Understanding the mechanisms of reversal of type 2 diabetes.

Clinical and pathophysiological studies have shown type 2 diabetes to be a condition mainly caused by excess, yet reversible, fat accumulation in the liver and pancreas. Within the liver, excess fat worsens hepatic responsiveness to insulin, leading to increased glucose production. Within the pancreas, the β cell seems to enter a survival mode and fails to function because of the fat-induced metabolic stress. Removal of excess fat from these organs via substantial weight loss can normalise hepatic insulin responsiveness and, in the early years post-diagnosis, is associated with β-cell recovery of acute insulin secretion in many individuals, possibly by redifferentiation. Collectively, these changes can normalise blood glucose levels. Importantly, the primary care-based Diabetes Remission Clinical Trial (DiRECT) showed that 46% of people with type 2 diabetes could achieve remission at 12 months, and 36% at 24 months, mediated by weight loss. This major change in our understanding of the underlying mechanisms of disease permits a reassessment of advice for people with type 2 diabetes.