Beta-Cell Rescue in Youth with New Onset T2DM

描述（由申请人提供）：成人2型糖尿病（T2DM）的发展源于胰岛素抵抗背景下p细胞功能的逐渐下降。在本RFA设想的研究中纳入儿童参与者是至关重要的，因为青少年T2DM病理生理存在细微但重要的差异，特别是在细胞功能的变化方面。事实上，与成年人相比，青少年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，补偿胰岛素抵抗的细胞分泌负担会不成比例地增加。第一阶段胰岛素分泌减少是细胞功能障碍的早期标志，早在肥胖青年中绝对葡萄糖浓度明显变化之前就出现了。在这些肥胖青年中，随着空腹血糖水平的升高，即使在非糖尿病的正常范围内，细胞功能相对于胰岛素敏感性的下降也很明显。我们建议的中心主题是细胞对葡萄糖水平变化的脱敏和由于糖脂毒性引起的细胞破坏可能有助于胰岛素分泌的改变。通过早期强化胰岛素治疗早期纠正糖毒性，允许细胞休息，可能是保护或产生新发T2DM青年细胞功能持续恢复的策略。因此，我们假设，与单用二甲双胍治疗相比，早期强化静脉注射胰岛素（ivi）加二甲双胍，通过严格控制空腹和餐后高血糖，在短期恢复和长期维持p细胞功能（第一阶段胰岛素分泌）和长期血糖控制方面具有良好的效果。为了验证这一假设，我们联合了3个儿科内分泌/代谢和糖尿病中心以及青少年2型糖尿病的专业知识来确定：与单用二甲双胍治疗相比，短期早期ivi加二甲双胍治疗肥胖青少年新发T2DM，快速达到空腹和副丘脑后正常血糖，能否恢复短期胰岛素分泌，维持长期胰岛素分泌的恢复，促进长期和持久的血糖控制。

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.