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Ha J, Kim JY, Springer M, Chhabra A, Chung ST, Sumner AE, Sherman AS, Arslanian S. A Mathematical Model-Derived Disposition Index Without Insulin Validated in Youth With Obesity. J Clin Endocrinol Metab 2025; 110:706-714. [PMID: 39172553 PMCID: PMC11834730 DOI: 10.1210/clinem/dgae582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 07/29/2024] [Accepted: 08/20/2024] [Indexed: 08/24/2024]
Abstract
CONTEXT The gold-standard clamp measurements for insulin sensitivity (cSI), β-cell function (cBCF), and disposition index (cDI = cSI × cBCF) are not practical in large-scale studies. OBJECTIVE We sought to 1) validate a mathematical model-derived DI from oral glucose tolerance tests (OGTT) with insulin (mDI) and without (mDI-woI) against cDI and oral disposition index (oDI) and 2) evaluate the ability of the novel indices to detect prediabetes and type 2 diabetes (T2D). METHODS We carried out a secondary analysis of previously reported cross-sectional observational studies. The Insulin Sensitivity and Secretion mathematical model for glucose-insulin dynamics was applied to 5-point and 3-point OGTTs synchronized with hyperinsulinemic-euglycemic and hyperglycemic clamps from 130 youth with obesity (68 normal glucose tolerance [NGT], 33 impaired glucose tolerance [IGT], 29 T2D). RESULTS Model-derived DI correlated well with clamp DI (R = 0.76 [logged]). Between NGT and IGT, mDI and mDI-woI decreased more than oDI and cDI, (60% and 59% vs 29% and 27%), and by receiver operating characteristic analysis were superior at detecting IGT compared with oDI and cDI (area under the curve [AUC] 0.88-0.87 vs 0.68-0.65), as was mean glucose (AUC 0.87). CONCLUSION mDI-woI is better than oDI or the labor-intensive cDI for detecting dysglycemia in obese youth. Bypassing insulin measurements with mDI-woI from the OGTT provides a cost-effective approach for large-scale epidemiological studies of dysglycemia in youth.
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Affiliation(s)
- Joon Ha
- Department of Mathematics, Howard University, Washington, DC 20059, USA
| | - Joon Young Kim
- Department of Exercise Science, David B. Falk College of Sport and Human Dynamics, Syracuse University, Syracuse, NY 13244, USA
| | - Max Springer
- Department of Mathematics, University of Maryland, College Park, MD 20742, USA
| | - Aaryan Chhabra
- Department of Biology, Indian Institute of Science Education and Research, Pune, Maharashtra 411008, India
| | - Stephanie T Chung
- Section on Pediatric Diabetes, Obesity, and Metabolism, NIDDK, NIH, Bethesda, MD 20892, USA
| | - Anne E Sumner
- Intramural Research Program, National Institute on Minority Health and Health Disparities (NIMHD), National Institutes of Health, Bethesda, MD 20892, USA
- Section on Ethnicity and Health, Diabetes Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD 20892, USA
- Hypertension in Africa Research Team, North-West University, Potchefstroom, North-West 2520, South Africa
| | - Arthur S Sherman
- Laboratory of Biological Modeling, NIDDK, NIH, Bethesda, MD 20892, USA
| | - Silva Arslanian
- Center for Pediatric Research in Obesity and Metabolism, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
- Division of Pediatric Endocrinology and Metabolism, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
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Bacha F, Hannon TS, Tosur M, Pike JM, Butler A, Tommerdahl KL, Zeitler PS. Pathophysiology and Treatment of Prediabetes and Type 2 Diabetes in Youth. Diabetes Care 2024; 47:2038-2049. [PMID: 39250166 PMCID: PMC11655414 DOI: 10.2337/dci24-0029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 07/20/2024] [Indexed: 09/10/2024]
Abstract
Youth-onset type 2 diabetes is a heterogeneous disease with increasing prevalence in relation to increased rates of obesity in children. It has genetic, epigenetic, social, and environmental determinants. Youth-onset type 2 diabetes is alarming given a rapidly progressive course compared with the course of adult-onset disease, early-onset vascular complications, and long-term exposure to hyperglycemia and associated complications. It is often preceded by prediabetes, a disease phase where defects in β-cell function relative to insulin sensitivity emerge. Herein, we review the current understanding of the pathophysiology of prediabetes and type 2 diabetes in youth. We describe the mechanisms underlying insulin resistance, the precipitous decline of β-cell function, and the role of other hormonal abnormalities in the pathogenesis of the disease. We discuss the critical importance of social determinants of health in the predisposition and progression of these conditions and present current management strategies and the advances in therapeutic approaches. These must adapt to meet the unique needs of the individual patient and family. Significant knowledge gaps remain that need to be addressed in future research.
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Affiliation(s)
- Fida Bacha
- USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX
- Division of Diabetes and Endocrinology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX
| | - Tamara S. Hannon
- Division of Pediatric Endocrinology and Diabetology, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN
- Pediatric Accelerator for Careers Engaged in Research, Children’s Health Services Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN
| | - Mustafa Tosur
- USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX
- Division of Diabetes and Endocrinology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX
| | - Julie M. Pike
- Division of Pediatric Endocrinology and Diabetology, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN
- Pediatric Accelerator for Careers Engaged in Research, Children’s Health Services Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN
| | - Ashley Butler
- Division of Psychology, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX
| | - Kalie L. Tommerdahl
- Section of Endocrinology, Department of Pediatrics, Children’s Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, CO
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO
- Ludeman Family Center for Women’s Health Research, Division of General Internal Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Philip S. Zeitler
- Section of Endocrinology, Department of Pediatrics, Children’s Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, CO
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Bacha F. Are Prediction Models Moving Closer to Clinical Application in the Diagnosis of Type of Diabetes in Youth? Diabetes Care 2024; 47:2102-2103. [PMID: 39602593 DOI: 10.2337/dci24-0006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 03/09/2024] [Indexed: 11/29/2024]
Affiliation(s)
- Fida Bacha
- USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX
- Division of Diabetes and Endocrinology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX
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Abu-Nejem R, Hannon TS. Insulin Dynamics and Pathophysiology in Youth-Onset Type 2 Diabetes. J Clin Endocrinol Metab 2024; 109:2411-2421. [PMID: 38963882 DOI: 10.1210/clinem/dgae463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 06/28/2024] [Accepted: 07/03/2024] [Indexed: 07/06/2024]
Abstract
Youth-onset type 2 diabetes (T2D) is increasing around the globe. The mounting disease burden of youth-onset T2D portends substantial consequences for the health outcomes of young people and for health care systems. The pathophysiology of this condition is characterized by insulin resistance and initial insulin hypersecretion ± an inherent insulin secretory defect, with progressive loss of stimulated insulin secretion leading to pancreatic β-cell failure. Research studies focusing on youth-onset T2D have illuminated key differences for youth- vs adult-onset T2D, with youth having more profound insulin resistance and quicker progression to loss of sufficient insulin secretion to maintain euglycemia. There is a need for therapies that are targeted to improve both insulin resistance and, importantly, maintain sufficient insulin secretory function over the lifespan in youth-onset T2D.
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Affiliation(s)
- Rozan Abu-Nejem
- Department of Pediatrics, Divisions of Pediatric Endocrinology and Diabetology and Pediatric Health Services Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Tamara S Hannon
- Department of Pediatrics, Divisions of Pediatric Endocrinology and Diabetology and Pediatric Health Services Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Gupta A, Choudhary N, Gupta N. Prediabetes in children and adolescents: A ticking bomb! World J Clin Pediatr 2024; 13:92127. [PMID: 38947990 PMCID: PMC11212763 DOI: 10.5409/wjcp.v13.i2.92127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 02/12/2024] [Accepted: 04/25/2024] [Indexed: 06/07/2024] Open
Abstract
Prediabetes in children and adolescents is on the rise which has drawn significant attention over the past decade. It is an early warning sign of the underlying pathophysiological changes which in due course of time might compound into type II diabetes mellitus. The incidence of prediabetes in adolescents ranges from 4%-23% which is alarmingly high and requires active intervention from the system. We have discussed early identification of high-risk patients, prompt screening and active intervention to manage this growing problem.
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Affiliation(s)
- Anju Gupta
- Department of Anesthesiology, Pain Medicine and Critical Care, All India Institute of Medical Science, New Delhi 110076, India
| | - Nitin Choudhary
- Department of Anesthesiology, Pain Medicine and Critical Care, All India Institute of Medical Science, New Delhi 110076, India
| | - Nishkarsh Gupta
- Department of Onco-Anesthesiology and Palliative Medicine, All India Institute of Medical Science, New Delhi 110029, India
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Ha J, Chung ST, Springer M, Kim JY, Chen P, Chhabra A, Cree MG, Diniz Behn C, Sumner AE, Arslanian SA, Sherman AS. Estimating insulin sensitivity and β-cell function from the oral glucose tolerance test: validation of a new insulin sensitivity and secretion (ISS) model. Am J Physiol Endocrinol Metab 2024; 326:E454-E471. [PMID: 38054972 PMCID: PMC11639675 DOI: 10.1152/ajpendo.00189.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 11/27/2023] [Accepted: 11/27/2023] [Indexed: 12/07/2023]
Abstract
Efficient and accurate methods to estimate insulin sensitivity (SI) and β-cell function (BCF) are of great importance for studying the pathogenesis and treatment effectiveness of type 2 diabetes (T2D). Existing methods range in sensitivity, input data, and technical requirements. Oral glucose tolerance tests (OGTTs) are preferred because they are simpler and more physiological than intravenous methods. However, current analytical methods for OGTT-derived SI and BCF also range in complexity; the oral minimal models require mathematical expertise for deconvolution and fitting differential equations, and simple algebraic surrogate indices (e.g., Matsuda index, insulinogenic index) may produce unphysiological values. We developed a new insulin secretion and sensitivity (ISS) model for clinical research that provides precise and accurate estimates of SI and BCF from a standard OGTT, focusing on effectiveness, ease of implementation, and pragmatism. This model was developed by fitting a pair of differential equations to glucose and insulin without need of deconvolution or C-peptide data. This model is derived from a published model for longitudinal simulation of T2D progression that represents glucose-insulin homeostasis, including postchallenge suppression of hepatic glucose production and first- and second-phase insulin secretion. The ISS model was evaluated in three diverse cohorts across the lifespan. The new model had a strong correlation with gold-standard estimates from intravenous glucose tolerance tests and insulin clamps. The ISS model has broad applicability among diverse populations because it balances performance, fidelity, and complexity to provide a reliable phenotype of T2D risk.NEW & NOTEWORTHY The pathogenesis of type 2 diabetes (T2D) is determined by a balance between insulin sensitivity (SI) and β-cell function (BCF), which can be determined by gold standard direct measurements or estimated by fitting differential equation models to oral glucose tolerance tests (OGTTs). We propose and validate a new differential equation model that is simpler to use than current models and requires less data while maintaining good correlation and agreement with gold standards. Matlab and Python code is freely available.
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Affiliation(s)
- Joon Ha
- Department of Mathematics, Howard University, Washington, District of Columbia, United States
| | - Stephanie T Chung
- Section on Pediatric Diabetes, Obesity, and Metabolism, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States
| | - Max Springer
- Department of Mathematics, University of Maryland, College Park, Maryland, United States
| | - Joon Young Kim
- Department of Exercise Science, David B. Falk College of Sport and Human Dynamics, Syracuse University, Syracuse, New York, United States
| | | | - Aaryan Chhabra
- Department of Biology, Indian Institute of Science Education and Research, Pune, India
| | - Melanie G Cree
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Cecilia Diniz Behn
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Department of Applied Mathematics and Statistics, Colorado School of Mines, Golden, Colorado, United States
| | - Anne E Sumner
- Intramural Research Program, National Institute on Minority Health and Health Disparities (NIMHD), National Institutes of Health, Bethesda, Maryland, United States
- Section on Ethnicity and Health, Diabetes Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, Maryland, United States
- Hypertension in Africa Research Team, North-West University, Potchefstroom, South Africa
| | - Silva A Arslanian
- Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, Center for Pediatric Research in Obesity and Metabolism, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States
| | - Arthur S Sherman
- Laboratory of Biological Modeling, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States
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Li YQ, Zhang LY, Zhao YC, Xu F, Hu ZY, Wu QH, Li WH, Li YN. Vascular endothelial growth factor B improves impaired glucose tolerance through insulin-mediated inhibition of glucagon secretion. World J Diabetes 2023; 14:1643-1658. [DOI: 10.4239/wjd.v14.i11.1643] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 07/11/2023] [Accepted: 09/06/2023] [Indexed: 11/14/2023] Open
Abstract
BACKGROUND Impaired glucose tolerance (IGT) is a homeostatic state between euglycemia and hyperglycemia and is considered an early high-risk state of diabetes. When IGT occurs, insulin sensitivity decreases, causing a reduction in insulin secretion and an increase in glucagon secretion. Recently, vascular endothelial growth factor B (VEGFB) has been demonstrated to play a positive role in improving glucose metabolism and insulin sensitivity. Therefore, we constructed a mouse model of IGT through high-fat diet feeding and speculated that VEGFB can regulate hyperglycemia in IGT by influencing insulin-mediated glucagon secretion, thus contributing to the prevention and cure of prediabetes.
AIM To explore the potential molecular mechanism and regulatory effects of VEGFB on insulin-mediated glucagon in mice with IGT.
METHODS We conducted in vivo experiments through systematic VEGFB knockout and pancreatic-specific VEGFB overexpression. Insulin and glucagon secretions were detected via enzyme-linked immunosorbent assay, and the protein expression of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) was determined using western blot. Further, mRNA expression of forkhead box protein O1, phosphoenolpyruvate carboxykinase, and glucose-6 phosphatase was detected via quantitative polymerase chain reaction, and the correlation between the expression of proteins was analyzed via bioinformatics.
RESULTS In mice with IGT and VEGFB knockout, glucagon secretion increased, and the protein expression of PI3K/AKT decreased dramatically. Further, in mice with VEGFB overexpression, glucagon levels declined, with the activation of the PI3K/AKT signaling pathway.
CONCLUSION VEGFB/vascular endothelial growth factor receptor 1 can promote insulin-mediated glucagon secretion by activating the PI3K/AKT signaling pathway to regulate glucose metabolism disorders in mice with IGT.
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Affiliation(s)
- Yu-Qi Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Lu-Yang Zhang
- Department of Rheumatology and Immunology, Yantaishan Hospital, Yantai 264000, Shandong Province, China
| | - Yu-Chi Zhao
- Department of Surgery, Yantaishan Hospital, Yantai 264000, Shandong Province, China
| | - Fang Xu
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Zhi-Yong Hu
- School of Public Health and Management, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Qi-Hao Wu
- The First School of Clinical Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Wen-Hao Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Ya-Nuo Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
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Ha J, Chung ST, Springer M, Kim JY, Chen P, Cree MG, Behn CD, Sumner AE, Arslanian S, Sherman AS. Estimating Insulin Sensitivity and Beta-Cell Function from the Oral Glucose Tolerance Test: Validation of a new Insulin Sensitivity and Secretion (ISS) Model. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.16.545377. [PMID: 37503271 PMCID: PMC10370185 DOI: 10.1101/2023.06.16.545377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
Efficient and accurate methods to estimate insulin sensitivity (SI) and beta-cell function (BCF) are of great importance for studying the pathogenesis and treatment effectiveness of type 2 diabetes. Many methods exist, ranging in input data and technical requirements. Oral glucose tolerance tests (OGTTs) are preferred because they are simpler and more physiological. However, current analytical methods for OGTT-derived SI and BCF also range in complexity; the oral minimal models require mathematical expertise for deconvolution and fitting differential equations, and simple algebraic models (e.g., Matsuda index, insulinogenic index) may produce unphysiological values. We developed a new ISS (Insulin Secretion and Sensitivity) model for clinical research that provides precise and accurate estimates of SI and BCF from a standard OGTT, focusing on effectiveness, ease of implementation, and pragmatism. The model was developed by fitting a pair of differential equations to glucose and insulin without need of deconvolution or C-peptide data. The model is derived from a published model for longitudinal simulation of T2D progression that represents glucose-insulin homeostasis, including post-challenge suppression of hepatic glucose production and first- and second-phase insulin secretion. The ISS model was evaluated in three diverse cohorts including individuals at high risk of prediabetes (adult women with a wide range of BMI and adolescents with obesity). The new model had strong correlation with gold-standard estimates from intravenous glucose tolerance tests and hyperinsulinemic-euglycemic clamp. The ISS model has broad clinical applicability among diverse populations because it balances performance, fidelity, and complexity to provide a reliable phenotype of T2D risk.
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Affiliation(s)
- Joon Ha
- Department of Mathematics, Howard University, Washington, DC
| | - Stephanie T. Chung
- Section on Pediatric Diabetes, Obesity, and Metabolism, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Max Springer
- Department of Mathematics, University of Maryland, College Park, MD
| | - Joon Young Kim
- Department of Exercise Science, David B. Falk College of Sport and Human Dynamics, Syracuse University, Syracuse, NY
| | | | - Melanie G. Cree
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Cecilia Diniz Behn
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO
- Department of Applied Mathematics and Statistics, Colorado School of Mines, Golden, Colorado
| | - Anne E. Sumner
- Intramural Research Program, National Institute on Minority Health and Health Disparities (NIMHD), National Institutes of Health, Bethesda, MD
- Section on Ethnicity and Health, Diabetes Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD
| | - Silva Arslanian
- Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, Center for Pediatric Research in Obesity and Metabolism, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA
| | - Arthur S. Sherman
- Laboratory of Biological Modeling, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD
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Vidmar AP, Durazo-Arvizu R, Weigensberg MJ, Alderete TL, Goran MI. Rapid Decline in β-Cell Function and Increasing Adiposity Are Associated With Conversion to Type 2 Diabetes in At-Risk Latino Youth. Diabetes 2023; 72:735-745. [PMID: 36972018 PMCID: PMC10202769 DOI: 10.2337/db22-1034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 03/22/2023] [Indexed: 04/16/2023]
Abstract
Youth-onset type 2 diabetes (T2D) is becoming increasingly prevalent, especially among Latino youth, and there is limited information on its pathophysiology and causative factors. Here, we describe findings from a longitudinal cohort study in 262 Latino children with overweight/obesity at risk of developing T2D with annual measures of oral and intravenous glucose tolerance (IVGTT), body composition, and fat distribution. Logistic binomial regression was used to identify significant predictors in those who developed T2D compared with matched control participants, and mixed-effects growth models were used to compare rates of change in metabolic versus adiposity measures between groups. Overall conversion rate to T2D at year 5 was 2% (n = 6). Rate of decline in disposition index (DI), measured with an IVGTT, over 5 years was three times higher in case patients (-341.7 units per year) compared with the extended cohort (-106.7 units per year) and 20 times higher compared with control participants (-15.2 units per year). Case patients had significantly higher annual increases in fasting glucose, hemoglobin A1c (HbA1c), waist circumference, and trunk fat, and there was an inverse correlation between rate of decline in DI and rates of increase in adiposity measures. T2D development in at-risk Latino youth is associated with a substantial and rapid decrease in DI that is directly correlated with increases in fasting glucose, HbA1c, and adiposity. ARTICLE HIGHLIGHTS Youth-onset type 2 diabetes is becoming increasingly prevalent, especially among Latino youth, and there is limited information on its pathophysiology and causative factors. Overall conversion rate to type 2 diabetes over 5 years was 2%. In youth who converted to type 2 diabetes, disposition index decreased rapidly by 85% compared with that in patients who did not convert during the study period. There was an inverse correlation between rate of decline in disposition index and rates of increase in various adiposity measures.
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Affiliation(s)
- Alaina P. Vidmar
- Division of Endocrinology, Department of Pediatrics, Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA
- Department of Pediatrics, Keck School of Medicine, Los Angeles, CA
| | - Ramon Durazo-Arvizu
- Southern California Clinical and Translational Science Institute Biostatistics Core, The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA
| | - Marc J. Weigensberg
- Department of Pediatrics, University of Southern California, Los Angeles, CA
| | - Tanya L. Alderete
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO
| | - Michael I. Goran
- Division of Endocrinology, Department of Pediatrics, Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA
- Department of Pediatrics, Keck School of Medicine, Los Angeles, CA
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Serbis A, Giapros V, Tsamis K, Balomenou F, Galli-Tsinopoulou A, Siomou E. Beta Cell Dysfunction in Youth- and Adult-Onset Type 2 Diabetes: An Extensive Narrative Review with a Special Focus on the Role of Nutrients. Nutrients 2023; 15:2217. [PMID: 37432389 PMCID: PMC10180650 DOI: 10.3390/nu15092217] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 05/04/2023] [Accepted: 05/06/2023] [Indexed: 07/12/2023] Open
Abstract
Traditionally a disease of adults, type 2 diabetes (T2D) has been increasingly diagnosed in youth, particularly among adolescents and young adults of minority ethnic groups. Especially, during the recent COVID-19 pandemic, obesity and prediabetes have surged not only in minority ethnic groups but also in the general population, further raising T2D risk. Regarding its pathogenesis, a gradually increasing insulin resistance due to central adiposity combined with a progressively defective β-cell function are the main culprits. Especially in youth-onset T2D, a rapid β-cell activity decline has been observed, leading to higher treatment failure rates, and early complications. In addition, it is well established that both the quantity and quality of food ingested by individuals play a key role in T2D pathogenesis. A chronic imbalance between caloric intake and expenditure together with impaired micronutrient intake can lead to obesity and insulin resistance on one hand, and β-cell failure and defective insulin production on the other. This review summarizes our evolving understanding of the pathophysiological mechanisms involved in defective insulin secretion by the pancreatic islets in youth- and adult-onset T2D and, further, of the role various micronutrients play in these pathomechanisms. This knowledge is essential if we are to curtail the serious long-term complications of T2D both in pediatric and adult populations.
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Affiliation(s)
- Anastasios Serbis
- Department of Pediatrics, School of Medicine, University of Ioannina, St. Niarhcos Avenue, 45500 Ioannina, Greece;
| | - Vasileios Giapros
- Neonatal Intensive Care Unit, School of Medicine, University of Ioannina, St. Νiarhcos Avenue, 45500 Ioannina, Greece (F.B.)
| | - Konstantinos Tsamis
- Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, St. Niarhcos Avenue, 45500 Ioannina, Greece
| | - Foteini Balomenou
- Neonatal Intensive Care Unit, School of Medicine, University of Ioannina, St. Νiarhcos Avenue, 45500 Ioannina, Greece (F.B.)
| | - Assimina Galli-Tsinopoulou
- Second Department of Pediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University Hospital, Stilponos Kyriakidi 1, 54636 Thessaloniki, Greece;
| | - Ekaterini Siomou
- Department of Pediatrics, School of Medicine, University of Ioannina, St. Niarhcos Avenue, 45500 Ioannina, Greece;
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Cioana M, Deng J, Nadarajah A, Hou M, Qiu Y, Chen SSJ, Rivas A, Banfield L, Toor PP, Zhou F, Guven A, Alfaraidi H, Alotaibi A, Thabane L, Samaan MC. The Prevalence of Obesity Among Children With Type 2 Diabetes: A Systematic Review and Meta-analysis. JAMA Netw Open 2022; 5:e2247186. [PMID: 36520430 PMCID: PMC9856349 DOI: 10.1001/jamanetworkopen.2022.47186] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 10/30/2022] [Indexed: 12/16/2022] Open
Abstract
Importance The childhood obesity epidemic is presumed to drive pediatric type 2 diabetes (T2D); however, the global scale of obesity in children with T2D is unknown. Objectives To evaluate the global prevalence of obesity in pediatric T2D, examine the association of sex and race with obesity risk, and assess the association of obesity with glycemic control and dyslipidemia. Data Sources MEDLINE, Embase, CINAHL, Cochrane Library, and Web of Science were searched from database inception to June 16, 2022. Study Selection Observational studies with at least 10 participants reporting the prevalence of obesity in patients with pediatric T2D were included. Data Extraction and Synthesis Following the Meta-analysis of Observational Studies in Epidemiology reporting guideline, 2 independent reviewers in teams performed data extraction and risk of bias and level of evidence analyses. The meta-analysis was conducted using a random-effects model. Main Outcomes and Measures The primary outcomes included the pooled prevalence rates of obesity in children with T2D. The secondary outcomes assessed pooled prevalence rates by sex and race and associations between obesity and glycemic control and dyslipidemia. Results Of 57 articles included in the systematic review, 53 articles, with 8942 participants, were included in the meta-analysis. The overall prevalence of obesity among pediatric patients with T2D was 75.27% (95% CI, 70.47%-79.78%), and the prevalence of obesity at diabetes diagnosis among 4688 participants was 77.24% (95% CI, 70.55%-83.34%). While male participants had higher odds of obesity than female participants (odds ratio, 2.10; 95% CI, 1.33-3.31), Asian participants had the lowest prevalence of obesity (64.50%; 95% CI, 53.28%-74.99%), and White participants had the highest prevalence of obesity (89.86%; 95% CI, 71.50%-99.74%) compared with other racial groups. High heterogeneity across studies and varying degrees of glycemic control and dyslipidemia were noted. Conclusions and Relevance The findings of this systematic review and meta-analysis suggest that obesity is not a universal phenotype in children with T2D. Further studies are needed to consider the role of obesity and other mechanisms in diabetes genesis in this population.
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Affiliation(s)
- Milena Cioana
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
- Division of Pediatric Endocrinology, McMaster Children’s Hospital, Hamilton, Ontario, Canada
| | - Jiawen Deng
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
- Division of Pediatric Endocrinology, McMaster Children’s Hospital, Hamilton, Ontario, Canada
| | - Ajantha Nadarajah
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
- Division of Pediatric Endocrinology, McMaster Children’s Hospital, Hamilton, Ontario, Canada
| | - Maggie Hou
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
- Division of Pediatric Endocrinology, McMaster Children’s Hospital, Hamilton, Ontario, Canada
| | - Yuan Qiu
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
- Division of Pediatric Endocrinology, McMaster Children’s Hospital, Hamilton, Ontario, Canada
- Michael G. De Groote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Sondra Song Jie Chen
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
- Division of Pediatric Endocrinology, McMaster Children’s Hospital, Hamilton, Ontario, Canada
| | - Angelica Rivas
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
- Division of Pediatric Endocrinology, McMaster Children’s Hospital, Hamilton, Ontario, Canada
- Michael G. De Groote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Laura Banfield
- Health Sciences Library, McMaster University, Hamilton, Ontario, Canada
| | - Parm Pal Toor
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
- Division of Pediatric Endocrinology, McMaster Children’s Hospital, Hamilton, Ontario, Canada
| | - Fangwen Zhou
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
- Division of Pediatric Endocrinology, McMaster Children’s Hospital, Hamilton, Ontario, Canada
| | - Ayla Guven
- Health Science University, Zeynep Kamil Maternity and Children Hospital, Pediatric Endocrinology Clinic, Istanbul, Turkey
| | - Haifa Alfaraidi
- College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Division of Endocrinology, Department of Pediatrics, Ministry of the National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Ahlam Alotaibi
- Division of Pediatric Endocrinology, Department of Pediatrics, King Abdullah bin Abdulaziz University Hospital, Princess Noura University, Riyadh, Saudi Arabia
| | - Lehana Thabane
- Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada
- Department of Anesthesia, McMaster University, Hamilton, Ontario, Canada
- Centre for Evaluation of Medicines, St Joseph’s Healthcare, Hamilton, Ontario, Canada
- Biostatistics Unit, St Joseph’s Healthcare, Hamilton, Ontario, Canada
| | - M. Constantine Samaan
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
- Division of Pediatric Endocrinology, McMaster Children’s Hospital, Hamilton, Ontario, Canada
- Michael G. De Groote School of Medicine, McMaster University, Hamilton, Ontario, Canada
- Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada
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12
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Stevens P, Hunter J, Molodysky E. The role of hyperinsulinaemia in screening for prediabetes in the adolescent population: A systematic literature review. Diabetes Metab Syndr 2022; 16:102445. [PMID: 35305511 DOI: 10.1016/j.dsx.2022.102445] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 02/22/2022] [Accepted: 02/24/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND/AIMS Present screening methods for Type 2 diabetes (T2DM) fall short of detecting prediabetes. This paper summarises the literature on the utility of insulin measurements (hyperinsulinemia) in detecting prediabetes in adolescents. METHODS A systematic literature review was conducted using EMBASE and Medline. Relevant data on hyperinsulinemia in the adolescent population is narrated. RESULTS The database search identified 174 potential articles; 106 underwent a full-paper review, and 36 were included. CONCLUSION Elevated fasting insulin is a marker of impaired insulin resistance and pending beta-cell dysfunction in at-risk adolescents and can be an early indicator of prediabetes.
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13
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Rosenberg J, Jacob J, Desai P, Park J, Donovan L, Kim JY. Incretin Hormones: Pathophysiological Risk Factors and Potential Targets for Type 2 Diabetes. J Obes Metab Syndr 2021; 30:233-247. [PMID: 34521773 PMCID: PMC8526293 DOI: 10.7570/jomes21053] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 07/11/2021] [Accepted: 07/14/2021] [Indexed: 02/06/2023] Open
Abstract
Type 2 diabetes (T2D) is a multifaceted metabolic disorder associated with distinctive pathophysiological disturbances. One of the pathophysiological risk factors observed in T2D is dysregulation of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Both hormones stimulate insulin secretion by acting postprandially on pancreatic β-cell receptors. Oral glucose administration stimulates increased insulin secretion in comparison with isoglycemic intravenous glucose administration, a phenomenon known as the incretin effect. While the evidence for incretin defects in individuals with T2D is growing, the etiology behind this attenuated incretin effect in T2D is not clearly understood. Given their central role in T2D pathophysiology, incretins are promising targets for T2D therapeutics. The present review synthesizes the recent attempts to explain the biological importance of incretin hormones and explore potential pharmacological approaches that target the incretins.
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Affiliation(s)
- Jared Rosenberg
- Department of Exercise Science, David B. Falk College of Sport and Human Dynamics, Syracuse University, Syracuse, NY, USA
| | - Jordan Jacob
- Department of Exercise Science, David B. Falk College of Sport and Human Dynamics, Syracuse University, Syracuse, NY, USA
| | - Priya Desai
- Department of Exercise Science, David B. Falk College of Sport and Human Dynamics, Syracuse University, Syracuse, NY, USA
| | - Jeremy Park
- Department of Exercise Science, David B. Falk College of Sport and Human Dynamics, Syracuse University, Syracuse, NY, USA
| | - Lorin Donovan
- Department of Exercise Science, David B. Falk College of Sport and Human Dynamics, Syracuse University, Syracuse, NY, USA
| | - Joon Young Kim
- Department of Exercise Science, David B. Falk College of Sport and Human Dynamics, Syracuse University, Syracuse, NY, USA
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14
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Kim JY, Tfayli H, Bacha F, Arslanian S. The Shape of the Oral Glucose Tolerance Test-Glucose Response Curve in Islet Cell Antibody-Positive vs. -Negative Obese Youth Clinically Diagnosed with Type 2 Diabetes. J Obes Metab Syndr 2021; 30:178-183. [PMID: 34059560 PMCID: PMC8277592 DOI: 10.7570/jomes20088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 03/17/2021] [Accepted: 03/26/2021] [Indexed: 11/02/2022] Open
Abstract
Background The oral glucose tolerance test (OGTT)-glucose response curves (GRCs; incessant increase, monophasic, and biphasic) reflect insulin sensitivity and β-cell function, being worse in the former and superior in the latter. Here, we examined if the OGTT-GRC pattern is worse in obese antibody (glutamic acid decarboxylase 65-kDa [GAD65] and insulinoma-associated protein-2 [IA-2])-positive (Ab+) vs. -negative (Ab-) youth clinically diagnosed with type 2 diabetes (CDX-T2D). Methods Forty-seven obese youth, 15 Ab+ and 32 Ab-, were divided into three OGTT-GRC groups: incessant increase, monophasic, and biphasic. The prevalence of OGTT-GRC, clamp-measured insulin sensitivity, and β-cell function was compared. Results Incessant increase OGTT-GRC is the most frequent curve type and is three-fold higher in Ab+ vs. Ab- youth CDX-T2D. In Ab+ youth, there was up to 40% lower second-phase insulin secretion in the incessant increase group vs. the other two groups combined (monophasic and biphasic). In Ab- youth, while first- and second-phase insulin secretion was significantly lower in the incessant increase vs. the other two groups combined, overall β-cell function was less impaired than in Ab+ youth. In neither Ab- or Ab+ youth was OGTT-GRC related to hepatic or peripheral insulin sensitivity. Conclusion Severe insulin deficiency, a characteristic of type 1 diabetes, seems to be related to higher prevalence of incessant increase in Ab+ vs. Ab- obese youth.
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Affiliation(s)
- Joon Young Kim
- Department of Exercise Science, David B. Falk College of Sport and Human Dynamics, Syracuse University, Syracuse, New York, NY, USA
| | - Hala Tfayli
- Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Fida Bacha
- Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA
| | - Silva Arslanian
- Center for Pediatric Research in Obesity and Metabolism, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.,Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
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15
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Esquivel Zuniga R, DeBoer MD. Prediabetes in Adolescents: Prevalence, Management and Diabetes Prevention Strategies. Diabetes Metab Syndr Obes 2021; 14:4609-4619. [PMID: 34858039 PMCID: PMC8629936 DOI: 10.2147/dmso.s284401] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Accepted: 11/03/2021] [Indexed: 12/16/2022] Open
Abstract
The ongoing obesity epidemic in children and adolescents has greatly increased the prevalence of related comorbidities. Prediabetes is defined based on levels of fasting glucose, oral glucose tolerance tests or hemoglobin A1c, that are intermediate between normal levels and thresholds that define type 2 diabetes mellitus (T2DM). As such, prediabetes represents a sign of early pathophysiology preceding T2DM development. Recent analyses of data from US adolescents estimate prediabetes to be present in 4-23% of adolescents, depending on criteria used, with other studies finding an 8% risk of progression from prediabetes to T2DM over a 3-year period. These data support the importance of intervention to avoid long-term sequelae, focusing on reducing degree of obesity and insulin resistance. Lifestyle modification, with increases in physical activity and dietary improvements, remains the first-line approach. Other interventions are based on additional long-term risks and range from metformin treatment for more moderate cases of prediabetes to bariatric surgery for adolescents with severe obesity and comorbidities. As data accumulate regarding sequelae of T2DM in adolescents, there remains a critical need for prevention of obesity and T2DM throughout childhood, and prediabetes should be a trigger for improving this risk profile.
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Affiliation(s)
- Rebeca Esquivel Zuniga
- Division of Pediatric Endocrinology, Department of Pediatrics, University of Virginia, Charlottesville, VA, USA
| | - Mark D DeBoer
- Division of Pediatric Endocrinology, Department of Pediatrics, University of Virginia, Charlottesville, VA, USA
- Correspondence: Mark D DeBoer Division of Pediatric Endocrinology, University of Virginia, PO Box 800386, Charlottesville, VA, 22903, USATel +1 434-924-5956Fax +1 434-924-9181 Email
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16
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Savic Hitt TA, Katz LEL. Pediatric Type 2 Diabetes: Not a Mini Version of Adult Type 2 Diabetes. Endocrinol Metab Clin North Am 2020; 49:679-693. [PMID: 33153674 PMCID: PMC7772966 DOI: 10.1016/j.ecl.2020.08.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Pediatric type 2 diabetes mellitus (T2DM) is increasing in incidence, with risk factors including obesity, puberty, family history of T2DM in a first-degree or second-degree relative, history of small-for-gestational-age at birth, child of a gestational diabetes pregnancy, minority racial group, and lower socioeconomic status. The pathophysiology of T2DM consists of insulin resistance and progression to pancreatic beta-cell failure, which is more rapid in pediatric T2DM compared with adult T2DM. Treatment options are limited. Treatment failure and nonadherence rates are high in pediatric T2DM; therefore, early diagnosis and treatment and new pharmacologic options and/or effective behavioral interventions are needed.
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Affiliation(s)
- Talia Alyssa Savic Hitt
- Division of Endocrinology & Diabetes, Department of Pediatrics, Children's Hospital of Philadelphia, 3500 Civic Center Boulevard, Buerger Building -12th Floor, Philadelphia, PA 19104, USA.
| | - Lorraine E Levitt Katz
- Division of Endocrinology & Diabetes, Department of Pediatrics, Children's Hospital of Philadelphia, 3500 Civic Center Boulevard, Buerger Building -12th Floor, Philadelphia, PA 19104, USA
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17
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Kim JY, Jeon JY. Role of exercise on insulin sensitivity and beta-cell function: is exercise sufficient for the prevention of youth-onset type 2 diabetes? Ann Pediatr Endocrinol Metab 2020; 25:208-216. [PMID: 33401879 PMCID: PMC7788350 DOI: 10.6065/apem.2040140.070] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 08/19/2020] [Indexed: 12/16/2022] Open
Abstract
Parallel with the current pediatric obesity epidemic, the escalating rates of youthonset type 2 diabetes mellitus (T2DM) have become a major public health burden. Although lifestyle modification can be the first-line prevention for T2DM in youths, there is a lack of evidence to establish optimal specific exercise strategies for obese youths at high risk for T2DM. The purpose of this narrative review is to summarize the potential impact of exercise on 2 key pathophysiological risk factors for T2DM, insulin sensitivity and β-cell function, among obese youths. The studies cited are grouped by use of metabolic tests, i.e., direct and indirect measures of insulin sensitivity and β-cell function. In general, there are an increasing number of studies that demonstrate positive effects of aerobic exercise, resistance exercise, and the 2 combined on insulin sensitivity. However, a lack of evidence exists for the effect of any exercise modality on β-cell functional improvement. We also suggest a future direction for research into exercise medical prevention of youth-onset T2DM. These suggestions focus on the effects of exercise modalities on emerging biomarkers of T2DM risk.
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Affiliation(s)
- Joon Young Kim
- Department of Exercise Science, David B. Falk College of Sport and Human Dynamics, Syracuse University, Syracuse, NY, USA
| | - Justin Y. Jeon
- Department of Sport Industry Studies, Exercise Medicine Center for Diabetes and Cancer Patients, ICONS Yonsei University, Seoul, Korea,Address for correspondence: Justin Y. Jeon, PhD Department of Sport Industry Studies, Exercise Medicine Center for Diabetes and Cancer Patients, ICONS Yonsei University, 50 Yonseiro, Seodaemun-gu, Seoul 03722, Korea Tel: +82-2-2123-6197 E-mail:
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18
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Castorani V, Polidori N, Giannini C, Blasetti A, Chiarelli F. Insulin resistance and type 2 diabetes in children. Ann Pediatr Endocrinol Metab 2020; 25:217-226. [PMID: 33401880 PMCID: PMC7788344 DOI: 10.6065/apem.2040090.045] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 06/05/2020] [Indexed: 12/27/2022] Open
Abstract
Type 2 diabetes (T2D) is an emerging health risk in obese children and adolescents. Both environmental (lack of physical activity, excess nutritional intake, sedentary lifestyle) and genetic factors contribute to this global epidemic. The growing prevalence of T2D in youth is also associated with a consistently increased incidence of metabolic and cardiovascular complications. Insulin resistance (IR), i.e., whole-body decreased glucose uptake in response to physiological insulin levels, determines impaired glucose homeostasis and it is recognized as cardinal trigger of T2D and cardiovascular disease in both adults and children. In particular, IR and beta-cell dysfunction lead to the persistent hyperglycemia which characterizes T2D. Indeed, both pathological states influence each other and presumably play a crucial, synergistic role in the pathogenesis of T2D, although the precise mechanisms are not completely understood. However, beta-cell dysfunction and IR induce impaired glucose metabolism, thus leading to the progression to T2D. Therefore, understanding the mechanisms correlated with the decline of beta-cell function and IR is crucial in order to control, prevent, and treat T2D in youth. This review focuses on the current knowledge regarding IR and T2D in children and adolescents and showcases interesting opportunities and stimulating challenges for the development of new preventative approaches and therapeutic strategies for young patients with T2D.
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Affiliation(s)
| | - Nella Polidori
- Department of Pediatrics, University of Chieti, Chieti, Italy
| | - Cosimo Giannini
- Department of Pediatrics, University of Chieti, Chieti, Italy
| | | | - Francesco Chiarelli
- Department of Pediatrics, University of Chieti, Chieti, Italy,Address for correspondence: Francesco Chiarelli, MD, PhD Department of Pediatrics, University of Chieti, Via dei Vestini, 5, I-66100 Chieti, Italy Tel: +39-0871-358015 Fax: +39-0871-574538 E-mail:
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19
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Kim JY, Tfayli H, Bacha F, Lee S, Gebara N, Arslanian S. β-cell impairment and clinically meaningful alterations in glycemia in obese youth across the glucose tolerance spectrum. Metabolism 2020; 112:154346. [PMID: 32835760 PMCID: PMC7897751 DOI: 10.1016/j.metabol.2020.154346] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 08/13/2020] [Accepted: 08/17/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND/AIMS In obese youth, it is not clear what degree of β-cell impairment translates to glucose dysregulation commensurate with shifts from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to type 2 diabetes. We aimed to investigate the quantitative relationship between β-cell (clamp-measured disposition index [DI]) and OGTT glucose area under the curve (G-AUC) in obese youth across the spectrum of glucose tolerance. METHODS Data from 152 youth (58 African-American [AA] and 94 American-White [AW]; 73 NGT, 48 IGT, and 31 type 2 diabetes) who completed a 3-h hyperinsulinemic (80 mu/m2/min)-euglycemic clamp, and a 2-h hyperglycemic (225 mg/dL) clamp synchronized with a 2-h OGTT were examined. RESULTS In IGT vs. NGT, 36% lower DI corresponded to 27% higher G-AUC; in type 2 diabetes vs. IGT, 65% lower DI related to 25% higher G-AUC, and in type 2 diabetes vs. NGT, 78% lower DI paralleled 59% higher G-AUC. Although AA vs. AW youth had larger decrements in DI, from NGT to IGT and from NGT to type 2 diabetes, they displayed comparable increments in G-AUC. CONCLUSION At least ~35-50% recovery in β-cell function might be needed to have clinically meaningful improvement in G-AUC commensurate with conversion to better glucose tolerance. Mechanism(s) protective against dysglycemia might be operative in AA vs. AW youth despite greater declines in DI. Treatments aiming to improve β-cell function should focus on degree of change in DI commensurate with clinically meaningful changes in glycemia, reflective of restoration of glucose tolerance.
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Affiliation(s)
- Joon Young Kim
- Department of Exercise Science, Syracuse University, Syracuse, NY, United States of America
| | - Hala Tfayli
- Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Fida Bacha
- Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, United States of America
| | - SoJung Lee
- Division of Sports Medicine, Graduate School of Physical Education, Kyung Hee University, Yongin, Republic of Korea
| | - Nour Gebara
- Center for Pediatric Research in Obesity and Metabolism, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, United States of America
| | - Silva Arslanian
- Center for Pediatric Research in Obesity and Metabolism, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, United States of America; Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, United States of America.
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20
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Carreau AM, Xie D, Garcia-Reyes Y, Rahat H, Bartlette K, Diniz Behn C, Pyle L, Nadeau KJ, Cree-Green M. Good agreement between hyperinsulinemic-euglycemic clamp and 2 hours oral minimal model assessed insulin sensitivity in adolescents. Pediatr Diabetes 2020; 21:1159-1168. [PMID: 32592269 PMCID: PMC7762730 DOI: 10.1111/pedi.13072] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 06/09/2020] [Accepted: 06/23/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND/OBJECTIVE Rates of dysglycemia are increasing in youth, secondary to obesity and decreased insulin sensitivity (IS) in puberty. The oral minimal model (OMM) has been developed in order to measure IS using an easy oral glucose load, such as an oral glucose tolerance test (OGTT), instead of an hyperinsulinemic-euglycemic clamp (HE-clamp), a more invasive and time-consuming procedure. However, this model, following a standard 2 hour- OGTT has never been validated in youth, a population known for a different physiologic response to OGTT than adults. Thus, we compared IS measurements obtained from OMM following a 2-hour OGTT to HE-clamp and isotope tracer-assessed tissue IS in adolescents. We also compared the liver/muscle-specific IS from HE-clamp with other liver/muscle-specific IS surrogates following an OGTT previously validated in adults. METHODS Secondary analysis of a cross-sectional study. Adolescent girls with (n = 26) and without (n = 7) polycystic ovary syndrome (PCOS) (14.6 ± 1.7 years; BMI percentile 23.3%-98.2%) underwent a 2-hour 75 g OGTT and a 4-phase HE-clamp. OMM IS (Si), dynamic Si (Sid ) and other OGTT-derived muscle and liver IS indices were correlated with HE-clamp tissue-specific IS. RESULTS OMM Si and Sid correlated with HE-clamp-measured peripheral IS (r = 0.64, P <.0001 and r = 0.73; P <.0001, respectively) and the correlation coefficient trended higher than the Matsuda index (r = 0.59; P =.003). The other tissue-specific indices were poorly correlated with their HE-clamp measurements. CONCLUSION In adolescent girls, the 2-hour OMM provided the best estimate of peripheral IS. Additional surrogates for hepatic IS are needed for youth.
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Affiliation(s)
- Anne-Marie Carreau
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Danielle Xie
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Yesenia Garcia-Reyes
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Haseeb Rahat
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Kai Bartlette
- Department of Applied Mathematics and Statistics, Colorado School of Mines, Golden, Colorado
| | - Cecilia Diniz Behn
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, Colorado,Department of Applied Mathematics and Statistics, Colorado School of Mines, Golden, Colorado
| | - Laura Pyle
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado,Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, Colorado
| | - Kristen J. Nadeau
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, Colorado,Center for Women’s Health Research, Aurora, Colorado
| | - Melanie Cree-Green
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, Colorado,Center for Women’s Health Research, Aurora, Colorado
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21
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Barrett JS, Bucci-Rechtweg C, Amy Cheung SY, Gamalo-Siebers M, Haertter S, Karres J, Marquard J, Mulugeta Y, Ollivier C, Strougo A, Yanoff L, Yao L, Zeitler P. Pediatric Extrapolation in Type 2 Diabetes: Future Implications of a Workshop. Clin Pharmacol Ther 2020; 108:29-39. [PMID: 32017043 PMCID: PMC7383960 DOI: 10.1002/cpt.1805] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 01/27/2020] [Indexed: 12/30/2022]
Abstract
Extrapolation from adults to youth with type 2 diabetes (T2D) is challenged by differences in disease progression and manifestation. This manuscript presents the results of a mock-team workshop focused on examining the typical team-based decision process used to propose a pediatric development plan for T2D addressing the viability of extrapolation. The workshop was held at the American Society for Clinical Pharmacology and Therapeutics (ASCPT) in Orlando, Florida on March 21, 2018.
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Affiliation(s)
- Jeffrey S Barrett
- Quantitative Sciences, Bill & Melinda Gates Medical Research Institute, Cambridge, Massachusetts, USA
| | - Christina Bucci-Rechtweg
- Pediatric & Maternal Health Policy, Regulatory Affairs, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA
| | | | | | - Sebastian Haertter
- Translational Med & Clinical Pharmacology, Boehringer Ingelheim, Biberach, Germany
| | - Janina Karres
- Paediatric Medicines Office, European Medicines Agency, Amsterdam, The Netherlands
| | - Jan Marquard
- Global Clinical Development CardioMetabolism, Boehringer Ingelheim, Ingelheim, Germany
| | - Yeruk Mulugeta
- Division of Pediatric and Maternal Health, Office of New Drugs, Center for Drug Evaluation and Research, Washington, DC, USA
| | | | - Ashley Strougo
- Translational Medicine, Pharmacokinetics, Dynamics and Metabolism, Sanofi, Frankfurt, Germany
| | - Lisa Yanoff
- Division of Metabolism and Endocrinology Products, Office of New Drugs, Center for Drug Evaluation and Research, Washington, DC, USA
| | - Lynne Yao
- Division of Pediatric and Maternal Health, Office of New Drugs, Center for Drug Evaluation and Research, Washington, DC, USA
| | - Philip Zeitler
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA
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22
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Kim JY, Tfayli H, Bacha F, Lee S, Michaliszyn SF, Yousuf S, Gebara N, Arslanian S. β-cell function, incretin response, and insulin sensitivity of glucose and fat metabolism in obese youth: Relationship to OGTT-time-to-glucose-peak. Pediatr Diabetes 2020; 21:18-27. [PMID: 31677208 DOI: 10.1111/pedi.12940] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 10/04/2019] [Accepted: 10/26/2019] [Indexed: 01/12/2023] Open
Abstract
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, β-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 β-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 β-cell function relative to insulin sensitivity. RESULTS Compared with the Early-peak group, the Late-peak group had impaired β-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 β-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.
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Affiliation(s)
- Joon Young Kim
- Department of Exercise Science, Syracuse University, Syracuse, New York
| | - Hala Tfayli
- Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Fida Bacha
- Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas
| | - SoJung Lee
- Division of Sports Medicine, Graduate School of Physical Education, Kyung Hee University, Yongin, Republic of Korea
| | - Sara F Michaliszyn
- Kinesiology and Sport Science, Youngstown State University, Youngstown, Ohio
| | - Shahwar Yousuf
- Center for Pediatric Research in Obesity and Metabolism, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
| | - Nour Gebara
- Center for Pediatric Research in Obesity and Metabolism, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
| | - Silva Arslanian
- Center for Pediatric Research in Obesity and Metabolism, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.,Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
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23
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Valaiyapathi B, Gower B, Ashraf AP. Pathophysiology of Type 2 Diabetes in Children and Adolescents. Curr Diabetes Rev 2020; 16:220-229. [PMID: 29879890 PMCID: PMC7516333 DOI: 10.2174/1573399814666180608074510] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Revised: 05/24/2018] [Accepted: 06/03/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND The prevalence of type 2 diabetes (DM) in children is disturbingly increasing in parallel with the increasing childhood obesity. Better knowledge regarding the pathophysiology of type 2 DM in children is paramount to devise an effective management plan. OBJECTIVE Discuss the pathophysiology of type 2 DM in children and adolescents. METHODS AND RESULTS This is a comprehensive review of the literature on this topic. Type 2 DM in childhood is viewed as a continuum of insulin resistance (IR) which is determined by an underlying genetic predisposition, intrauterine environment, excessive food consumption, continued rapid weight gain, and poor lifestyle. Besides IR, this is compounded by multiple metabolic defects including β-cell dysfunction and inadequate insulin secretion, α-cell dysfunction, hyperglucagonemia and increased hepatic glucose production, lipotoxicity, inflammation, deficiencies in incretin production and action, and increased renal glucose reabsorption. The confluence of genetic and environmental factors underscores the complexity in disease progression. CONCLUSION A consistent single risk factor for type 2 DM is obesity and related IR and therefore it is essential to curtail the progression of obesity. It is important to investigate the role of stringent dietary and nutritional approaches, medications that enhance β-cell function and insulin sensitivity.
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Affiliation(s)
- Badhma Valaiyapathi
- Department of Epidemiology, School of Public Health, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Barbara Gower
- Department of Nutrition Sciences, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Ambika P. Ashraf
- Department of Pediatrics/Division of Pediatric Endocrinology and Metabolism, The University of Alabama at Birmingham, Birmingham, AL, USA
- Address correspondence to this author at the Department Pediatric Endocrinology, The University of Alabama at Birmingham, Birmingham, AL 35233, USA; Tel: 205 638 9107, Fax: 205 638 9821; E-mail:
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24
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Obesity and insulin sensitivity effects on cardiovascular risk factors: Comparisons of obese dysglycemic youth and adults. Pediatr Diabetes 2019; 20:849-860. [PMID: 31301210 PMCID: PMC6786916 DOI: 10.1111/pedi.12883] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 05/01/2019] [Accepted: 06/03/2019] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND Obesity and pubertal insulin resistance worsen cardiovascular (CV) risk factors in youth. It is unclear how the relationships of obesity and insulin resistance with CV risk compare to adults. SUBJECTS AND METHODS We evaluated 66 pubertal youth (mean ± SD: age 14.2 ± 2.0 years, body mass index [BMI] 36.6 ± 6.0 kg/m2 , hemoglobin A1c [HbA1c] 38.5 ± 6.1 mmol/mol) and 355 adults with comparable BMI (age 52.7 ± 9.4 years, BMI 35.1 ± 5.1 kg/m2 , HbA1c 39.8 ± 4.2 mmol/mol) participating in a multicenter study. Insulin sensitivity was quantified using hyperglycemic clamps. Assessment of CV risk factors was standardized across sites. Regression analyses compared the impact of insulin sensitivity and CV risk factors between youth and adults. RESULTS Obese pubertal youth were more insulin resistant than comparably obese adults (P < .001), but with similar slopes for the inverse relationship between insulin sensitivity and obesity. The impact of obesity on CV risk factors was explained by insulin sensitivity (P = NS after adjustment for sensitivity). The two age groups did not differ in relationships between insulin sensitivity and diastolic blood pressure, total cholesterol, and low-density lipoprotein (LDL) cholesterol, after adjusting for obesity. However, while systolic blood pressure (SBP) and high-density lipoprotein (HDL) cholesterol exhibited the expected direct and inverse relationships, respectively with insulin sensitivity in adults, these slopes were flat in youth across the range of insulin sensitivity (P ≤ .05 for group differences). CONCLUSIONS Effects of obesity on CV risk factors were attributable to insulin sensitivity in both groups. The relationships between insulin sensitivity and CV risk factors were similar in obese youth and adult groups except for SBP and HDL cholesterol. CLINICAL TRIAL REGISTRATION The RISE consortium studies are registered through Clinicaltrials.gov as NCT01779362 (Adult Medication Study); NCT01763346 (Adult Surgery Study); and NCT01779375 (Pediatric Medication Study). Clinical trial registration numbers: NCT01779362, NCT01779375 and NCT01763346 at clinicaltrials.gov.
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Affiliation(s)
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- RISE Coordinating Center, Rockville, Maryland
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25
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Li GH, Chen XF, Liang XY, Lin H, Zhang L, Xu XQ, Wu W, Huang K, Dong GP, Zhang JW, Rose SR, Ullah R, Zeitler P, Fu JF. β-Cell function in obese children and adolescents with metabolic syndrome compared to isolated obesity. Pediatr Diabetes 2019; 20:861-870. [PMID: 31408243 DOI: 10.1111/pedi.12905] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 05/05/2019] [Accepted: 05/08/2019] [Indexed: 11/26/2022] Open
Abstract
OBJECTIVE To evaluate β-cell function in obese children and adolescents meeting clinical criteria for isolated obesity (iOB), isolated components of dysmetabolism (cMD), or metabolic syndrome (MS), and in obese children and adolescents with normal glucose tolerance (NGT), impaired glucose regulation (IGR), or type 2 diabetes (T2DM). STUDY DESIGN We undertook a prospective study of Han Chinese children and adolescents aged 8-16 years (median 11 ± 1.4) seen in an obesity clinic between May 2013 and 2018. Patients were classified as iOB (53), cMD (139), and MS (139) groups based on clinical criteria. The same patients were also classified as NGT (212), IGR (111), or T2DM (8) based on results of an oral glucose tolerance test (OGTT). The MS patients were classified as NGT [MS](59) and IGR [MS](72) for the further study. All participants also completed a mixed-meal tolerance test (MMTT). RESULTS Compared with the iOB group, the MS group had significantly higher area under the curve of C-peptide up to the 2 hours (AUC CP) (P = .03) and peak C-peptide (P = .03), adjusted for BMI, age and Tanner stage, on MMTT. However, there was no difference in the insulinogenic index (ΔI30/ΔG30) or oral disposition index (oDI) derived from the OGTT among the three groups. However, 52% of participants with MS had IGR, compared to 28% in the cMD group. Compared with the NGT group, the individuals with IGR had significantly lower ΔI30/ΔG30 (P = .001) and oDI (P < .001). Compared with the iOB group, the NGT[MS] had significantly higher AUC CP (P = .004), peak C-peptide (P = .004) and ΔI30/ΔG30 (P = .007) adjusted for age, but no difference in oDI. Compared with the NGT[MS], the IGR[MS] had significantly lower ΔI30/ΔG30 (P = .005) and oDI (P < .001), but the AUC CP and peak C-peptide had no difference. CONCLUSION Although the MS youth have β-cell hyperfunction as a whole, β-cell dysfunction is present in the early stages of dysmetabolism in obese youth with cMD or MS and worsened across the spectrum from iOB to cMD and MS, contributing to development of T2DM.
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Affiliation(s)
- Guo-Hua Li
- Department of Endocrinology, The Children's Hospital of the Zhejiang University School of Medicine, Hangzhou, China
| | - Xue-Feng Chen
- Department of Endocrinology, The Children's Hospital of the Zhejiang University School of Medicine, Hangzhou, China
| | - Xin-Yi Liang
- Department of Endocrinology, The Children's Hospital of the Zhejiang University School of Medicine, Hangzhou, China
| | - Hu Lin
- Department of Endocrinology, The Children's Hospital of the Zhejiang University School of Medicine, Hangzhou, China
| | - Li Zhang
- Department of Endocrinology, The Children's Hospital of the Zhejiang University School of Medicine, Hangzhou, China
| | - Xiao-Qin Xu
- Department of Endocrinology, The Children's Hospital of the Zhejiang University School of Medicine, Hangzhou, China
| | - Wei Wu
- Department of Endocrinology, The Children's Hospital of the Zhejiang University School of Medicine, Hangzhou, China
| | - Ke Huang
- Department of Endocrinology, The Children's Hospital of the Zhejiang University School of Medicine, Hangzhou, China
| | - Guan-Ping Dong
- Department of Endocrinology, The Children's Hospital of the Zhejiang University School of Medicine, Hangzhou, China
| | - Jian-Wei Zhang
- Department of Endocrinology, The Children's Hospital of the Zhejiang University School of Medicine, Hangzhou, China
| | - Susan R Rose
- Pediatric Endocrinology and Metabolism, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Rahim Ullah
- Department of Endocrinology, The Children's Hospital of the Zhejiang University School of Medicine, Hangzhou, China
| | - Phil Zeitler
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado
| | - Jun-Fen Fu
- Department of Endocrinology, The Children's Hospital of the Zhejiang University School of Medicine, Hangzhou, China
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26
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Cree-Green M, Wiromrat P, Stuppy JJ, Thurston J, Bergman BC, Baumgartner AD, Bacon S, Scherzinger A, Pyle L, Nadeau KJ. Youth with type 2 diabetes have hepatic, peripheral, and adipose insulin resistance. Am J Physiol Endocrinol Metab 2019; 316:E186-E195. [PMID: 30562061 PMCID: PMC6397366 DOI: 10.1152/ajpendo.00258.2018] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 11/27/2018] [Accepted: 12/06/2018] [Indexed: 12/28/2022]
Abstract
Adolescents with type 2 diabetes (T2D) have severe insulin resistance (IR) secondary to obesity, genetics, and puberty, and IR predicts metabolic comorbidities. Adults with T2D have multitissue IR, which has guided therapeutic developments, but this is not established in youth. We sought to assess adipose, hepatic, and peripheral insulin sensitivity in adolescents with and without T2D. Twenty-seven youth with T2D [age: 15.6 ± 0.4 yr; female: 78%; body mass index (BMI) percentile: 96.1 (52.6, 95.9), late puberty; hemoglobin A1c (HbA1c) 7.3% (6.2, 10.1)] and 21 controls of similar BMI, pubertal stage, and habitual activity were enrolled. Insulin action was measured with a four-phase hyperinsulinemic-euglycemic clamp (basal, 10, 16, and 80 mU·m-2·min-1 for studying adipose, hepatic, and peripheral IR, respectively) with glucose and glycerol isotope tracers. Total fat mass, fat-free mass, liver fat fraction, and visceral fat were measured with dual-energy x-ray absorptiometry (DXA) and MRI, respectively. Free fatty acids (FFAs), lipid profile, and inflammatory markers were also measured. Adolescents with T2D had higher lipolysis ( P = 0.012), endogenous glucose production ( P < 0.0001), and lower glucose clearance ( P = 0.002) during hyperinsulinemia than controls. In T2D, peripheral IR positively correlated to FFA ( P < 0.001), inflammatory markers, visceral ( P = 0.004) and hepatic fat ( P = 0.007); hepatic IR correlated with central obesity ( P = 0.004) and adipose IR ( P = 0.003). Youth with T2D have profound multitissue IR compared with BMI-equivalent youth without T2D. The development of multitissue interactions appears crucial to the pathogenesis of T2D. Therapeutic targets on multitissue IR may be of benefit, deserving of further research.
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Affiliation(s)
- Melanie Cree-Green
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus , Aurora, Colorado
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus , Aurora, Colorado
| | - Pattara Wiromrat
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus , Aurora, Colorado
| | - Jacob J Stuppy
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus , Aurora, Colorado
- Department of Biomedical Sciences and Biotechnology, University of Colorado Anschutz Medical Campus , Aurora, Colorado
| | - Jessica Thurston
- Department of Biostatistics and Informatics, Colorado School of Public Health , Aurora, Colorado
| | - Bryan C Bergman
- Department of Medicine, Division of Endocrinology, University of Colorado Anschutz Medical Campus , Aurora, Colorado
| | - Amy D Baumgartner
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus , Aurora, Colorado
| | - Samantha Bacon
- Department of Medicine, Division of Endocrinology, University of Colorado Anschutz Medical Campus , Aurora, Colorado
| | - Ann Scherzinger
- Department of Radiology, University of Colorado Anschutz Medical Campus , Aurora, Colorado
| | - Laura Pyle
- Department of Biostatistics and Informatics, Colorado School of Public Health , Aurora, Colorado
- Department of Pediatrics, University of Colorado Anschutz Medical Campus , Aurora, Colorado
| | - Kristen J Nadeau
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus , Aurora, Colorado
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus , Aurora, Colorado
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27
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Kim JY, Bacha F, Tfayli H, Michaliszyn SF, Yousuf S, Arslanian S. 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. Diabetes Care 2019; 42:265-272. [PMID: 30455334 PMCID: PMC6341282 DOI: 10.2337/dc18-1178] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 10/25/2018] [Indexed: 02/03/2023]
Abstract
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.
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Affiliation(s)
- Joon Young Kim
- Center for Pediatric Research in Obesity and Metabolism, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Fida Bacha
- Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX
| | - Hala Tfayli
- Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Sara F Michaliszyn
- Department of Kinesiology and Sport Science, Youngstown State University, Youngstown, OH
| | - Shahwar Yousuf
- Center for Pediatric Research in Obesity and Metabolism, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Silva Arslanian
- Center for Pediatric Research in Obesity and Metabolism, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA
- Division of Pediatric Endocrinology, Diabetes, and Metabolism, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA
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28
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Arslanian S, Bacha F, Grey M, Marcus MD, White NH, Zeitler P. Evaluation and Management of Youth-Onset Type 2 Diabetes: A Position Statement by the American Diabetes Association. Diabetes Care 2018; 41:2648-2668. [PMID: 30425094 PMCID: PMC7732108 DOI: 10.2337/dci18-0052] [Citation(s) in RCA: 216] [Impact Index Per Article: 30.9] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Silva Arslanian
- Division of Pediatric Endocrinology, Metabolism, and Diabetes Mellitus, University of Pittsburgh, Pittsburgh, PA
- Center for Pediatric Research in Obesity and Metabolism, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA
| | - Fida Bacha
- Children's Nutrition Research Center, Texas Children's Hospital and Baylor College of Medicine, Houston, TX
| | - Margaret Grey
- Yale School of Nursing, New Haven, CT
- Yale School of Medicine, New Haven, CT
| | | | - Neil H White
- Washington University School of Medicine in St. Louis, St. Louis, MO
| | - Philip Zeitler
- Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO
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29
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Arslanian S, Kim JY, Nasr A, Bacha F, Tfayli H, Lee S, Toledo FGS. Insulin sensitivity across the lifespan from obese adolescents to obese adults with impaired glucose tolerance: Who is worse off? Pediatr Diabetes 2018; 19:205-211. [PMID: 28726334 DOI: 10.1111/pedi.12562] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 06/06/2017] [Accepted: 06/20/2017] [Indexed: 12/29/2022] Open
Abstract
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 β-cell destined to decompensate, and explicate their lower therapeutic response to insulin sensitizers.
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Affiliation(s)
- Silva Arslanian
- Division of Weight Management and Wellness, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.,Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
| | - Joon Young Kim
- Division of Weight Management and Wellness, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
| | - Alexis Nasr
- Division of Weight Management and Wellness, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
| | - Fida Bacha
- Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas
| | - Hala Tfayli
- Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - SoJung Lee
- Division of Weight Management and Wellness, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
| | - Frederico G S Toledo
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
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30
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Chen ME, Chandramouli AG, Considine RV, Hannon TS, Mather KJ. Comparison of β-Cell Function Between Overweight/Obese Adults and Adolescents Across the Spectrum of Glycemia. Diabetes Care 2018; 41:318-325. [PMID: 29183909 PMCID: PMC5780051 DOI: 10.2337/dc17-1373] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Accepted: 10/25/2017] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Type 2 diabetes is a growing health problem among both adults and adolescents. To better understand the differences in the pathogenesis of diabetes between these groups, we examined differences in β-cell function along the spectrum of glucose tolerance. RESEARCH DESIGN AND METHODS We evaluated 89 adults and 50 adolescents with normal glucose tolerance (NGT), dysglycemia, or type 2 diabetes. Oral glucose tolerance test results were used for C-peptide and insulin/glucose minimal modeling. Model-derived and direct measures of insulin secretion and insulin sensitivity were compared across glycemic stages and between age-groups at each stage. RESULTS In adolescents with dysglycemia, there was marked insulin resistance (insulin sensitivity index: adolescents, median [interquartile range] 1.8 [1.1-2.4] × 10-4; adults, 5.0 [2.3-9.9]; P = 0.01). The nature of β-cell dysfunction across stages of dysglycemia differed between the groups. We observed higher levels of secretion among adolescents than adults (total insulin secretion: NGT, 143 [103-284] × 10-9/min adolescent vs. 106 [71-127], P = 0.001); adults showed stepwise impairments in static insulin secretion (NGT, 7.5 [4.0-10.3] × 10-9/min; dysglycemia, 5.0 [2.3-9.9]; type 2 diabetes, 0.7 [0.1-2.45]; P = 0.003), whereas adolescents showed diabetes-related impairment in dynamic secretion (NGT, 1,905 [1,630-3,913] × 10-9; dysglycemia, 2,703 [1,323-3,637]; type 2 diabetes, 1,189 [269-1,410]; P = 0.001). CONCLUSIONS Adults and adolescents differ in the underlying defects leading to dysglycemia, and in the nature of β-cell dysfunction across stages of dysglycemia. These results may suggest different approaches to diabetes prevention in youths versus adults.
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Affiliation(s)
- Melinda E Chen
- Department of Pediatrics, Indiana University School of Medicine and Riley Hospital for Children, Indianapolis, IN
| | | | - Robert V Considine
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Tamara S Hannon
- Department of Pediatrics, Indiana University School of Medicine and Riley Hospital for Children, Indianapolis, IN
| | - Kieren J Mather
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
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31
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Kim JY, Tfayli H, Michaliszyn SF, Arslanian S. Impaired Lipolysis, Diminished Fat Oxidation, and Metabolic Inflexibility in Obese Girls With Polycystic Ovary Syndrome. J Clin Endocrinol Metab 2018; 103:546-554. [PMID: 29220530 PMCID: PMC5800835 DOI: 10.1210/jc.2017-01958] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2017] [Accepted: 12/01/2017] [Indexed: 01/01/2023]
Abstract
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.
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Affiliation(s)
- Joon Young Kim
- Center for Pediatric Research in Obesity and Metabolism, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15224
- Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213
| | - Hala Tfayli
- Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Sara F. Michaliszyn
- Human Performance and Exercise Science, Youngstown State University, Youngstown, Ohio 44555
| | - Silva Arslanian
- Center for Pediatric Research in Obesity and Metabolism, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15224
- Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224
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Hannon TS, Kahn SE, Utzschneider KM, Buchanan TA, Nadeau KJ, Zeitler PS, Ehrmann DA, Arslanian SA, Caprio S, Edelstein SL, Savage PJ, Mather KJ. Review of methods for measuring β-cell function: Design considerations from the Restoring Insulin Secretion (RISE) Consortium. Diabetes Obes Metab 2018; 20:14-24. [PMID: 28493515 PMCID: PMC6095472 DOI: 10.1111/dom.13005] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Revised: 05/04/2017] [Accepted: 05/06/2017] [Indexed: 01/09/2023]
Abstract
The Restoring Insulin Secretion (RISE) study was initiated to evaluate interventions to slow or reverse the progression of β-cell failure in type 2 diabetes (T2D). To design the RISE study, we undertook an evaluation of methods for measurement of β-cell function and changes in β-cell function in response to interventions. In the present paper, we review approaches for measurement of β-cell function, focusing on methodologic and feasibility considerations. Methodologic considerations included: (1) the utility of each technique for evaluating key aspects of β-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 β-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 β-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.
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Affiliation(s)
- Tamara S Hannon
- Departments of Pediatrics (T. S. H.) and Medicine (K. J. M.), Indiana University School of Medicine, Indianapolis, Indiana
| | - Steven E Kahn
- VA Puget Sound Health Care System and Department of Medicine, University of Washington, Seattle, Washington
| | - Kristina M Utzschneider
- VA Puget Sound Health Care System and Department of Medicine, University of Washington, Seattle, Washington
| | - Thomas A Buchanan
- University of Southern California Keck School of Medicine/Kaiser Permanente Southern California, Department of Medicine, Los Angeles, California
| | - Kristen J Nadeau
- University of Colorado Denver/Children's Hospital Colorado, Department of Pediatrics, Denver, Colorado
| | - Philip S Zeitler
- University of Colorado Denver/Children's Hospital Colorado, Department of Pediatrics, Denver, Colorado
| | | | - Silva A Arslanian
- Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Department of Pediatrics, Pittsburgh, Pennsylvania
| | - Sonia Caprio
- Department of Pediatrics, Yale University, New Haven, Connecticut
| | - Sharon L Edelstein
- George Washington University Biostatistics Center (RISE Coordinating Center), Rockville, Maryland
| | - Peter J Savage
- National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland
| | - Kieren J Mather
- Departments of Pediatrics (T. S. H.) and Medicine (K. J. M.), Indiana University School of Medicine, Indianapolis, Indiana
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Kim JY, Nasr A, Tfayli H, Bacha F, Michaliszyn SF, Arslanian S. Increased Lipolysis, Diminished Adipose Tissue Insulin Sensitivity, and Impaired β-Cell Function Relative to Adipose Tissue Insulin Sensitivity in Obese Youth With Impaired Glucose Tolerance. Diabetes 2017; 66:3085-3090. [PMID: 28887312 PMCID: PMC5697947 DOI: 10.2337/db17-0551] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Accepted: 09/04/2017] [Indexed: 12/24/2022]
Abstract
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.
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Affiliation(s)
- Joon Young Kim
- Center for Pediatric Research in Obesity and Metabolism, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Alexis Nasr
- Center for Pediatric Research in Obesity and Metabolism, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Hala Tfayli
- Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Fida Bacha
- Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX
| | - Sara F Michaliszyn
- Human Performance and Exercise Science, Youngstown State University, Youngstown, OH
| | - Silva Arslanian
- Center for Pediatric Research in Obesity and Metabolism, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA
- Division of Pediatric Endocrinology, Diabetes and Metabolism Consultation, Children's Hospital of Pittsburgh, Pittsburgh, PA
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34
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Michaliszyn SF, Lee S, Bacha F, Tfayli H, Farchoukh L, Mari A, Ferrannini E, Arslanian S. Differences in β-cell function and insulin secretion in Black vs. White obese adolescents: do incretin hormones play a role? Pediatr Diabetes 2017; 18:143-151. [PMID: 26799689 PMCID: PMC4958038 DOI: 10.1111/pedi.12364] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Revised: 12/21/2015] [Accepted: 12/22/2015] [Indexed: 12/27/2022] Open
Abstract
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 β-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 β-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 β-cell glucose sensitivity (βCGS), 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 βCGS, 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 β-cell glucose sensitivity, rate sensitivity, and potentiation factor. These racial disparities in β-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.
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Affiliation(s)
- Sara F Michaliszyn
- Human Performance and Exercise Science, Youngstown State University, Youngstown, OH 44555
| | - SoJung Lee
- Division of Weight Management, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224
| | - Fida Bacha
- Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030
| | - Hala Tfayli
- Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Lama Farchoukh
- Division of Weight Management, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224
| | - Andrea Mari
- CNR Institute of Neuroscience, Padova, Italy
| | - Ele Ferrannini
- Department of Clinical & Experimental Medicine, University of Pisa School of Medicine, Pisa, Italy
| | - Silva Arslanian
- Division of Weight Management, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224,Division of Pediatric Endocrinology, Metabolism & Diabetes Mellitus, Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224
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35
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Kovač J, Šutuš Temovski T, Rozmarič T, Horvat S, Beltram J, Trebušak Podkrajšek K, Battelino T, Kotnik P. DEPTOR promoter genetic variants and insulin resistance in obese children and adolescents. Pediatr Diabetes 2017; 18:152-158. [PMID: 26871578 DOI: 10.1111/pedi.12371] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Revised: 01/14/2016] [Accepted: 12/03/2015] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Insulin resistance (IR) is one of the major metabolic complications of obesity in children and adolescents. DEP domain-containing mammalian target of rapamycin interacting protein (DEPTOR) is involved in downstream insulin signaling and DEPTOR's effects are regulated by its level of expression. OBJECTIVES To analyze promoter region of DEPTOR for genetic variants associated with altered IR in obese children and adolescents. SUBJECTS AND METHODS IR was determined in 322 normoglycemic obese subjects [173 females, 149 males; mean age 13.3 ± 3.5 yr, mean BMI-SDS 2.85 ± 0.83, HbA1C 5.2 ± 0.2% (33 ± 2.5 mmol/mol)] using homeostatic model assessment - insulin resistance [HOMA-IR (>2 prepubertal and >3 pubertal)] and whole body insulin sensitivity index [WBISI (<6.5 prepubertal and <4.5 pubertal)]. Genetic variants, determined by high resolution melting analysis, were confirmed by Sanger sequencing, whereas population allele distribution was determined by TaqMan genotyping probes. RESULTS Genetic variant c.-143T>C (rs7840156) was associated with a significant 2-fold decreased risk to present with IR, determined by HOMA-IR [odds ratio (OR) = 0.614, 95% confidence interval (CI) = 0.435-0.867, p = 0.0057) and WBISI (OR = 0.582, 95% CI = 0.414-0.817, p = 0.0018). The CC genotype had lower mean HOMA-IR value (2.47 ± 0.44 vs. 3.04 ± 0.14, p = 0.0177) and higher mean WBISI value (7.00 ± 0.71 vs. 5.27 ± 0.33, p = 0.0235) than TT genotype. Variant c.-143T>C was located in evolutionary highly conserved region in DEPTOR promoter region. CONCLUSION Presented results on association between insulin sensitivity and genetic variants in DEPTOR gene suggest DEPTOR and mammalian target of rapamycin signaling pathway to be potential target for future research and pharmacological interventions.
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Affiliation(s)
- Jernej Kovač
- Unit of Special Laboratory Diagnostics, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Tamara Šutuš Temovski
- Unit of Special Laboratory Diagnostics, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Tomaž Rozmarič
- Unit of Special Laboratory Diagnostics, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Simon Horvat
- National Institute of Chemistry, Ljubljana, Slovenia.,Biotechnical faculty, University of Ljubljana, Ljubljana, Slovenia
| | | | - Katarina Trebušak Podkrajšek
- Unit of Special Laboratory Diagnostics, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia.,Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Tadej Battelino
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia.,Department of Pediatrics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Primož Kotnik
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia.,Department of Pediatrics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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36
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Yeow TP, Pacini G, Tura A, Hor CP, Lim SL, Tan FHS, Tong CV, Hong JYH, Md Zain F, Holst JJ, Wan Mohamud WN. Preserved glucagon-like peptide-1 responses to oral glucose, but reduced incretin effect, insulin secretion and sensitivity in young Asians with type 2 diabetes mellitus. BMJ Open Diabetes Res Care 2017; 5:e000352. [PMID: 28321312 PMCID: PMC5353273 DOI: 10.1136/bmjdrc-2016-000352] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2016] [Revised: 12/31/2016] [Accepted: 01/24/2017] [Indexed: 11/03/2022] Open
Abstract
OBJECTIVE Youth onset type 2 diabetes mellitus (YT2DM) is a globally rising phenomenon with substantial Asians representation. The understanding of its pathophysiology is derived largely from studies in the obese African-American and Caucasian populations, while studies on incretin effect are scarce. We examined the insulin resistance, β-cell function (BC), glucagon-like peptide (GLP)-1 hormone and incretin effect in Asian YT2DM. RESEARCH DESIGN AND METHODS This case-control study recruited 25 Asian YT2DM and 15 healthy controls, matched for gender, ethnicity and body mass index. Serum glucose, insulin, C peptide and GLP-1 were sampled during 2-hour oral glucose tolerance tests (OGTTs) and 1-hour intravenous glucose tolerance tests (IVGTTs). Insulin sensitivity was derived from the Quantitative Insulin Sensitivity Check Index (QUICKI), Oral Glucose Insulin Sensitivity Index (OGIS) in OGTT and surrogate index of SI from the minimal model (calculated SI, CSI). Acute insulin response (AIR) was obtained from IVGTT. Total BC was computed as incremental area under the curve of insulin/incremental area under the curve of glucose, during OGTT (BCOG) and IVGTT (BCIV), respectively. Disposition index (DI) was calculated using the product of insulin sensitivity and insulin secretion. GLP-1 response to oral glucose was calculated as incremental area under the curve of GLP-1 (ΔAUCGLP-1). Per cent incretin effect was estimated as 100×(BCOG-BCIV)/BCOG). RESULTS The YT2DM had marked impairment in BC (>80% reduction in AIR and BCOG, p<0.001) and lower QUICKI (p<0.001), OGIS (p<0.001) and CSI (p=0.015) compared with controls. There was no difference in GLP-1 at all time points and ΔAUCGLP-1 but the per cent incretin effect was reduced in the YT2DM compared with controls (12.1±8.93 vs 70.0±4.03, p<0.001). CONCLUSIONS Asian YT2DM showed similar GLP-1 response to oral glucose as controls but reduced incretin effect, BC and insulin sensitivity. The lack of compensatory mechanisms, as shown by the DI may be partly ascribed to the impaired incretin effect, similar to that of adult T2DM. TRIAL REGISTRATION NUMBER NMRR-12-1042-13254.
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Affiliation(s)
- Toh Peng Yeow
- Penang Medical College, Penang, Malaysia
- Department of Medicine, Penang General Hospital, Penang, Malaysia
| | - Giovanni Pacini
- Metabolic Unit, Institute of Neuroscience, National Research Council, Padova, Italy
| | - Andrea Tura
- Metabolic Unit, Institute of Neuroscience, National Research Council, Padova, Italy
| | - Chee Peng Hor
- Clinical Research Centre, Seberang Jaya Hospital, Penang, Malaysia
- Kepala Batas Hospital, Penang, Malaysia
| | - Shueh Lin Lim
- Department of Medicine, Penang General Hospital, Penang, Malaysia
| | | | - Chin Voon Tong
- Department of Medicine, Penang General Hospital, Penang, Malaysia
| | | | | | - Jens Juul Holst
- NNF Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Wan Nazaimoon Wan Mohamud
- Department of Cardiovascular, Diabetes and Nutrition Research Centre, Institute for Medical Research, Kuala Lumpur, Malaysia
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37
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Kim JY, Michaliszyn SF, Nasr A, Lee S, Tfayli H, Hannon T, Hughan KS, Bacha F, Arslanian S. The Shape of the Glucose Response Curve During an Oral Glucose Tolerance Test Heralds Biomarkers of Type 2 Diabetes Risk in Obese Youth. Diabetes Care 2016; 39:1431-9. [PMID: 27293201 PMCID: PMC4955931 DOI: 10.2337/dc16-0352] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 05/10/2016] [Indexed: 02/03/2023]
Abstract
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.
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Affiliation(s)
- Joon Young Kim
- Division of Weight Management and Wellness, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Sara F Michaliszyn
- Human Performance and Exercise Science, Youngstown State University, Youngstown, OH
| | - Alexis Nasr
- Division of Weight Management and Wellness, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - SoJung Lee
- Division of Weight Management and Wellness, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Hala Tfayli
- Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Tamara Hannon
- Sections of Pediatric Endocrinology and Diabetology, and Pediatric Comparative Effectiveness Research, Department of Pediatrics, School of Medicine, Indiana University, Indianapolis, IN
| | - Kara S Hughan
- Division of Weight Management and Wellness, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, Children's Hospital of Pittsburgh, Pittsburgh, PA
| | - Fida Bacha
- Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX
| | - Silva Arslanian
- Division of Weight Management and Wellness, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, Children's Hospital of Pittsburgh, Pittsburgh, PA
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38
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Abstract
Childhood obesity has been linked to cardiovascular disease (CVD) risk in adulthood. Of great concern is the expected increase in the population's CVD burden in relation to childhood obesity. This is compounded by the risk related to chronic hyperglycemia exposure in youth with type 2 diabetes. We herein provide an overview of the spectrum of early cardiovascular disease manifestation in youth with obesity and type 2 diabetes, in particular abnormalities in cardiac structure and function. Cardiac remodeling and adverse target organ damage is already evident in the pediatric age group in children with obesity and type 2 diabetes. This supports the importance of intensifying obesity prevention efforts and early intervention to treat comorbidities of obesity in the pediatric age group to prevent cardiac events in early adulthood.
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Affiliation(s)
- Fida Bacha
- USDA/ARS Children's Nutrition Research Center, Texas Children's Hospital, Baylor College of Medicine, 1100 Bates Street, Houston, TX, USA.
- Division of Pediatric Endocrinology and Diabetes, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
| | - Samuel S Gidding
- Nemours Cardiac Center, A.I. DuPont Hospital for Children, Wilmington, DE, USA
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39
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Dasari PS, Gandomani BS, Teague AM, Pitale A, Otto M, Short KR. Glycemic Variability Is Associated with Markers of Vascular Stress in Adolescents. J Pediatr 2016; 172:47-55.e2. [PMID: 26922105 DOI: 10.1016/j.jpeds.2016.01.065] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Revised: 12/28/2015] [Accepted: 01/27/2016] [Indexed: 01/01/2023]
Abstract
OBJECTIVES We used continuous glucose monitoring to test the hypothesis that mean amplitude of glycemic excursions (MAGE) is associated with circulating markers of oxidative and vascular stress in adolescents with habitually low physical activity classified as healthy weight, healthy obese, or obese with type 2 diabetes mellitus (T2DM). STUDY DESIGN A group of 13- to 21-year-olds (healthy weight = 12, healthy obese = 10, T2DM = 12) wore a continuous glucose monitor and step activity monitor for 5 days. RESULTS Physical activity was similar among groups (6551 ± 401 steps/d), but aerobic fitness (peak rate of oxygen consumption) was lower (P < .05) in T2DM (15.6 ± 1.8 mL/kg/min) than either healthy weight (26.2 ± 2.2) or healthy obese (24.4 ± 2.5). MAGE (mg/dL) was higher (P < .01) in T2DM (82 ± 10) vs healthy obese (33 ± 3) and healthy weight (30 ± 3). Average glucose followed a similar pattern as MAGE. Oxidized low density lipoprotein was higher (P < .05) in T2DM (70.3 ± 5.0 U/L) and healthy obese (58.1 ± 3.8) than healthy weight (48.4 ± 2) and positively correlated with MAGE (r = 0.77). Other stress markers that were both elevated in T2DM and correlated with MAGE included E-selectin (r = 0.50), intercellular adhesion molecule 1 (r = 0.35), and C-reactive protein (r = 0.52); soluble receptor for advanced glycosylation end product was lower in T2DM and inversely correlated with MAGE (r = -0.38). CONCLUSIONS MAGE is highest in obese youth with T2DM. The associations between MAGE and oxidative stress markers support the proposed contribution of glycemic variability to risk for future cardiovascular disease.
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Affiliation(s)
- Paul S Dasari
- Department of Pediatrics, Section of Diabetes and Endocrinology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Benjamin S Gandomani
- College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - April M Teague
- Department of Pediatrics, Section of Diabetes and Endocrinology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | | | | | - Kevin R Short
- Department of Pediatrics, Section of Diabetes and Endocrinology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
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40
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Caminiti C, Armeno M, Mazza CS. Waist-to-height ratio as a marker of low-grade inflammation in obese children and adolescents. J Pediatr Endocrinol Metab 2016; 29:543-51. [PMID: 26887032 DOI: 10.1515/jpem-2014-0526] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Accepted: 12/07/2015] [Indexed: 01/01/2023]
Abstract
BACKGROUND The epidemic of childhood obesity is associated with early atherosclerosis. Several reports have related this event to low-grade inflammation described in obesity. CRP and IL6 are markers that correlate with adiposity. The waist-to-height ratio (WtHR) is an anthropometric marker associated with insulin resistance and inflammation. The objective of this study was to assess the correlation between WtHR, metabolic complications and pro-inflammatory factors in obese children and adolescents. METHODS Weight, height, waist circumference, glycemia, insulin, CRP, TNF-α and IL-6 were measured in the baseline sample in 280 patients 6-19 years of age with overweight or obesity (OW/OB) and 112 normal-weight controls. Logistic regression was performed using WtHR as an independent variable. p>0.05 STATA11. RESULTS Mean WtHR was 0.6±0.06 in OW/OB and 0.43±0.02 in controls (p<0.01). WtHR was increased in 93% of the OW/OB vs. 2% of the controls. In the OW/OB inflammatory markers were significantly increased (p<0.01) compared to the controls (CRP 2.2 vs. 0.8; Il-6 2.9 vs. 2.1; and TNF-α 6.2 vs. 5.5). In the WtHR>0.5, insulin resistence and inflammatory markers were significantly increased (p<0.01) compared to the WtHR<0.5 (HOMA 3.4 vs. 1.4; CRP 2.3 vs. 0.6; Il-6 2.9 vs. 2.1; and TNF-α 6.4 vs. 5.55). In logistic regression, a significant independent association was found between WtHR with CRP (OR1.47), IL6 (OR1.60) and TNF-α (OR1.79). CONCLUSIONS Obese children and adolescents have high inflammatory markers that may increase cardiovascular risk. WtHR is associated with low-grade inflammation and may be considered a relevant anthropometric marker in the clinical practice.
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41
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Hannon TS, Arslanian SA. The changing face of diabetes in youth: lessons learned from studies of type 2 diabetes. Ann N Y Acad Sci 2015; 1353:113-37. [PMID: 26448515 DOI: 10.1111/nyas.12939] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 08/17/2015] [Accepted: 08/19/2015] [Indexed: 12/18/2022]
Abstract
The incidence of youth type 2 diabetes (T2D), linked with obesity and declining physical activity in high-risk populations, is increasing. Recent multicenter studies have led to a number of advances in our understanding of the epidemiology, pathophysiology, diagnosis, treatment, and complications of this disease. As in adult T2D, youth T2D is associated with insulin resistance, together with progressive deterioration in β cell function and relative insulin deficiency in the absence of diabetes-related immune markers. In contrast to adult T2D, the decline in β cell function in youth T2D is three- to fourfold faster, and therapeutic failure rates are significantly higher in youth than in adults. Whether the more aggressive nature of youth T2D is driven by genetic heterogeneity or physiology/metabolic maladaptation is yet unknown. Besides metformin, the lack of approved pharmacotherapeutic agents for youth T2D that target the pathophysiological mechanisms is a major barrier to optimal diabetes management. There is a significant need for effective therapeutic options, in addition to increased prevention, to halt the projected fourfold increase in youth T2D by 2050 and the consequences of heightened diabetes-related morbidity and mortality at younger ages.
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Affiliation(s)
- Tamara S Hannon
- Indiana University School of Medicine, Department of Pediatrics, Sections of Pediatric Endocrinology & Diabetology and Pediatric Comparative Effectiveness Research, Indianapolis, Indiana
| | - Silva A Arslanian
- Children's Hospital of University of Pittsburgh Medical Center, Department of Pediatrics, Divisions of Weight Management and Pediatric Endocrinology, Metabolism and Diabetes Mellitus, Pittsburgh, Pennsylvania
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Rivera-Vega MY, Flint A, Winger DG, Libman I, Arslanian S. Obesity and youth diabetes: distinguishing characteristics between islet cell antibody positive vs. negative patients over time. Pediatr Diabetes 2015; 16:375-81. [PMID: 25482141 PMCID: PMC4457715 DOI: 10.1111/pedi.12249] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Revised: 11/10/2014] [Accepted: 11/10/2014] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE Obese youth clinically diagnosed with type 2 diabetes mellitus (T2DM) frequently have evidence of islet cell autoimmunity. We investigated the clinical and biochemical differences, and therapeutic modalities among autoantibody positive (Ab+) vs. autoantibody negative (Ab-) youth at the time of diagnosis and over time in a multi-provider clinical setting. STUDY DESIGN Chart review of 145 obese youth diagnosed with T2DM from January 2003 to July 2012. Of these, 70 patients were Ab+ and 75 Ab-. The two groups were compared with respect to clinical presentation, physical characteristics, laboratory data, and therapeutic modalities at diagnosis and during follow up to assess the changes in these parameters associated with disease progression. RESULTS At presentation, Ab+ youth with a clinical diagnosis of T2DM were younger, had higher rates of ketosis, higher hemoglobin A1c (HbA1c) and glucose levels, and lower insulin and c-peptide concentrations compared with the Ab- group. The Ab- group had a higher body mass index (BMI) z-score and cardiometabolic risk factors at diagnosis and such difference remained over time. Univariate analysis revealed that treatment modality had no effect on BMI in either group. Generalized estimating equations for longitudinal data analysis revealed that (i) BMI z-score and diastolic blood pressure (DBP) were significantly affected by duration of diabetes; (ii) systolic blood pressure (SBP) and ALT were affected by changes in BMI z-score; and (iii) changes in HbA1c had an effect on lipid profile and cardiometabolic risk factors regardless of antibody status. CONCLUSIONS Irrespective of antibody status and treatment modality, youth who present with obesity and diabetes, show no improvement in obesity status over time, with the deterioration in BMI z-score affecting blood pressure (BP) and ALT, but the lipid profile being mostly impacted by HbA1c and glycemic control. Effective control of BMI and glycemia are needed to lessen the future macrovascular complications irrespective of antibody status.
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Affiliation(s)
- Michelle Y. Rivera-Vega
- Division of Weight Management and Wellness, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA
- Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA
| | - Amanda Flint
- Division of Weight Management and Wellness, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA
- Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA
| | - Daniel G. Winger
- Department of Biostatistics, Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, PA
| | - Ingrid Libman
- Division of Weight Management and Wellness, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA
- Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA
| | - Silva Arslanian
- Division of Weight Management and Wellness, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA
- Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA
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Ek AE, Rössner SM, Hagman E, Marcus C. High prevalence of prediabetes in a Swedish cohort of severely obese children. Pediatr Diabetes 2015; 16:117-28. [PMID: 24635861 DOI: 10.1111/pedi.12136] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2013] [Revised: 01/20/2014] [Accepted: 02/06/2014] [Indexed: 01/11/2023] Open
Abstract
OBJECTIVE In this cohort of severely obese children and adolescents in Sweden we investigate the prevalence of impaired fasting glucose (IFG), impaired glucose tolerance, (IGT) and silent type 2 diabetes (T2D), in relation to insulin resistance, insulin secretion, disposition index and cardio respiratory fitness. METHODS A total of 134 obese children and adolescents [57 females, 77 males, age 13.7 ± 2.7, body mass index (BMI) standard deviation score (SDS) 3.6 ± 0.6] consecutively referred to the National Childhood Obesity Centre performed an oral glucose tolerance test (OGTT), frequently sampled intravenous glucose tolerance test (fs-IVGTT), dual X-ray absorptiometry (DEXA), bicycle ergometer test and fasting levels of glucose, insulin and c-peptide were obtained and homeostatic model of insulin resistance (HOMA-IR) was calculated. RESULTS Isolated impaired fasting glucose (i-IFG) were present in 35.8 and 6% had isolated IGT. Combined IGT and IFG were present in 14.2%. The subjects with combined IGT/IFG had significantly lower acute insulin response (AIR) compared with subjects who had normal glucose metabolism or i-IFG (p < 0.05). Among the prepubertal children (n = 24), 25% (6/24) had i-IFG and 25% (6/24) had IGT/IFG and it was predominantly males. Disposition index was the major determinant of 2-h glucose levels (β = -0.49, p = 0.0126). No silent diabetes was detected. CONCLUSION In this cohort of severely obese children and adolescents the prevalence of prediabetes was very high. IFG was two times higher in this cohort of severely obese children than in a recently published unselected cohort of obese children in Sweden. In spite of the high prevalence of prediabetes, no subjects with silent diabetes were found.
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Affiliation(s)
- Anna E Ek
- Division of Pediatrics, National Childhood Obesity Centre, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
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Michaliszyn SF, Mari A, Lee S, Bacha F, Tfayli H, Farchoukh L, Ferrannini E, Arslanian S. β-cell function, incretin effect, and incretin hormones in obese youth along the span of glucose tolerance from normal to prediabetes to type 2 diabetes. Diabetes 2014; 63:3846-55. [PMID: 24947360 PMCID: PMC4207396 DOI: 10.2337/db13-1951] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2013] [Accepted: 05/30/2014] [Indexed: 12/22/2022]
Abstract
Using the hyperglycemic and euglycemic clamp, we demonstrated impaired β-cell function in obese youth with increasing dysglycemia. Herein we describe oral glucose tolerance test (OGTT)-modeled β-cell function and incretin effect in obese adolescents spanning the range of glucose tolerance. β-Cell function parameters were derived from established mathematical models yielding β-cell glucose sensitivity (βCGS), 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-βCGS to the 2-h hyperglycemic clamp-βCGS. Incretin and glucagon concentrations were measured during the OGTT. Compared with NGT, βCGS 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.
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Affiliation(s)
- Sara F Michaliszyn
- Division of Weight Management, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Andrea Mari
- CNR Institute of Biomedical Engineering, Padova, Italy
| | - SoJung Lee
- Division of Weight Management, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Fida Bacha
- Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX
| | - Hala Tfayli
- Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Lama Farchoukh
- Division of Weight Management, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Ele Ferrannini
- Department of Clinical and Experimental Medicine, University of Pisa School of Medicine, Pisa, Italy
| | - Silva Arslanian
- Division of Weight Management, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA Division of Pediatric Endocrinology, Diabetes and Metabolism, Children's Hospital of Pittsburgh, Pittsburgh, PA
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Abstract
Background Prediabetes is characterized by isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT), and combined IFG/IGT. This study aimed to establish the prevalence of prediabetes and examine possible contributory factors in a cohort of obese adolescents. Methods In this prospective study, we recruited 85 obese patients from the Obesity Clinic at the University Children’s Hospital and 17 normal weight controls. All patients were of Caucasian origin, 60 males/42 females, aged 7.4–18.3 years, with at least Tanner 2 stage of puberty. Results Depending on criteria we used, insulin resistance was confirmed in 62–100% of obese patients, predominantly in the group with BMI SDS > 3. oGTT revealed isolated impaired fasting glucose (IFG) in 13.9%, impaired glucose tolerance (IGT) in 20.8% and combined IFG and IGT only in 2.8% of the obese patients. Patients in the prediabetes group were older (14±2.4 vs 12.8±2.5 p=0.04) and had higher glucose levels (p<0.001) during the whole oGTT compared to normal glucose tolerance (NGT) group. There was no difference between groups in respect to family history, BMI, lipids and fasting insulin. Insulinogenic index, WBISI and HOMA%B were significantly lower in the prediabetes group compared to the NGT group (p=0.07, 0.01 and 0.04 respectively). HbA1c level was measured in 58% of patients and was significantly higher in the prediabetes group (5.4±0.3 vs 5.7±0.4, p=0.002). Conclusion Prediabetes occurrence was fairly high in our obese adolescents. Further studies should establish what would be the most appropriate screening test to diagnose these patients at risk for type 2 diabetes and initiate treatment without delay.
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Bacha F, Edmundowicz D, Sutton-Tyrell K, Lee S, Tfayli H, Arslanian SA. Coronary artery calcification in obese youth: what are the phenotypic and metabolic determinants? Diabetes Care 2014; 37:2632-9. [PMID: 25147256 PMCID: PMC4392940 DOI: 10.2337/dc14-0193] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Obesity in adolescence has been associated with increased risk for coronary heart disease in adulthood. This study evaluated subclinical atherosclerosis in obese youth and the underlying risk factors. RESEARCH DESIGN AND METHODS Ninety obese adolescents (37 normal glucose tolerant, 27 prediabetes, and 26 type 2 diabetes) underwent evaluation of coronary artery calcifications (CACs) by electron beam computed tomography, aortic pulse wave velocity (PWV), carotid intima-media thickness (IMT), lipids, leptin, inflammatory markers, and body composition (DEXA). A total of 68 underwent evaluation of insulin sensitivity (IS) (hyperinsulinemic-euglycemic clamp) and abdominal adiposity (computed tomography). RESULTS A total of 50% had CACs (CAC+: Agatston CAC score ≥1). CAC+ youth had higher BMI, fat mass, and abdominal fat, with no difference in sex, race, IS per fat-free mass (ISFFM), glucose tolerance, PWV, or IMT compared with the CAC- group. PWV was inversely related to IS. In multiple regression analyses with age, race, sex, HbA1c, BMI (or waist circumference), ISFFM, diastolic blood pressure, non-HDL cholesterol, and leptin as independent variables, BMI (or waist) (R(2) = 0.41; P = 0.001) was the significant determinant of CAC; leptin (R(2) = 0.37; P = 0.034) for PWV; and HbA1c, race, and age (R(2) = 0.34; P = 0.02) for IMT. CONCLUSIONS Early in the course of obesity, there is evidence of CAC independent of glycemia. The different biomarkers of subclinical atherosclerosis appear to be differentially modulated, adiposity being the major determinant of CAC, hyperglycemia, age, and race for IMT, and leptin and IS for arterial stiffness. These findings highlight the increased cardiovascular disease risk in obese youth and the need for early interventions to reverse obesity and atherosclerosis.
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Affiliation(s)
- Fida Bacha
- Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX
| | - Daniel Edmundowicz
- Department of Medicine, Section of Cardiology, Temple University, Philadelphia, PA
| | | | - SoJung Lee
- Weight Management and Wellness Center, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA
| | - Hala Tfayli
- Department of Pediatrics, American University of Beirut, Beirut, Lebanon
| | - Silva A Arslanian
- Weight Management and Wellness Center, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA
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Halban PA, Polonsky KS, Bowden DW, Hawkins MA, Ling C, Mather KJ, Powers AC, Rhodes CJ, Sussel L, Weir GC. β-cell failure in type 2 diabetes: postulated mechanisms and prospects for prevention and treatment. J Clin Endocrinol Metab 2014; 99:1983-92. [PMID: 24712577 PMCID: PMC5393482 DOI: 10.1210/jc.2014-1425] [Citation(s) in RCA: 153] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE This article examines the foundation of β-cell failure in type 2 diabetes (T2D) and suggests areas for future research on the underlying mechanisms that may lead to improved prevention and treatment. RESEARCH DESIGN AND METHODS A group of experts participated in a conference on 14-16 October 2013 cosponsored by the Endocrine Society and the American Diabetes Association. A writing group prepared this summary and recommendations. RESULTS The writing group based this article on conference presentations, discussion, and debate. Topics covered include genetic predisposition, foundations of β-cell failure, natural history of β-cell failure, and impact of therapeutic interventions. CONCLUSIONS β-Cell failure is central to the development and progression of T2D. It antedates and predicts diabetes onset and progression, is in part genetically determined, and often can be identified with accuracy even though current tests are cumbersome and not well standardized. Multiple pathways underlie decreased β-cell function and mass, some of which may be shared and may also be a consequence of processes that initially caused dysfunction. Goals for future research include to 1) impact the natural history of β-cell failure; 2) identify and characterize genetic loci for T2D; 3) target β-cell signaling, metabolic, and genetic pathways to improve function/mass; 4) develop alternative sources of β-cells for cell-based therapy; 5) focus on metabolic environment to provide indirect benefit to β-cells; 6) improve understanding of the physiology of responses to bypass surgery; and 7) identify circulating factors and neuronal circuits underlying the axis of communication between the brain and β-cells.
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Halban PA, Polonsky KS, Bowden DW, Hawkins MA, Ling C, Mather KJ, Powers AC, Rhodes CJ, Sussel L, Weir GC. β-cell failure in type 2 diabetes: postulated mechanisms and prospects for prevention and treatment. Diabetes Care 2014; 37:1751-8. [PMID: 24812433 PMCID: PMC4179518 DOI: 10.2337/dc14-0396] [Citation(s) in RCA: 344] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE This article examines the foundation of β-cell failure in type 2 diabetes (T2D) and suggests areas for future research on the underlying mechanisms that may lead to improved prevention and treatment. RESEARCH DESIGN AND METHODS A group of experts participated in a conference on 14-16 October 2013 cosponsored by the Endocrine Society and the American Diabetes Association. A writing group prepared this summary and recommendations. RESULTS The writing group based this article on conference presentations, discussion, and debate. Topics covered include genetic predisposition, foundations of β-cell failure, natural history of β-cell failure, and impact of therapeutic interventions. CONCLUSIONS β-Cell failure is central to the development and progression of T2D. It antedates and predicts diabetes onset and progression, is in part genetically determined, and often can be identified with accuracy even though current tests are cumbersome and not well standardized. Multiple pathways underlie decreased β-cell function and mass, some of which may be shared and may also be a consequence of processes that initially caused dysfunction. Goals for future research include to (1) impact the natural history of β-cell failure; (2) identify and characterize genetic loci for T2D; (3) target β-cell signaling, metabolic, and genetic pathways to improve function/mass; (4) develop alternative sources of β-cells for cell-based therapy; (5) focus on metabolic environment to provide indirect benefit to β-cells; (6) improve understanding of the physiology of responses to bypass surgery; and (7) identify circulating factors and neuronal circuits underlying the axis of communication between the brain and β-cells.
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Affiliation(s)
- Philippe A Halban
- Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland
| | - Kenneth S Polonsky
- Department of Medicine, Section of Endocrinology, University of Chicago, Chicago, IL
| | - Donald W Bowden
- Center for Genomics and Personalized Medicine Research and Center for Diabetes Research, Wake Forest University, Winston-Salem, NC
| | - Meredith A Hawkins
- Department of Medicine (Endocrinology) and Global Diabetes Institute, Albert Einstein College of Medicine, Bronx, NY
| | - Charlotte Ling
- Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Kieren J Mather
- Department of Endocrinology, Indiana University, Indianapolis, IN
| | - Alvin C Powers
- Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University School of Medicine, Nashville, TN
| | - Christopher J Rhodes
- Kovler Diabetes Center, Department of Medicine, University of Chicago, Chicago, IL
| | - Lori Sussel
- Naomi Berrie Diabetes Center, Columbia University, New York, NY
| | - Gordon C Weir
- Joslin Diabetes Center, Harvard Medical School, Boston, MA
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de las Heras J, Rajakumar K, Lee S, Bacha F, Holick MF, Arslanian SA. 25-Hydroxyvitamin D in obese youth across the spectrum of glucose tolerance from normal to prediabetes to type 2 diabetes. Diabetes Care 2013; 36:2048-53. [PMID: 23340897 PMCID: PMC3687316 DOI: 10.2337/dc12-1288] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To 1) determine if plasma 25-hydroxyvitamin D (25[OH]D) concentrations differ among obese youth with normal glucose tolerance (NGT) versus prediabetes versus type 2 diabetes and 2) assess the relationships between 25(OH)D and in vivo insulin sensitivity and β-cell function in this cohort. RESEARCH DESIGN AND METHODS Plasma 25(OH)D concentrations were examined in banked specimens in 9- to 20-year-old obese youth (n = 175; male 42.3%, black 46.3%) (NGT, n = 105; impaired glucose tolerance [IGT], n = 43; type 2 diabetes, n = 27) who had in vivo insulin sensitivity and secretion measured by hyperinsulinemic-euglycemic and hyperglycemic clamp techniques and had an assessment of total body composition and abdominal adiposity. RESULTS The mean age and BMI of the subjects were 14.3 ± 2.1 years and 35.7 ± 5.6 kg/m(2), respectively. BMI, plasma 25(OH)D, and the proportion of vitamin D-deficient and -insufficient children did not differ across the three groups. Furthermore, there was no association between 25(OH)D and in vivo insulin sensitivity or β-cell function relative to insulin sensitivity (disposition index) in all groups combined or in each group separately. CONCLUSIONS Our data in obese youth show 1) no differences in plasma 25(OH)D concentrations across the glucose tolerance groups and 2) no relationship between 25(OH)D and in vivo insulin sensitivity and β-cell function relative to insulin sensitivity in any of the groups. It remains uncertain if enhancement of the vitamin D status could improve pathophysiological mechanisms of prediabetes and type 2 diabetes in obese youth.
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Affiliation(s)
- Javier de las Heras
- Division of Pediatric Metabolism, Hospital Universitario de Cruces, Barakaldo, Vizcaya, Spain
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Effects of metformin, metformin plus rosiglitazone, and metformin plus lifestyle on insulin sensitivity and β-cell function in TODAY. Diabetes Care 2013; 36:1749-57. [PMID: 23704674 PMCID: PMC3661836 DOI: 10.2337/dc12-2393] [Citation(s) in RCA: 230] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) trial demonstrated that combination therapy with metformin plus rosiglitazone provided superior durability of glycemic control compared with metformin alone, with significantly lower treatment failure rates (38.6 vs. 51.7%), and metformin plus lifestyle was intermediate. Herein we describe the temporal changes in measures of β-cell function and insulin sensitivity over a 4-year period among the three treatments. RESEARCH DESIGN AND METHODS TODAY participants (699) were tested periodically with an oral glucose tolerance test to determine insulin sensitivity (1/fasting insulin [1/IF]), insulinogenic index (ΔI(30)/ΔG(30)) or C-peptide index (ΔC(30)/ΔG(30)), and β-cell function relative to insulin sensitivity (oral disposition index [oDI]). RESULTS During the first 6 months, metformin plus rosiglitazone exhibited a significantly greater improvement in insulin sensitivity and oDI versus metformin alone and versus metformin plus lifestyle; these improvements were sustained over 48 months of TODAY. Irrespective of treatment, those who failed to maintain glycemic control had significantly lower β-cell function (~50%), higher fasting glucose concentration, and higher HbA1c at randomization compared with those who did not fail. CONCLUSIONS The beneficial change in insulin sensitivity and the resultant lower burden on β-cell function achieved in the first 6 months with metformin plus rosiglitazone appear to be responsible for its superior glycemic durability over metformin alone and metformin plus lifestyle. However, initial β-cell reserve and HbA1c at randomization are independent predictors of glycemic durability. Therefore, efforts to preserve β-cell function before significant loss occurs and to reduce HbA1c may be beneficial in the treatment of youth with type 2 diabetes.
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