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(T2D)病因学中的一个关键事件。尽管β细胞衰竭的原因尚不清楚，但已经有人提出了“脂毒性”。T2D患者的减肥手术和极低热量饮食导致疾病缓解，其特征是第一时相胰岛素分泌恢复和胰腺脂肪耗尽。然而，这些都是治疗T2D的极端方法，需要非侵入性、可持续但同样有效的治疗方法。我们已经在有T2D风险的个体中表明，维持体重的低血糖(LG)饮食的干预可以选择性地消耗内脏脂肪组织和肌肉中的异位脂肪，同时保留大腿皮下脂肪和瘦体重。这一观察表明，这种饮食能够通过将能量从对新陈代谢有害的脂肪储存中重新分配出来，来“重塑”身体成分。LG饮食的参与者还表现出胰岛素敏感性的改善和第一时相胰岛素分泌的戏剧性增加(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，包括胰腺脂肪，并将允许T2D患者的β细胞功能恢复。在非洲裔美国人(AA)中，挽救β细胞功能可能特别重要，因为他们作为一个群体表现出T2D的高患病率，原因无法用生活方式解释。再生障碍性贫血可能容易受到β细胞衰竭的影响，这是由于天生的高β细胞反应性(在健康的幼儿中表现明显)。此外，已有研究表明，胰腺脂肪是糖尿病前期的一个决定因素，尤其是在再障患者。因此，我们假设LG饮食对再生障碍性贫血患者的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，以检验维持体重的LG饮食与对照饮食(ADA/USDA)在所有食物供应下对早期T2D AA和欧美(EA)患者的磁共振成像(MRI)和高血糖钳夹胰岛素分泌第一时相胰岛素分泌的影响。这项研究将被用来检查特定种族的影响(种族x饮食交互作用)。该提案回应了PA-17-021，“解决NIDDK疾病中的健康差距”。这项研究的结果可能会改变临床护理指南，纳入LG饮食，这可能会减少AA经历的T2D及其并发症的不成比例的负担。

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.