metab ; 103(6): 2309-2318, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29697830

RESUMO

Context: Little is known about reproductive function in girls with youth-onset type 2 diabetes. Objectives: To characterize girls with irregular menses and effects of glycemic treatments on menses and sex steroids in the Treatment Options for Type 2 Diabetes in Youth (TODAY) study. Design: Differences in demographic, metabolic, and hormonal characteristics between regular- vs irregular-menses groups were tested; treatment group (metformin with or without rosiglitazone, metformin plus lifestyle) effect on menses and sex steroids over time in the study was assessed. This is a secondary analysis of TODAY data. Setting: Multicenter study in an academic setting. Patients: TODAY girls not receiving hormonal contraception and those at least 1-year postmenarche were included. Irregular menses was defined as three or fewer periods in the prior 6 months. Results: Of eligible participants with serum measurement of sex steroids (n = 190; mean age, 14 years), 21% had irregular menses. Those with irregular vs regular menses had higher body mass index (BMI) (P = 0.001), aspartate aminotransferase (AST) (P = 0.001), free androgen index (P = 0.0003), and total testosterone (P = 0.01) and lower sex hormone-binding globulin (SHBG) (P = 0.004) and estradiol (P = 0.01). Differences remained after adjustment for BMI. There was no treatment group effect on menses or sex steroids at 12 or 24 months, and no association of sex steroids was seen with measures of insulin sensitivity or secretion. Conclusions: Menstrual dysfunction is common in girls with recently diagnosed type 2 diabetes and associated with alterations in sex steroids, SHBG, and AST but not with alteration in insulin sensitivity or ß-cell function and did not improve with 2 years of antihyperglycemic treatment.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Resistência à Insulina/fisiologia , Distúrbios Menstruais/complicações , Adolescente , Androgênios/sangue , Aspartato Aminotransferases/sangue , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Quimioterapia Combinada , Estradiol/sangue , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Hipoglicemiantes/uso terapêutico , Estilo de Vida , Distúrbios Menstruais/sangue , Metformina/uso terapêutico , Rosiglitazona/uso terapêutico , Globulina de Ligação a Hormônio Sexual/metabolismo , Testosterona/sangue
15.
Pediatr Diabetes ; 19(2): 205-211, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28726334

RESUMO

OBJECTIVE: Youth type 2 diabetes mellitus (T2DM) occurs decades earlier than adult T2DM and is characterized by high therapeutic failure rates and decreased response to insulin sensitizers suggesting a more severe disease process than in adults. To explain these observations, we hypothesized that insulin resistance is worse in obese youth than adults with impaired glucose tolerance (IGT), a state of high-risk for T2DM. As proof-of-concept, we compared insulin sensitivity between BMI-, sex-, and race-matched obese youth vs adults with IGT. METHODS: This retrospective analysis of IGT youth and adults included 34 obese adolescents matched (2:1) for BMI, sex, and race to 17 adults. Hepatic and peripheral insulin sensitivity were measured by [6,6-2 H2 ]glucose and hyperinsulinemic-euglycemic clamp. Body composition (DEXA) and serum lipid profile were examined. RESULTS: Despite similar percent body fat, obese adolescents had 2-fold higher fasting insulin concentration, lower hepatic (~53%) and peripheral (~42%) insulin sensitivity and lower HDL compared with adults (all P < .01). Surrogate estimate of insulin sensitivity, 1/fasting insulin was lower and HOMA-IR was higher in adolescents vs adults. Adults had a more atherogenic lipid profile with higher total-, LDL-, and non-HDL cholesterol. CONCLUSIONS: Obese youth and adults with IGT differ in that youth are more insulin resistant than adults in spite of similar adiposity. This could potentially explain the earlier onset of T2DM in youth through an early and amplified burden on a ß-cell destined to decompensate, and explicate their lower therapeutic response to insulin sensitizers.


Assuntos
Adiposidade , Envelhecimento , Diabetes Mellitus Tipo 2/etiologia , Intolerância à Glucose/metabolismo , Resistência à Insulina , Obesidade/metabolismo , Obesidade Pediátrica/metabolismo , Adolescente , Adulto , Índice de Massa Corporal , Criança , Estudos de Coortes , Comorbidade , Diabetes Mellitus Tipo 2/epidemiologia , Progressão da Doença , Feminino , Técnica Clamp de Glucose , Intolerância à Glucose/epidemiologia , Intolerância à Glucose/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Obesidade Pediátrica/epidemiologia , Pennsylvania/epidemiologia , Estudo de Prova de Conceito , Estudos Retrospectivos , Risco , Índice de Gravidade de Doença
16.
Diabetes Obes Metab ; 20(1): 14-24, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28493515

RESUMO

The Restoring Insulin Secretion (RISE) study was initiated to evaluate interventions to slow or reverse the progression of ß-cell failure in type 2 diabetes (T2D). To design the RISE study, we undertook an evaluation of methods for measurement of ß-cell function and changes in ß-cell function in response to interventions. In the present paper, we review approaches for measurement of ß-cell function, focusing on methodologic and feasibility considerations. Methodologic considerations included: (1) the utility of each technique for evaluating key aspects of ß-cell function (first- and second-phase insulin secretion, maximum insulin secretion, glucose sensitivity, incretin effects) and (2) tactics for incorporating a measurement of insulin sensitivity in order to adjust insulin secretion measures for insulin sensitivity appropriately. Of particular concern were the capacity to measure ß-cell function accurately in those with poor function, as is seen in established T2D, and the capacity of each method for demonstrating treatment-induced changes in ß-cell function. Feasibility considerations included: staff burden, including time and required methodological expertise; participant burden, including time and number of study visits; and ease of standardizing methods across a multicentre consortium. After this evaluation, we selected a 2-day measurement procedure, combining a 3-hour 75-g oral glucose tolerance test and a 2-stage hyperglycaemic clamp procedure, augmented with arginine.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Modelos Biológicos , Projetos de Pesquisa , Arginina/administração & dosagem , Biomarcadores/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/terapia , Técnica Clamp de Glucose , Teste de Tolerância a Glucose/tendências , Humanos , Infusões Intravenosas , Resistência à Insulina , Secreção de Insulina , Células Secretoras de Insulina/patologia , Período Pós-Prandial , Projetos de Pesquisa/tendências
17.
Am J Kidney Dis ; 71(1): 65-74, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29157731

RESUMO

BACKGROUND: Diabetic kidney disease is a major cause of premature mortality in type 2 diabetes mellitus (T2DM). Worsening insulin sensitivity independent of glycemic control may contribute to the development of diabetic kidney disease. We investigated the longitudinal association of insulin sensitivity with hyperfiltration and increased albumin excretion in adolescents with T2DM. STUDY DESIGN: Observational prospective cohort study. SETTING & PARTICIPANTS: 532 TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) participants aged 12 to 17 years with T2DM duration less than 2 years at baseline. The TODAY Study was a multicenter randomized clinical trial that examined the efficacy of 3 treatment regimens (metformin monotherapy, metformin plus rosiglitazone, or metformin plus an intensive lifestyle intervention program) to achieve durable glycemic control. PREDICTORS: Natural log-transformed estimated insulin sensitivity (reciprocal of fasting insulin), hemoglobin A1c concentration, age, race-ethnicity, treatment group, body mass index, loss of glycemic control, and hypertension. OUTCOMES: Hyperfiltration was defined as 99th percentile or higher of estimated glomerular filtration rate (≥140mL/min/1.73m2) when referenced to healthy adolescents (NHANES 1999-2002) and albumin-creatinine ratio ≥ 30µg/mg at 3 consecutive annual visits. RESULTS: Hyperfiltration was observed in 7.0% of participants at baseline and in 13.3% by 5 years, with a cumulative incidence of 5.0% over 5 years. The prevalence of increased albumin excretion was 6% at baseline and 18% by 5 years, with a cumulative incidence of 13.4%. There was an 8% increase in risk for hyperfiltration per 10% lower estimated insulin sensitivity in unadjusted and adjusted models (P=0.01). Increased albumin excretion was associated with hemoglobin A1c concentration, but not estimated insulin sensitivity. LIMITATIONS: Longer follow-up is needed to capture the transition from hyperfiltration to rapid glomerular filtration rate decline in youth-onset T2DM. CONCLUSIONS: Lower estimated insulin sensitivity was associated with risk for hyperfiltration over time, whereas increased albumin excretion was associated with hyperglycemia in youth-onset T2DM.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Nefropatias Diabéticas/sangue , Resistência à Insulina/fisiologia , Inquéritos Nutricionais , Adolescente , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/etiologia , Progressão da Doença , Seguimentos , Taxa de Filtração Glomerular , Hemoglobina A Glicada/metabolismo , Humanos , Morbidade/tendências , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida/tendências , Fatores de Tempo , Estados Unidos
18.
J Clin Endocrinol Metab ; 103(2): 546-554, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29220530

RESUMO

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.


Assuntos
Metabolismo dos Lipídeos/fisiologia , Lipólise/fisiologia , Obesidade Pediátrica/complicações , Obesidade Pediátrica/metabolismo , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/metabolismo , Gordura Abdominal/metabolismo , Gordura Abdominal/patologia , Adolescente , Composição Corporal , Estudos de Casos e Controles , Criança , Feminino , Humanos , Resistência à Insulina/fisiologia , Oxirredução
19.
Diabetes ; 67(3): 496-506, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29229615

RESUMO

In vivo studies have investigated the role of ß-cell dysfunction in type 2 diabetes (T2D), whereas in vitro research on islets has elucidated key mechanisms that control the insulin secretion rate. However, the relevance of the cellular mechanisms identified in vitro (i.e., the triggering and amplifying pathways) has not been established in vivo. Furthermore, the mechanisms underpinning ß-cell dysfunction in T2D remain undetermined. We propose a unifying explanation of several characteristic features of insulin secretion both in vitro and in vivo by using a mathematical model. The model describes the triggering and amplifying pathways and reproduces a variety of in vitro and in vivo tests in subjects with and without T2D, identifies the mechanisms modulating first-phase insulin secretion rate in response to basal hyperglycemia or insulin resistance, and shows that ß-cell dysfunction in T2D can be explained by an impaired amplifying pathway with no need to postulate defects in intracellular calcium handling.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Regulação para Baixo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Modelos Biológicos , Via Secretória , Animais , Glicemia/metabolismo , Sinalização do Cálcio , Simulação por Computador , Diabetes Mellitus Tipo 2/sangue , Exocitose , Glucose/metabolismo , Humanos , Resistência à Insulina , Secreção de Insulina , Camundongos , Reprodutibilidade dos Testes , Taxa Secretória , Vesículas Secretórias/metabolismo , Especificidade da Espécie , Técnicas de Cultura de Tecidos
20.
Diabetes ; 66(12): 3085-3090, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28887312

RESUMO

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.


Assuntos
Tecido Adiposo/metabolismo , Intolerância à Glucose/metabolismo , Resistência à Insulina , Células Secretoras de Insulina/fisiologia , Lipólise , Obesidade/metabolismo , Adolescente , Feminino , Glucose/metabolismo , Humanos , Masculino
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