Depletion of pancreatic lipid improves beta-cell function in early type 2 diabetes

第一时相胰岛素分泌下降是2型糖尿病（T2 D）病因学中的关键事件。虽然β细胞衰竭的原因尚不清楚，但已经提出了“脂毒性”。T2 D患者的减肥手术和极低热量饮食可诱导疾病缓解，其特征为第一时相胰岛素分泌恢复和胰腺脂质耗竭。然而，这些都是治疗T2 D的极端方法，需要非侵入性，可持续，但同样有效的治疗方法。我们已经在T2 D风险个体中表明，采用体重维持低血糖（LG）饮食的干预选择性地消耗内脏脂肪组织和肌肉中的异位脂质，同时保留大腿皮下脂肪和瘦体重。这一观察结果表明，这种饮食能够通过将能量从代谢有害的脂质储存中重新分配出来来“重塑”身体组成。LG饮食的参与者也表现出胰岛素敏感性的改善和第一阶段胰岛素分泌的显着增加（9倍）。因此，我们假设维持体重的LG饮食将选择性地消耗异位脂肪组织，包括胰腺脂质，并允许T2 D患者的β细胞功能恢复。β细胞功能的拯救在非洲裔美国人（AA）中可能特别重要，他们作为一个群体表现出T2 D的高患病率，原因无法用生活方式来解释。由于固有的高β细胞反应性（在健康幼儿中可证实），AA可能容易受到β细胞衰竭的影响。此外，已经表明胰腺脂质是糖尿病前期的决定因素，特别是在AA中。因此，我们假设LG饮食对AA患者的β细胞功能和血糖控制特别有益。为了验证这些假设，我们将进行一项随机临床试验，以检查维持体重的LG饮食与对照饮食（ADA/USDA）的影响，所有食物均通过磁共振成像（MRI）和高血糖钳夹和口服餐试验在AA和欧美（EA）早期T2 D（自诊断以来<5年）个体中的第一时相胰岛素分泌对胰腺脂质变化的影响。本研究将检验种族特异性效应（种族x饮食相互作用）。本提案是对PA-17-021“解决NIDDK疾病中的健康差异”的回应。这项研究的结果可能会改变临床护理指南，以纳入LG饮食，这可能会减少AA所经历的T2 D及其并发症的不成比例负担。

The decline in first-phase insulin secretion is a key event in the etiology of type 2 diabetes (T2D). Although the cause of beta-cell failure is not clear, “lipotoxicity” has been proposed. Bariatric surgery and very-low calorie diets in patients with T2D induce disease remission, characterized by a return of first-phase insulin secretion and a depletion of pancreas lipid. However, these are extreme approaches to treating T2D, and non-invasive, sustainable, yet equally effective, treatments are needed. We have shown in individuals at risk for T2D that an intervention with a weight-maintaining low-glycemic (LG) diet selectively depletes visceral adipose tissue and ectopic lipid in muscle while preserving thigh subcutaneous adipose and lean body mass. This observation suggests that such diets are able to “remodel” body composition by re-partitioning energy away from metabolically harmful lipid stores. Participants on the LG diet also demonstrated improved insulin sensitivity and a dramatic (9-fold) increase in first-phase insulin secretion. Thus, we hypothesize that a weight-maintaining LG diet will selectively deplete ectopic adipose tissue, including pancreatic lipid, and will permit recovery of beta-cell function in individuals with T2D. Rescue of beta-cell function may be particularly important in African-Americans (AA), who as a group demonstrate a high prevalence of T2D, for reasons that cannot be explained by lifestyle. AA are likely to be vulnerable to beta-cell failure due to inherently high beta-cell responsiveness (demonstrable in healthy young children). Further, it has been shown that pancreas lipid is a determinant of prediabetes specifically in AA. Thus, we hypothesize that an LG diet will be particularly beneficial to beta-cell function and glycemic control among AA. To test these hypotheses, we will conduct a randomized clinical trial to examine the impact a weight-maintaining LG diet vs a Control diet (ADA/USDA) with all food provided on changes in pancreatic lipid by magnetic resonance imaging (MRI) and first-phase insulin secretion by hyperglycemic clamp and oral meal test in AA and European-American (EA) individuals with early T2D (<5 yr since diagnosis). The study will be powered to examine race-specific effects (race x diet interaction). This proposal responds to PA-17-021, “Addressing Health Disparities in NIDDK Diseases.” The results from this study could change clinical care guidelines to incorporate an LG diet, which may reduce the disproportionate burden of T2D and its complications experienced by AA.