New evaluations of data from the DiRECT study show for the first time that, after weight reduction, not only diabetes remissions are possible, but also the pancreas morphology returns to normal.
We should first remember the 2018 DiRECT study (Diabetes Remission Clinical Trial), in which 306 type-2 diabetics from 49 British general practitioners were randomly assigned to lifestyle intervention (weight loss program) or standard management, with the result that after 12 months almost half of the participants in the intervention achieved remission and no longer needed any anti-diabetics.1
For an analysis published in The Lancet in autumn 2020, the proportion of DiRECT patients who were able to come to the Newcastle University Magnetic Resonance Centre also had pancreatic volume, organ boundary irregularities, and intrapancreatic fat content measured by MRI (at baseline and 5, 12 and 24 months after intervention).2 Beta-cell function and biomarkers of tissue growth were also recorded.
MRI studies have described a 20-30% reduction in organ size and organ shape changes in type 2 diabetics.2, 3 It is not known whether people with a pancreas that is smaller or dysmorphic at birth are more likely to develop type 2 diabetes or whether the reduced size is a result of the disease process. Insulin is a potent growth hormone in the high postprandial concentrations to which the pancreatic parenchyma is normally exposed. A loss of these "peaks" of insulin secretion in diabetes could lead to organ involution.
Intervening participants were classified as responders (HbA1c < 6.5%, fasting blood glucose < 7.0 mmol/l, all antidiabetic drugs discontinued) or non-responders.
A total of 90 type-2 diabetics were randomised to the weight management programme (n = 64) or standard care (n = 26). A further 25 patients were recruited into a non-diabetic control group to evaluate the extent of normalization (matched to the intervention group in terms of age, sex, and weight after weight loss).
At baseline, the average pancreas size of all diabetics was significantly lower than that of the non-diabetic reference group (61.7 cm3 vs. 79.8 cm3, p < 0.0001).
Responders showed a volume increase of 9.4 cm3 after 24 months (vs. 6.4 cm3 for non-responders; p = 0.0008). In addition, type-2 diabetics showed significantly more organ border irregularities at baseline than non-diabetics (fractal dimension 1.138 vs. 1.097; p < 0.0001), which normalised for responders after 24 months (1.099). Intrapancreatic fat decreased by 1.02 percentage points among responders (vs. 0.51% among non-responders; p = 0.23).
This study is the first to show normalization of gross organ morphology after weight loss-induced diabetes remission. "We observed a significant increase in pancreatic volume and a decrease in organ shape irregularities over two years with recovered postprandial insulin secretion," the authors conclude. The increase in pancreatic size was accompanied by a restoration of beta-cell function as well as a decrease in intrapancreatic fat content and changes in circulating growth factors.
The scientists point out that the pancreas - despite its central importance for the metabolic control of the entire organism - is still relatively little researched. Its difficult to reach anatomical position makes in vivo studies difficult. The authors searched Pubmed for the keywords "diabetes type 2" and "pancreas volume" and received only 15 hits. Most of the papers were cross-sectional studies. None dealt with the effects of weight loss-induced diabetes remission on pancreas size. Most studies on diabetes focused on islet cell function and paid little attention to the organ as a whole. In the present work, too, the complexity of repeated MRIs may have made it difficult to recruit a sufficient number of patients.
The fact that type-2 diabetics can return to normal blood sugar levels in the long term after losing weight is well documented, but not yet generally accepted. These results underline that type 2 diabetes is a potentially reversible disease affecting the whole pancreas and that gradual morphological and functional recovery is possible in the context of remissions.
References:
1. Lean, M. E. et al Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. The Lancet 391, 541-551 (2018).
2. Al-Mrabeh, A. et al. 2-year remission of type 2 diabetes and pancreas morphology: a post-hoc analysis of the DiRECT open-label, cluster-randomised trial. The Lancet Diabetes & Endocrinology 0, (2020).
3. Yagihashi, S. Diabetes and pancreas size, does it matter? J Diabetes Investig 8, 413-415 (2017).