Our results provide the first genetic evidence that the decrease in pancreas volume may be causal of type 2 diabetes. Our results support the hypothesis that underlying mechanisms associated with reduced pancreatic volume precede diagnosis of type 2 diabetes. However, we did not see any evidence for a causal role of reduced pancreas volume in the risk of type 1 diabetes, which could be explained by two main factors. First, our genetic instrument for pancreas volume is based on MRI scan data of pancreas in adults with a mean age of 63.8 ± 7.52 years. It is possible that adult pancreas volume does not correlate with pancreas volume in childhood when type 1 diabetes starts. However, observationally, pancreas volume had a stronger association with the risk of type 1 diabetes versus type 2 diabetes in our data. Second, we had less power to detect a causal association with risk of type 1 diabetes compared with type 2 diabetes (9,358 cases vs. 55,005 cases, respectively). However, the direction of effect from the MR study was not consistent with a tentative causal effect between reduced pancreas volume and higher risk of type 1 diabetes. The variant with the strongest effect on pancreas volume is located near CTRB2 and has opposing effects on risk of type 1 and type 2 diabetes; the pancreas volume–increasing allele is associated with lower risk of type 2 diabetes and higher risk of type 1 diabetes. Given that the pathogeneses of type 1 and type 2 diabetes are clearly different, it could be that the process driving the development of the former, probably autoimmune reaction, may override any effect of organ size. Furthermore, there may be some variants linked to higher volume that may also be linked to greater likelihood of an autoimmune reaction. The minor allele of a correlated variant (rs7202877; r2 = 0.66) was previously identified to be a risk factor for type 1 (29) and a protective factor for type 2 (30) diabetes. The protective effect of the allele against type 2 diabetes has been reported to be associated with glucagon-like peptide 1–stimulated insulin secretion (31). Moreover, a recent interventional study showed that weight gain and prolonged diabetes duration often lead to smaller pancreases, while weight loss reverses this effect, a narrative supportive of the relationship of pancreatic size and type 2 diabetes (32), although our work adds support for pancreatic size being causal for type 2 diabetes, opening the potential for a bidirectional relationship.

Our study had some limitations: 1) We used organ volume and fat content measured in adulthood, which could bias the association with type 1 diabetes toward the null effect. 2) For some genetic variants we used as instruments, the causal genes and therefore the biological mechanisms are unknown, which makes it difficult to test bias and pleiotropy. However, we used rigorous sensitivity tests that supported the main results. 3) Our measurement of pancreas volume does not differentiate between endocrine and exocrine pancreas, and more specific data are needed to understand the role of β-cell mass or exocrine inflammation in mechanisms that link reduced pancreas volume to higher risk of diabetes. 4) The phenotyping of liver and pancreas volume/fat was performed on tractable measures derived from image segmentation. Although it is possible that some imaging artifacts are introduced in the results, any variance due to this is likely negligible given the size of the cohort and could not have affected our genetic instruments. 5) Using three-point Dixon MRI of the pancreas, we may not have perfectly captured the pathological areas of pancreatic fat in comparison with the more sophisticated technique of the magnetic resonance image “biopsy” method (MR-opsy) (28). However, MR-opsy is not practical for the very large cohorts required for genetic studies, the scale of which demands automated analysis, and the overall impact of the method we used in the current study on the PDFF values and therefore the genetic associations would be minimal. 6) The small difference (∼1.25-fold) in pancreas fat content between people with and without type 2 diabetes, and the wide range among people, raises the question of sensitivity of our approach to detect a genuine difference. By taking an MR approach and using a strong instrument for pancreas fat and a large sample size, we had 99% power to detect any association between pancreas fat and risk of type 2 diabetes. However, we suggest that replication of the association between the instrument and pancreas fat in an independent cohort would be valuable. 7) The MRI-derived phenotypes represent the tissue as a whole, without investigation of within-organ heterogeneity, e.g., differences in the regional distribution of fatty deposits within the liver and pancreas or differences in cell type or tissue sections. Also, the present set of parameters does not account for differences in organ shape or position. 8) This study was conducted in a cohort of European ancestry. Even modest differences across populations in contributions of common variation to complex traits necessitate broadening the diversity of populations studied (33). Therefore, our findings are only generalizable to the European population. Finally, change in liver and pancreas fat content or volume could also be affected by pathophysiological mechanisms secondary to type 1 or type 2 diabetes. For example, subclinical exocrine inflammation of the pancreas associated with insulitis (34), as well as insulin deficiency and the lack of a trophic effect on pancreas exocrine tissue (3), could contribute to reduced pancreatic volume in type 1 diabetes, while atherosclerosis might cause reduction in pancreas volume in type 2 diabetes (35). Future MR studies investigating the role of type 1 and type 2 diabetes on changes in these features are needed to understand the role of other mechanisms or whether there is a mutual causal effect. We hope other groups can validate or expand our findings in relevant data sets, should they exist with sufficient power.

In summary, our results are in line with a causal role for higher liver fat and reduced pancreas volume in type 2 diabetes etiology and show consistency in sensitivity analyses. Given the worldwide increasing prevalence of type 1 and type 2 diabetes, better understanding of the underlying mechanisms involving liver and pancreas volume and fat content may provide new insights into preventing and treating diabetes.