Aetiology of type 2 diabetes: an experimental medicine odyssey.

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.