Recovery β cell function important for reversal T2DM after substantial weight loss
Remission of human type 2 diabetes requires decrease in liver and pancreas fat content but is dependent upon capacity for β cell recovery
Introduction and methods
The Diabetes Remission Clinical Trial (DiRECT) showed that almost half of those with early (<6 years) of type 2 diabetes (T2DM) can be returned to long-term non-diabetic glucose control by substantial weight loss. Weight loss was achieved and maintained up to 12 months with a very low-calorie diet .
It is thought that in the process of development of T2DM, different, but related processes occur in liver and pancreas, involving a major decline in β cell function [2,3]. Metabolic stress can induce β cell de-differentiation and it has been demonstrated that significant weight loss can lead to re-differentiation. This may explain return from T2DM to normal glucose tolerance [4-7].
This pathophysiologic subanalysis of the DiRECT study investigated liver fat content, liver export of triglycerides, pancreas fat content and β cell function in a geographically pre-defined subgroup of participants. Participants with T2DM were randomized to either a low-calorie diet (intervention group, n=64) or usual diabetes management (control group, n=26). The intervention group received liquid formula (825-853 kcal/day) for 12-20 weeks (weight loss phase), followed by a 2-6 week stepped food reintroduction and ongoing support for weight maintenance. Responders were defined as those who returned to non-diabetic glucose control after the weight loss phase.
- At baseline, responders were similar to non-responders, but diabetes duration was longer in non-responders (2.7 ± 0.3 vs 3.8 ± 0.4 years, P=0.02).
- As a result of the weight loss intervention, weight decreased to a similar extent in responders and non-responders (responders: 100.6 ± 2.6 to 84.4 ± 2.1 kg, P<0001, non-responders: 102.1 ± 4.4 to 88.7 ± 4.4 kg, P<0.0001).
- Between the end of the weight loss phase and at 12 months, weight increased in responders (3.3 ± 0.8 to 86.2 ± 3.0 kg, P<0.0001) and non-responders (4.9 ± 0.8 to 92.5 ± 4.6 kg). At 12 months, weight in non-responders was lower compared to baseline (P<0.0001), but overall change from baseline was greatest in responders (-14.1 ± 1.5 vs. -9.4 ± 1.3 kg, P=0.02).
- Fasting plasma glucose levels and HbA1c decreased after the weight loss phase in responders (from 148.9 ± 6.8 to 102.2 ± 2.2 mg/dL, P<0.0001 and from 7.4% to 5.9% ± 0.1%, P<0.0001, respectively). No significant changes were seen in non-responders.
- Liver fat content reduced after weight loss in both responders (to 3.3% ± 0.6%, P<0.0001) and non-responders (to 2.6% ± 0.5%, P<0.0001), and the change in liver fat content was similar in both groups (P=0.60). At 12 months, responders had 3.0% ±0.6% liver fat and non-responders 6.1% ± 1.9%, which reflected a significant increase in non-responders as compared with after the weight loss phase. The increase in liver fat during the weight maintenance phase correlated with the degree of weight gain.
- Pancreatic fat was reduced after weight loss, independently of glucose control normalization (responders: 8.7% to 7.8% ± 0.4%, P<0.0001 and non-responders: 7.9% to 7.1% ± 0.5%, P=0.004). Pancreatic fat remained stable during the weight maintenance phase.
- Fasting plasma insulin levels decreased after weight loss in responders (108.3 ± 10.0 to 38.7 ± 4,4 pmol/L, P<0.0001) and non-responders (77.2 ± 8.5 to 35.5 ± 5.3 pmol/L, P=0.0002). Because of higher baseline levels, the reduction was stronger in responders (-69.7 ± 9.3 vs -41.7 ± 5,8 pmol/L, P<0.01). Fasting plasma insulin remained stable in the weight maintenance phase in both responders and non-responders.
- First-phase insulin secretion recovered in those with normalized glucose control after weight loss (0.04 [-0.05-0.32] tot 0.11 [0.00005-0.51] nmol/min/m2 (P<0.0001), while no change was seen in non-responders. The increase in first-phase insulin secretion in responders was maintained during the weight maintenance phase.
Weight loss and return to normal glucose homeostasis were achieved with a structured weight loss intervention in T2DM patients. Those who returned to normal glucose regulation showed sustained recovery of the first-phase insulin response. Irrespective of whether participants showed normalized glucose regulation, liver fat content was reduced, which was maintained up to 12 months. These data suggest that weight loss in early T2DM can lower intra-organ fat content in all, and return to glucose homeostasis appears to be dependent on recovery of β cell function.