Taylor Roy
Magnetic Resonance Centre, Translational and Clinical Research Institute, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK.
Diabetologia. 2025 May 2. doi: 10.1007/s00125-025-06428-0.
This review describes a prolonged research endeavour to test the twin cycle hypothesis that type 2 diabetes is caused by fat-induced dysfunction of the liver and pancreas, guided by the happenstance of clinical practice. Testing of the personal fat threshold hypothesis, that individuals exhibit different levels of tolerance to intra-organ fat accumulation, is also described. Both hypotheses predict that type 2 diabetes is potentially reversible by weight loss. The results of the Counterpoint study supported the twin cycle hypothesis, leading to a second study which determined that short-duration diabetes was more likely to remit following the 10-15 kg weight loss. It also confirmed that remission was durable over 6 months on an isoenergetic, normal diet. Subsequently, it was shown that weight loss caused an immediate decrease of pancreas fat only in people with type 2 diabetes and also that postprandial incretin spikes after bariatric surgery had no role in normalising fasting plasma glucose. DiRECT, a 2 year randomised controlled study, demonstrated clinical utility, observing functional beta cell capacity to return almost to normal over 12 months. A small group of participants regained weight and redeveloped type 2 diabetes, allowing observation that the underlying pathophysiological mechanisms during onset of diabetes were as postulated by the twin cycle hypothesis. Major clinical benefit was demonstrated after a further 3 year follow-up in routine care, halving the incidence of serious adverse effect compared with the standard treatment control group. In answer to the question of whether individuals have a personal fat threshold for tolerance of fat, stepwise weight loss in people with type 2 diabetes and BMI in the range 21-27 kg/m resulted in remission in 70%, with a wide range of fat thresholds. Type 2 diabetes can be regarded as a condition of homogenous aetiology in genetically heterogenous individuals.
本综述描述了一项长期的研究工作，以检验双循环假说，即2型糖尿病是由脂肪诱导的肝脏和胰腺功能障碍引起的，该研究受临床实践中的偶然事件所引导。文中还描述了对个人脂肪阈值假说的测试，即个体对器官内脂肪堆积表现出不同程度的耐受性。这两种假说都预测2型糖尿病可能通过减肥而逆转。对位研究的结果支持了双循环假说，从而促成了第二项研究，该研究确定短期糖尿病患者在体重减轻10 - 15公斤后更有可能缓解。研究还证实，在等能量的正常饮食下，缓解状态可持续6个月以上。随后发现，体重减轻仅在2型糖尿病患者中导致胰腺脂肪立即减少，并且减肥手术后餐后肠促胰岛素峰值对空腹血糖正常化没有作用。DIRECT，一项为期2年的随机对照研究，证明了其临床实用性，观察到功能性β细胞能力在12个月内几乎恢复正常。一小部分参与者体重反弹并再次患上2型糖尿病，这使得人们观察到糖尿病发病期间的潜在病理生理机制与双循环假说所假设的一致。在常规护理中进行的进一步3年随访显示出主要的临床益处，与标准治疗对照组相比，严重不良反应的发生率减半。对于个体是否存在脂肪耐受性的个人脂肪阈值这一问题，2型糖尿病且体重指数在21 - 27 kg/m范围内的患者逐步减肥，70%的患者实现了缓解，且脂肪阈值范围广泛。在基因异质性个体中，2型糖尿病可被视为一种病因同质的疾病。
