RISE: The Restoring Insulin Secretion Pediatric Medication Study

描述（由申请人提供）：成人2型糖尿病（T2 DM）的发生是由于在胰岛素抵抗背景下发生的p细胞功能逐渐下降。在本RFA设想的研究中纳入儿科受试者至关重要，因为青少年T2 DM病理生理学存在细微但重要的差异，特别是在β细胞功能变化方面。事实上，青年T2 DM患者β细胞功能的恶化相对于成人中观察到的加速。此外，在儿童时期，当青春期胰岛素抵抗出现时，β细胞分泌负担会不成比例地增加，以补偿胰岛素抵抗。第一时相胰岛素分泌减少是β细胞功能障碍的早期标志，在肥胖青年中绝对葡萄糖浓度明显变化之前很久就出现了。在这些肥胖青年中，随着空腹血糖水平的增加，即使在非糖尿病正常范围内，β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β细胞对葡萄糖水平变化的脱敏和由于糖脂毒性引起的β细胞破坏可能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葡萄糖毒性，允许β细胞静息，可能是保护新发T2 DM青年患者β细胞功能或使其持续恢复的策略。因此，我们假设，与二甲双胍单药治疗相比，近期诊断为T2 DM的青年患者早期强化静脉胰岛素输注（IVII）联合二甲双胍，通过严格控制空腹和餐后高血糖，将对短期恢复和长期维持p细胞功能（第一时相胰岛素分泌）以及长期血糖控制产生有利影响。为了解决这一假设，我们召集了3个具有青少年T2 DM专业知识的儿科内分泌/代谢和糖尿病中心，以确定：在新发T2 DM的肥胖青少年中，早期IVII加二甲双胍的短期疗程是否能快速达到空腹和餐后血糖正常，是否能恢复短期胰岛素分泌，维持长期胰岛素分泌的恢复，并相对于单独的二甲双胍治疗促进延长和持久的血糖控制。

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 beta-cell function. Indeed, the deterioration in beta-cell functio in youth with T2DM is accelerated relative to than that observed in adults. Furthermore, in childhood, the beta-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 beta-cell dysfunction, appearing long before significant changes in absolute glucose concentrations are apparent in obese youth. Declining beta-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 beta-cell to changes in glucose levels and beta-cell destruction due to glucolipotoxicity may contribute to alterations in insulin secretion. Early correction of glucotoxicity via early intensive insulin therapy, allowing beta-cell rest, may be a strategy to protet or produce sustained recovery of beta-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.