Beta-Cell Rescue in Youth with New Onset T2DM

β 细胞拯救新发 T2DM 青少年

• 批准号: 8336912
• 负责人: KRISTEN Jane NADEAU
• 金额: $ 106.15万
• 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/8336912
• 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.

描述（由申请人提供）：成人 2 型糖尿病 (T2DM) 的发生是由于胰岛素抵抗背景下 p 细胞功能逐渐下降所致，将儿科参与者纳入本 RFA 设想的研究至关重要，因为。青少年 T2DM 病理生理学存在微妙但重要的差异，特别是在 ¿ -细胞功能确实恶化。与成人相比，患有 T2DM 的青少年的细胞功能加速。 - 当青春期胰岛素抵抗恶化时，补偿胰岛素抵抗的细胞分泌负担会不成比例地增加，第一相胰岛素分泌减少是 ¿ -细胞功能障碍，早在肥胖青年的绝对葡萄糖浓度明显变化之前就出现了 ¿ -即使在非糖尿病正常范围内，随着空腹血糖水平的增加，这些肥胖青少年的细胞功能相对于胰岛素敏感性也很明显。 -细胞对葡萄糖水平的变化和¿ -由于糖脂毒性导致的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来早期纠正糖毒性，从而允许 ¿ -细胞休息，可能是保护或产生持续恢复的策略 ¿因此，我们认为，通过严格控制空腹和餐后高血糖，对新近诊断的 T2DM 青年进行早期强化静脉注射胰岛素 (IVII) 加二甲双胍，将对短期恢复和健康产生有利的影响。与单独使用二甲双胍治疗相比，可以长期维持 p 细胞功能（第一相胰岛素分泌）和长期血糖控制。为了解决这一假设，我们汇集了 3 个儿科中心。内分泌/代谢和糖尿病，具有青少年 T2DM 方面的专业知识，旨在确定：对新发 T2DM 的肥胖青少年进行短期 IVII 联合二甲双胍治疗，以快速达到空腹和餐后血糖正常，是否可以恢复短期胰岛素分泌，维持与单独的二甲双胍治疗相比，可以恢复长期胰岛素分泌，并促进延长和持久的血糖控制。