Remission of human type 2 diabetes requires decrease in liver and pancreas fat content but is dependent upon capacity for β cell recovery

Literature - Taylor R, Al-Mrabeh A, Zhyzhneuskaya S et al. - Cell Metabolism 2018; DOI: https://doi.org/10.1016/j.cmet.2018.07.003

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 [1].

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.

Main results

• 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.

Conclusion

References

Find this article online at Cell Metabolism Read our summary of the original DiRECT study results