Beta-Cell Rescue in Youth with New Onset T2DM

β 细胞拯救新发 T2DM 青少年

• 批准号: 8248477
• 负责人: KRISTEN Jane NADEAU
• 金额: $ 71.18万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-24 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8248477
• 关键词: Address; Adolescent; Adult; Beta Cell; Blood Glucose; C-Peptide; Cardiovascular Diseases; Cell physiology; Cells; Cessation of life; Child; Childhood; Critiques; Deterioration; Development; Diabetes Mellitus; Diagnosis; Disease; Endocrinology; Epidemiology; Face; Failure; Fasting; Functional disorder; Glucose; Goals; Hyperglycemia; Infusion procedures; Insulin; Insulin Resistance; Interphase Cell; Intravenous; Longevity; Maintenance; Measures; Metformin; Non-Insulin-Dependent Diabetes Mellitus; Normal Range; Obesity; Outcome; Participant; Patients; Pediatrics; Phase; Physiological; Positioning Attribute; Prevalence; Puberty; Published Comment; Recovery; Relative (related person); Rest; Role; Secretory Cell; Youth; desensitization; falls; fasting glucose; glycemic control; improved; insulin secretion; insulin sensitivity; named group; non-diabetic; obesity in children; peer; treatment trial

DESCRIPTION (provided by applicant): The development of Type 2 diabetes (T2DM) in adults results from the gradual fall in p-cell function occurring on a background of insulin resistance. The inclusion of pediatric participants in studies envisioned by this RFA is critical because there are subtle but important differences in T2DM pathophysiology in adolescents, particularly with regard to changes in ¿-cell function. Indeed, the deterioration in ¿-cell functio in youth with T2DM is accelerated relative to than that observed in adults. Furthermore, in childhood, the ¿-cell secretory burden to compensate for insulin resistance grows disproportionately larger when insulin resistance worsens during puberty. Diminished first-phase insulin secretion is an early marker of ¿-cell dysfunction, appearing long before significant changes in absolute glucose concentrations are apparent in obese youth. Declining ¿-cell function relative to insulin sensitivity in these obese youth is evident with increasing fasting glucose levels even in the non-diabetic normal range. The central theme of our proposal is that desensitization of the ¿-cell to changes in glucose levels and ¿-cell destruction due to glucolipotoxicity may contribute to alterations in insulin secretion. Early correction of glucotoxicity via early intensive insulin therapy, allowing ¿-cell rest, may be a strategy to protet or produce sustained recovery of ¿-cell function in youth with new onset T2DM. Therefore, we hypothesize that early intensive intravenous insulin infusion (IVII) plus metformin in youth with recently diagnosed T2DM, by tightly controlling fasting and postprandial hyperglycemia, will have favorable effects on short-term recovery and long-term maintenance of p-cell function (first phase insulin secretion) and long-term glycemic control compared with treatment with metformin alone. To address this hypothesis, we have brought together 3 centers of Pediatric Endocrinology/Metabolism and Diabetes Mellitus with expertise in adolescent T2DM to determine: whether a short course of early IVII plus metformin in obese adolescents with new onset T2DM, to rapidly attain fasting and post-parandial normoglyemia, can restore short-term insulin secretion, sustain the recovery of long-term insulin secretion, and promote extended and durable glycemic control relative to metformin therapy alone. PUBLIC HEALTH RELEVANCE (provided by applicant): T2DM is a common disease characterized by ¿-cell failure and insulin resistance, shortening lifespan despite advances in blood sugar and cardiovascular disease (CVD) treatment. T2DM is increasingly prevalent in youth, forecasting early complications, including CVD and death. Improving ¿-cell function may improve glycemic control and decrease later need for insulin, and could thereby decrease diabetes-associated complications. NOTE: The following critiques were prepared by the reviewers assigned to this application. These commentaries may not necessarily reflect the position of the reviewers at the close of the group discussion or the final majority opinion of the group, although the reviewers were asked to amend their critiques if their positions changed during the discussion. The resume and other initial sections of the summary statement are the authoritative representations of the final outcome of group discussion. If there is any discrepancy between the peer reviewers' commentaries and the numerical score on the face page of this summary statement, the numerical score should be considered the most accurate representation of the final outcome of the group discussion.

描述(申请人提供)：成人2型糖尿病(T2 DM)的发展是在胰岛素抵抗的背景下发生的p细胞功能逐渐下降的结果。将儿科参与者纳入本RFA设想的研究是至关重要的，因为在青少年T2 DM病理生理学方面存在着微妙但重要的差异，特别是在细胞功能的变化方面。的确，与成人相比，青年2型糖尿病患者的细胞功能恶化速度更快。此外，在儿童时期，当胰岛素抵抗在青春期恶化时，用于补偿胰岛素抵抗的细胞分泌负担变得不成比例地大。第一时相胰岛素分泌减少是细胞功能障碍的早期标志，在肥胖青年的绝对葡萄糖浓度明显变化之前很久就出现了。在这些肥胖的年轻人中，即使在非糖尿病的正常范围内，随着空腹血糖水平的升高，细胞功能相对于胰岛素敏感性的下降也是明显的。我们建议的中心主题是，细胞对血糖水平变化的脱敏和糖脂毒性导致的细胞破坏可能会导致胰岛素分泌的改变。通过早期强化胰岛素治疗早期纠正糖毒性，允许细胞休息，可能是预防或产生新发T2 DM青年细胞功能持续恢复的一种策略。因此，我们推测在新近确诊的青年T2 DM患者中，早期强化静脉胰岛素输注(IVII)联合二甲双胍治疗，通过严格控制空腹和餐后高血糖，与单用二甲双胍治疗相比，在短期恢复和长期维持胰岛细胞功能(第一时相胰岛素分泌)和长期血糖控制方面将具有良好的效果。为了解决这一假设，我们汇集了3个在青少年T2 DM方面具有专业知识的儿科内分泌学/代谢和糖尿病中心，以确定：相对于单用二甲双胍，肥胖青少年新发T2 DM患者早期短期IVII加二甲双胍能否迅速达到空腹和餐后正常血糖，可以恢复短期胰岛素分泌，维持长期胰岛素分泌的恢复，并促进延长和持久的血糖控制。 公共卫生相关性(申请人提供)：T2 DM是一种常见疾病，以细胞衰竭和胰岛素抵抗为特征，尽管血糖和心血管疾病(CVD)治疗取得了进展，但它缩短了寿命。T2 DM在年轻人中日益流行，预示着早期并发症，包括心血管疾病和死亡。改善细胞功能可能会改善血糖控制，减少以后对胰岛素的需求，从而减少糖尿病相关的并发症。 注意：以下评论是由分配给此应用程序的评审员准备的。这些评注不一定反映审评人在小组讨论结束时的立场或小组的最后多数意见，尽管审评人被要求修改他们的批评意见，如果他们的立场在讨论期间发生变化。摘要说明的简历和其他开头部分是小组讨论最后结果的权威性表述。如果同行评审员的评论与本摘要说明页面上的数字分数之间存在任何差异，则数字分数应被视为最准确地代表小组讨论的最终结果。