Depression and Insulin Resistance in Adolescents

描述（由申请人提供）：2型糖尿病（T2D）是一种慢性疾病，伴有严重健康并发症的高风险，如心血管和外周血管疾病、中风、失明和肾衰竭。青少年和青壮年患糖尿病的人数惊人地增加，造成了巨大的公共卫生负担。胰岛素抵抗（IR）是T2D的主要生理前兆。因此，针对可改变的IR危险因素的预防工作有可能显著降低发生T2D的风险。抑郁症状通常首先出现在青春期，与青少年和成人的IR相关，预测成人发病的T2D，并导致T2D死亡率和发病率的风险增加，而不仅仅是抑郁与肥胖的相互关系。抑郁症状和IR之间联系的潜在机制尚不清楚。从理论上讲，抑郁症状通过促进应激性行为（改变饮食、降低健康水平）和上调生理应激机制（皮质醇、神经肽Y）来诱发IR。抑郁症的心理治疗可改善成人的IR，但尚不确定抑郁症状的改善是否能预防有T2D风险的青少年IR的进展。本建议的目的是：1)评估6周认知行为（CB）抑郁预防组与6周标准护理健康教育（HE）组在减少T2D风险少女抑郁症状和改善IR方面的效果；2)评估应激相关的行为和生理因素在抑郁症状减轻和IR改善之间的中介作用；3)对有患T2D风险的少女试行正念减压（MBSR）小组。首席研究员Lauren Shomaker博士是一名儿童临床心理学家，她在青少年发展/精神病理学、饮食行为和儿童肥胖/肥胖相关健康合并症方面的背景非常适合推进本提案的目标。在K99阶段，Shomaker博士将获得培训，以提高她在以下方面的专业知识：1)在青少年中进行随机对照试验（rct）， ii)测量IR，以及iii)评估心血管健康。Shomaker博士组建了一个强大的指导和顾问团队，具有儿科肥胖和IR随机对照试验的专业知识（共同导师：Marian Tanofsy-Kraff博士，Jack Yanovski医学博士），CB抑郁干预（Eric Stice博士，Marjan Holloway博士），心血管健康（Kong Chen博士），压力生理学（Zofia Zukowska医学博士），高级统计分析（Cara Olsen博士）和MBSR （Kirk Brown博士）。提出的K99/R00申请是促进Shomaker博士过渡到一个独立的职业生涯的最终目标的理想工具，该职业专注于青少年心理社会发展与身体健康之间的相互联系，以及心理社会因素与身体健康之间联系的假定机制。

DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) is a chronic disease accompanied by heightened risk for severe health complications such as cardiovascular and peripheral vascular disease, stroke, blindness, and renal failure. The alarming rise in the manifestation of T2D among adolescents and young adults poses an enormous public health burden. Insulin resistance (IR) is a major physiological precursor to T2D. Thus, prevention efforts targeting modifiable risk factors for IR have the potential to diminish the risk of developing T2D significantly. Depressive symptoms often first appear during adolescence, are associated with IR in adolescents and adults, predict adult-onset T2D, and contribute to increased risk for T2D mortality and morbidity, beyond the interrelationship of depression with obesity. The mechanisms underlying the link between depressive symptoms and IR are unclear. Depressive symptoms theoretically induce IR by promoting stress-induced behaviors (altered eating, lowered fitness) and up regulating physiological stress mechanisms (cortisol, neuropeptide Y). Psychotherapy for depression improves IR in adults, but it is uncertain whether ameliorating depressive symptoms prevent progression of IR in adolescents at risk for T2D. The aims of this proposal are: 1) to assess the effects of a 6-wk cognitive-behavioral (CB) depression prevention group vs. a 6-wk standard-of-care health education (HE) group on reducing depressive symptoms and improving IR in adolescent girls at risk for T2D; 2) to assess the stress-related behavioral and physiological factors that mediate the relationship underlying decreases in depressive symptoms and improvements in IR; and 3) to pilot delivery of a mindfulness-based stress reduction (MBSR) group to adolescents girls at risk for T2D. The PI, Dr. Lauren Shomaker, is a child clinical psychologist whose background in adolescent development/psychopathology, eating behavior, and pediatric obesity/obesity related health co-morbidities is uniquely suited to advance the aims in this proposal. During the K99 phase, Dr. Shomaker will obtain training to enhance her expertise in: 1) conduct of randomized controlled trials (RCTs) in adolescents, ii) measurement of IR, and iii) assessment of cardiovascular fitness. Dr. Shomaker has assembled a strong mentoring and consultant team with expertise in RCTs for pediatric obesity and IR (Co- Mentors: Marian Tanofsy-Kraff, PhD, Jack Yanovski, MD, PhD), CB depression interventions (Eric Stice, PhD, Marjan Holloway, PhD), cardiovascular fitness (Kong Chen, PhD), stress physiology (Zofia Zukowska, MD, PhD), advanced statistical analysis (Cara Olsen, PhD), and MBSR (Kirk Brown, PhD). The proposed K99/R00 application is the ideal vehicle to promote Dr. Shomaker's ultimate goal of transitioning to an independent career focused upon the interconnections between adolescent psychosocial development and physical health, and the putative mechanisms underlying the links between psychosocial factors and physical well-being. PUBLIC HEALTH RELEVANCE: Type 2 diabetes (T2D) is one of our nation's most common chronic diseases. It affects >7.8% of the U.S., and the societal cost is >$90 billion/yr. In the past, T2D was considered a disease limited to older adults. Yet, there has been an alarming rise in its manifestation among adolescents and young adults. Early onset T2D has been associated with greater risk of end-stage renal disease and death and a shorter life expectancy of 15-27 yrs. Insulin resistance (IR) is a major physiological precursor to T2D. The normative rise in IR that characterizes puberty may render adolescence a sensitive period, triggering the progression of worsening IR among adolescents at risk for T2D. Adolescence also marks a peak period for the onset of elevated depressive symptoms among girls. Elevated depressive symptoms affect over 25% of adolescents. Even in the absence of full criteria for major depressive disorder (MDD), adolescent depressive symptoms are associated with considerable psychosocial and behavioral impairment and a 2-4-fold greater risk of developing MDD. Depressive symptoms also are associated with IR in adolescents and adults and predict T2D onset. Therefore, amelioration of elevated depressive symptoms in adolescent girls who are at risk for T2D has the potential to improve IR and risk for T2D in a considerable subset of youth.