Randomized Controlled Trial

. 2018 May:196:208-216.e2.

doi: 10.1016/j.jpeds.2017.12.052. Epub 2018 Feb 2.

Lipid Profiles, Inflammatory Markers, and Insulin Therapy in Youth with Type 2 Diabetes

Lorraine E Levitt Katz¹, Fida Bacha², Samuel S Gidding³, Ruth S Weinstock⁴, Laure El Ghormli⁵, Ingrid Libman⁶, Kristen J Nadeau⁷, Kristin Porter⁶, Santica Marcovina⁸; TODAY Study Group

Collaborators, Affiliations

Collaborators

TODAY Study Group:
S McKay⁹, M Haymond⁹, B Anderson⁹, C Bush⁹, S Gunn⁹, H Holden⁹, S M Jones⁹, G Jeha⁹, S McGirk⁹, S Thamotharan⁹, L Cuttler¹⁰, E Abrams¹⁰, T Casey¹⁰, W Dahms¹⁰, C Ievers-Landis¹⁰, B Kaminski¹⁰, M Koontz¹⁰, S MacLeish¹⁰, P McGuigan¹⁰, S Narasimhan¹⁰, M Geffner¹¹, V Barraza¹¹, N Chang¹¹, B Conrad¹¹, D Dreimane¹¹, S Estrada¹¹, L Fisher¹¹, E Fleury-Milfort¹¹, S Hernandez¹¹, B Hollen¹¹, F Kaufman¹¹, E Law¹¹, V Mansilla¹¹, D Miller¹¹, C Muñoz¹¹, R Ortiz¹¹, A Ward¹¹, K Wexler¹¹, Y K Xu¹¹, P Yasuda¹¹, R Berkowitz¹², S Boyd¹², B Johnson¹², J Kaplan¹², C Keating¹², C Lassiter¹², T Lipman¹², G McGinley¹², H McKnight¹², B Schwartzman¹², S Willi¹², S Arslanian¹³, S Foster¹³, B Galvin¹³, T Hannon¹³, A Kriska¹³, M Marcus¹³, T Songer¹³, E Venditti¹³, R Goland¹⁴, D Gallagher¹⁴, P Kringas¹⁴, N Leibel¹⁴, D Ng¹⁴, M Ovalles¹⁴, D Seidman¹⁴, L Laffel¹⁵, A Goebel-Fabbri¹⁵, M Hall¹⁵, L Higgins¹⁵, J Keady¹⁵, M Malloy¹⁵, K Milaszewski¹⁵, L Rasbach¹⁵, D M Nathan¹⁶, A Angelescu¹⁶, L Bissett¹⁶, C Ciccarelli¹⁶, L Delahanty¹⁶, V Goldman¹⁶, O Hardy¹⁶, M Larkin¹⁶, L Levitsky¹⁶, R McEachern¹⁶, D Norman¹⁶, D Nwosu¹⁶, S Park-Bennett¹⁶, D Richards¹⁶, N Sherry¹⁶, B Steiner¹⁶, S Tollefsen¹⁷, S Carnes¹⁷, D Dempsher¹⁷, D Flomo¹⁷, T Whelan¹⁷, B Wolff¹⁷, D Bowerman¹⁸, S Bristol¹⁸, J Bulger¹⁸, J Hartsig¹⁸, R Izquierdo¹⁸, J Kearns¹⁸, R Saletsky¹⁸, P Trief¹⁸, P Zeitler¹⁹, N Abramson¹⁹, A Bradhurst¹⁹, N Celona-Jacobs¹⁹, J Higgins¹⁹, M Kelsey¹⁹, G Klingensmith¹⁹, T Witten¹⁹, K Copeland²⁰, E Boss²⁰, R Brown²⁰, J Chadwick²⁰, L Chalmers²⁰, S Chernausek²⁰, A Hebensperger²⁰, C Macha²⁰, R Newgent²⁰, A Nordyke²⁰, D Olson²⁰, T Poulsen²⁰, L Pratt²⁰, J Preske²⁰, J Schanuel²⁰, S Sternlof²⁰, J Lynch²¹, N Amodei²¹, R Barajas²¹, C Cody²¹, D Hale²¹, J Hernandez²¹, C Ibarra²¹, E Morales²¹, S Rivera²¹, G Rupert²¹, A Wauters²¹, N White²², A Arbeláez²², D Flomo²², J Jones²², T Jones²², M Sadler²², M Tanner²², A Timpson²², R Welch²², S Caprio²³, M Grey²³, C Guandalini²³, S Lavietes²³, P Rose²³, A Syme²³, W Tamborlane²³, K Hirst²⁴, S Edelstein²⁴, P Feit²⁴, N Grover²⁴, C Long²⁴, L Pyle²⁴, B Linder²⁵, J Harting²⁶, J Shepherd²⁷, B Fan²⁷, L Marquez²⁷, M Sherman²⁷, J Wang²⁷, M Nichols²⁸, E Mayer-Davis²⁸, Y Liu²⁸, J Lima²⁹, J Puccella²⁹, E Ricketts²⁹, R Danis³⁰, A Domalpally³⁰, A Goulding³⁰, S Neill³⁰, P Vargo³⁰, D Wilfley³¹, D Aldrich-Rasche³¹, K Franklin³¹, C Massmann³¹, D O'Brien³¹, J Patterson³¹, T Tibbs³¹, D Van Buren³¹, M Palmert³², R Ratner³³, D Dremaine³⁴, J Silverstein³⁵

Affiliations

¹ Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
² Texas Children's Hospital, Baylor College of Medicine, Houston, TX.
³ Nemours Cardiac Center, Alfred I. DuPont Hospital for Children, Wilmington, DE.
⁴ SUNY Upstate Medical University, Department of Medicine, Syracuse, NY.
⁵ George Washington University Biostatistics Center, Rockville, MD. Electronic address: elghorml@bsc.gwu.edu.
⁶ Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA.
⁷ University of Colorado Anschutz Medical Campus, Aurora, CO.
⁸ Northwest Lipid Research Laboratories, University of Washington, Seattle, WA.
⁹ Clinical Centers Baylor College of Medicine.
¹⁰ Case Western Reserve University.
¹¹ Children's Hospital Los Angeles.
¹² Children's Hospital of Philadelphia.
¹³ Children's Hospital of Pittsburgh.
¹⁴ Columbia University Medical Center.
¹⁵ Joslin Diabetes Center.
¹⁶ Massachusetts General Hospital.
¹⁷ Saint Louis University.
¹⁸ State University of New York Upstate Medical University.
¹⁹ University of Colorado Denver.
²⁰ University of Oklahoma Health Sciences Center.
²¹ University of Texas Health Science Center at San Antonio.
²² Washington University in St Louis.
²³ Yale University.
²⁴ Coordinating Center, George Washington University Biostatistics Center.
²⁵ Project Office, National Institute of Diabetes and Digestive and Kidney Diseases.
²⁶ Central Units, Central Blood Laboratory, Northwest Lipid Research Laboratories, University of Washington).
²⁷ DEXA Reading Center, University of California at San Francisco.
²⁸ Diet Assessment Center, University of South Carolina.
²⁹ Echocardiogram Reading Center, Johns Hopkins University.
³⁰ Fundus Photography Reading Center, University of Wisconsin.
³¹ Lifestyle Program Core, Washington University.
³² Other Hospital for Sick Children, Toronto.
³³ Medstar Research Institute, Washington DC.
³⁴ Texas Tech University Health Sciences Center.
³⁵ University of Florida.

PMID: 29398050
PMCID: PMC6436626
DOI: 10.1016/j.jpeds.2017.12.052

Randomized Controlled Trial

Lipid Profiles, Inflammatory Markers, and Insulin Therapy in Youth with Type 2 Diabetes

Lorraine E Levitt Katz et al. J Pediatr. 2018 May.

. 2018 May:196:208-216.e2.

doi: 10.1016/j.jpeds.2017.12.052. Epub 2018 Feb 2.

Authors

Lorraine E Levitt Katz¹, Fida Bacha², Samuel S Gidding³, Ruth S Weinstock⁴, Laure El Ghormli⁵, Ingrid Libman⁶, Kristen J Nadeau⁷, Kristin Porter⁶, Santica Marcovina⁸; TODAY Study Group

Collaborators

TODAY Study Group:
S McKay⁹, M Haymond⁹, B Anderson⁹, C Bush⁹, S Gunn⁹, H Holden⁹, S M Jones⁹, G Jeha⁹, S McGirk⁹, S Thamotharan⁹, L Cuttler¹⁰, E Abrams¹⁰, T Casey¹⁰, W Dahms¹⁰, C Ievers-Landis¹⁰, B Kaminski¹⁰, M Koontz¹⁰, S MacLeish¹⁰, P McGuigan¹⁰, S Narasimhan¹⁰, M Geffner¹¹, V Barraza¹¹, N Chang¹¹, B Conrad¹¹, D Dreimane¹¹, S Estrada¹¹, L Fisher¹¹, E Fleury-Milfort¹¹, S Hernandez¹¹, B Hollen¹¹, F Kaufman¹¹, E Law¹¹, V Mansilla¹¹, D Miller¹¹, C Muñoz¹¹, R Ortiz¹¹, A Ward¹¹, K Wexler¹¹, Y K Xu¹¹, P Yasuda¹¹, R Berkowitz¹², S Boyd¹², B Johnson¹², J Kaplan¹², C Keating¹², C Lassiter¹², T Lipman¹², G McGinley¹², H McKnight¹², B Schwartzman¹², S Willi¹², S Arslanian¹³, S Foster¹³, B Galvin¹³, T Hannon¹³, A Kriska¹³, M Marcus¹³, T Songer¹³, E Venditti¹³, R Goland¹⁴, D Gallagher¹⁴, P Kringas¹⁴, N Leibel¹⁴, D Ng¹⁴, M Ovalles¹⁴, D Seidman¹⁴, L Laffel¹⁵, A Goebel-Fabbri¹⁵, M Hall¹⁵, L Higgins¹⁵, J Keady¹⁵, M Malloy¹⁵, K Milaszewski¹⁵, L Rasbach¹⁵, D M Nathan¹⁶, A Angelescu¹⁶, L Bissett¹⁶, C Ciccarelli¹⁶, L Delahanty¹⁶, V Goldman¹⁶, O Hardy¹⁶, M Larkin¹⁶, L Levitsky¹⁶, R McEachern¹⁶, D Norman¹⁶, D Nwosu¹⁶, S Park-Bennett¹⁶, D Richards¹⁶, N Sherry¹⁶, B Steiner¹⁶, S Tollefsen¹⁷, S Carnes¹⁷, D Dempsher¹⁷, D Flomo¹⁷, T Whelan¹⁷, B Wolff¹⁷, D Bowerman¹⁸, S Bristol¹⁸, J Bulger¹⁸, J Hartsig¹⁸, R Izquierdo¹⁸, J Kearns¹⁸, R Saletsky¹⁸, P Trief¹⁸, P Zeitler¹⁹, N Abramson¹⁹, A Bradhurst¹⁹, N Celona-Jacobs¹⁹, J Higgins¹⁹, M Kelsey¹⁹, G Klingensmith¹⁹, T Witten¹⁹, K Copeland²⁰, E Boss²⁰, R Brown²⁰, J Chadwick²⁰, L Chalmers²⁰, S Chernausek²⁰, A Hebensperger²⁰, C Macha²⁰, R Newgent²⁰, A Nordyke²⁰, D Olson²⁰, T Poulsen²⁰, L Pratt²⁰, J Preske²⁰, J Schanuel²⁰, S Sternlof²⁰, J Lynch²¹, N Amodei²¹, R Barajas²¹, C Cody²¹, D Hale²¹, J Hernandez²¹, C Ibarra²¹, E Morales²¹, S Rivera²¹, G Rupert²¹, A Wauters²¹, N White²², A Arbeláez²², D Flomo²², J Jones²², T Jones²², M Sadler²², M Tanner²², A Timpson²², R Welch²², S Caprio²³, M Grey²³, C Guandalini²³, S Lavietes²³, P Rose²³, A Syme²³, W Tamborlane²³, K Hirst²⁴, S Edelstein²⁴, P Feit²⁴, N Grover²⁴, C Long²⁴, L Pyle²⁴, B Linder²⁵, J Harting²⁶, J Shepherd²⁷, B Fan²⁷, L Marquez²⁷, M Sherman²⁷, J Wang²⁷, M Nichols²⁸, E Mayer-Davis²⁸, Y Liu²⁸, J Lima²⁹, J Puccella²⁹, E Ricketts²⁹, R Danis³⁰, A Domalpally³⁰, A Goulding³⁰, S Neill³⁰, P Vargo³⁰, D Wilfley³¹, D Aldrich-Rasche³¹, K Franklin³¹, C Massmann³¹, D O'Brien³¹, J Patterson³¹, T Tibbs³¹, D Van Buren³¹, M Palmert³², R Ratner³³, D Dremaine³⁴, J Silverstein³⁵

Affiliations

¹ Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
² Texas Children's Hospital, Baylor College of Medicine, Houston, TX.
³ Nemours Cardiac Center, Alfred I. DuPont Hospital for Children, Wilmington, DE.
⁴ SUNY Upstate Medical University, Department of Medicine, Syracuse, NY.
⁵ George Washington University Biostatistics Center, Rockville, MD. Electronic address: elghorml@bsc.gwu.edu.
⁶ Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA.
⁷ University of Colorado Anschutz Medical Campus, Aurora, CO.
⁸ Northwest Lipid Research Laboratories, University of Washington, Seattle, WA.
⁹ Clinical Centers Baylor College of Medicine.
¹⁰ Case Western Reserve University.
¹¹ Children's Hospital Los Angeles.
¹² Children's Hospital of Philadelphia.
¹³ Children's Hospital of Pittsburgh.
¹⁴ Columbia University Medical Center.
¹⁵ Joslin Diabetes Center.
¹⁶ Massachusetts General Hospital.
¹⁷ Saint Louis University.
¹⁸ State University of New York Upstate Medical University.
¹⁹ University of Colorado Denver.
²⁰ University of Oklahoma Health Sciences Center.
²¹ University of Texas Health Science Center at San Antonio.
²² Washington University in St Louis.
²³ Yale University.
²⁴ Coordinating Center, George Washington University Biostatistics Center.
²⁵ Project Office, National Institute of Diabetes and Digestive and Kidney Diseases.
²⁶ Central Units, Central Blood Laboratory, Northwest Lipid Research Laboratories, University of Washington).
²⁷ DEXA Reading Center, University of California at San Francisco.
²⁸ Diet Assessment Center, University of South Carolina.
²⁹ Echocardiogram Reading Center, Johns Hopkins University.
³⁰ Fundus Photography Reading Center, University of Wisconsin.
³¹ Lifestyle Program Core, Washington University.
³² Other Hospital for Sick Children, Toronto.
³³ Medstar Research Institute, Washington DC.
³⁴ Texas Tech University Health Sciences Center.
³⁵ University of Florida.

PMID: 29398050
PMCID: PMC6436626
DOI: 10.1016/j.jpeds.2017.12.052

Abstract

Objectives: Data regarding atherogenic dyslipidemia and the inflammation profile in youth with type 2 diabetes is limited and the effect of insulin therapy on these variables has not previously been studied in youth. We determined the impact of insulin therapy on lipid and inflammatory markers in youth with poorly controlled type 2 diabetes.

Study design: In the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) multicenter trial, 285 participants failed to sustain glycemic control on randomized treatment (primary outcome, glycated hemoglobin A1c [HbA1c] at ≥8% for 6 months); 363 maintained glycemic control (never reached primary outcome). Statins were used for a low-density lipoprotein cholesterol of ≥130 mg/dL. Upon reaching the primary outcome, insulin was started. Changes in lipids and inflammatory markers (slopes over time) were examined.

Results: Progression of dyslipidemia was related to glycemic control. In those with the primary outcome, insulin therapy impacted HbA1c modestly, and dampened the increase in total cholesterol, low-density lipoprotein cholesterol, and total apolipoprotein B, although statin use increased from 8.6% to 22% year after the primary outcome. The increase in triglycerides and plasma nonesterified fatty acids stabilized after insulin was started, independent of HbA1c. There was an increase in high-sensitivity C-reactive protein that continued after insulin initiation, related to HbA1c and percent overweight.

Conclusions: Worsening dyslipidemia and inflammation over time raise concern regarding premature development of atherosclerosis in youth with type 2 diabetes. Insulin therapy has a limited benefit in the absence of glycemic control. Strategies to achieve better glycemic control are needed.

Trial registration: ClinicalTrials.gov: NCT00081328.

Keywords: adolescent; inflammatory markers; insulin; lipids; type 2 diabetes mellitus.

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Figures

**Figure I**
Plots of lipids showing slopes (solid line) before and after ‘time 0’ in the primary outcome group imposed on raw means. ‘Time 0’ is defined as the date long-term insulin therapy was started (vertical reference line). The short dashed line represents the raw means.

**Figure II**
Plots of inflammatory markers showing slopes (solid line) before and after ‘time 0’ in the primary outcome group imposed on raw means. ‘Time 0’ is defined as the date long-term insulin therapy was started (vertical reference line). The short dashed line represents the raw means.

**Figure III**
online Plots of LDL-C showing slopes before and after ‘time 30’ in the primary outcome group, by race-ethnicity (non-Hispanic Black: solid line; Hispanic: short dashed line; and non-Hispanic White: long dashed line). ‘Time 0’ is defined as the date long-term insulin therapy was started (vertical reference line).

See this image and copyright information in PMC

References

1. Capewell S, Buchan I. Why have sustained increases in obesity and type 2 diabetes not offset declines in cardiovascular mortality over recent decades in Western countries? Nutr Metab Cardiovasc Dis 2012; 22:307–311. - PubMed
1. Wang YC, McPherson K, Marsh T, Gortmaker SL, Brown M. Health and economic burden of the projected obesity trends in the USA and the UK. Lancet 2011; 378:815–825. - PubMed
1. Maahs DM, Daniels SR, de Ferranti SD, Dichek HL, Flynn J, Goldstein BI, et al. ; on behalf of the American Heart Association Atherosclerosis, Hypertension and Obesity in Youth Committee of the Council on Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Cardiovascular and Stroke Nursing, Council for High Blood Pressure Research, and Council on Lifestyle and Cardiometabolic Health. Cardiovascular disease risk factors in youth with diabetes mellitus: a scientific statement from the American Heart Association. Circulation 2014; 130:1532–1558. - PubMed
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Lipid Profiles, Inflammatory Markers, and Insulin Therapy in Youth with Type 2 Diabetes

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Lipid Profiles, Inflammatory Markers, and Insulin Therapy in Youth with Type 2 Diabetes

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