Effects of Pancreatitis and Type 2 Diabetes Mellitus on the Development of Pancreatic Cancer: A Nationwide Nested Case-Control Study (Diabetes Metab J 2025;49:252-63)

Young-eun Kim; Min Heui Yu; Chung Mo Nam; Eun Seok Kang

doi:10.4093/dmj.2025.0314

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Response Effects of Pancreatitis and Type 2 Diabetes Mellitus on the Development of Pancreatic Cancer: A Nationwide Nested Case-Control Study (Diabetes Metab J 2025;49:252-63): Young-eun Kim¹, Min Heui Yu², Chung Mo Nam^3,4, Eun Seok Kang¹; Diabetes & Metabolism Journal 2025;49(3):522-523.
DOI: https://doi.org/10.4093/dmj.2025.0314
Published online: May 1, 2025

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¹Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea

²SENTINEL Team, Division of Endocrinology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea

³Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Korea

⁴Institute of Health Services Research, Yonsei University College of Medicine, Seoul, Korea

Corresponding author: Eun Seok Kang

Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea E-mail: edgo@yuhs.ac

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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See the letter "Pancreatitis, Type 2 Diabetes Mellitus, and Pancreatic Cancer (Diabetes Metab J 2025;49:252-63)" on page 518.

We sincerely appreciate the insightful comments provided by Dr. Lai and Dr. Liao regarding our recent publication entitled, ‘Effects of pancreatitis and type 2 diabetes mellitus on the development of pancreatic cancer: a nationwide nested case-control study’ [1]. We also would like to thank the editor for the opportunity to further discuss our findings and address the points raised.

First, we fully agree with your interpretation that the coexistence of type 2 diabetes mellitus (T2DM) and pancreatitis may have an additive effect on the risk of pancreatic cancer. In our study, the risk of pancreatic cancer was significantly higher in patients with both T2DM and pancreatitis than in those with either condition alone. A recent review has emphasized that these two conditions independently influence pancreatic cancer development, and their coexistence may further deteriorate the pancreatic tumor microenvironment, promoting the initiation and progression of pancreatic cancer [2].

Pancreatitis induces persistent inflammation characterized by recurrent cellular injury, cytokine secretion, fibrosis, and increased proliferative activity, creating a microenvironment favorable for tumor development. Specifically, cytokines such as interleukin 6 (IL-6) and IL-8, as well as activation of transcription factors like nuclear factor-κB, are closely associated with the development and progression of pancreatic neoplasms [3]. Meanwhile, T2DM, characterized by hyperinsulinemia and insulin resistance, stimulates insulin receptor and insulin like growth factor-1 (IGF-1) receptor signaling pathways such as phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK), which may promote pancreatic cell proliferation, survival, and tumorigenesis [4].

Moreover, recent literature highlights the significance of endocrine–exocrine crosstalk in the pancreas as a critical factor influencing disease progression. The simultaneous presence of metabolic and inflammatory stressors may further deteriorate the pancreatic tumor microenvironment and facilitate carcinogenesis [2]. Therefore, we concur that patients with both pancreatitis and diabetes mellitus should be considered at high risk for pancreatic cancer and may benefit from early screening and close clinical surveillance.

Furthermore, in our study, the pancreatic cancer risk did not significantly differ between patients with diabetes mellitus followed by pancreatitis and those with post-pancreatitis diabetes mellitus. This finding indicates that the simultaneous presence of the two conditions, regardless of their temporal order, is the primary determinant of pancreatic cancer risk. We fully concur with your interpretation on this point.

We concur that the exact mechanism underlying the increased pancreatic cancer risk in insulin users remains unclear—specifically, whether it results from poor glycemic control or β-cell dysfunction induced by pancreatic cancer. Future studies based on data sources that include glycosylated hemoglobin would help clarify the relationship among glycemic status, insulin use, and cancer risk.

Regarding your point on reverse causality, in our main analyses, we applied a one-year lag period to minimize this bias, and we performed sensitivity analyses using different lag periods to evaluate the robustness and consistency of our findings. As you correctly pointed out, the association was stronger with shorter lag periods, reinforcing the clinical implication that pancreatic cancer screening may be particularly important in individuals with newly diagnosed diabetes.

Furthermore, as this study employed a nested case-control design, we acknowledge that the reported odds ratios indicate associations rather than absolute risks. We appreciate your emphasis on this methodological point, which may help readers interpret our findings with appropriate caution.

In conclusion, we sincerely thank Dr. Lai and Dr. Liao for their insightful comments and constructive suggestions. Their points have allowed us to further clarify and underscore the significance and implications of our findings. We believe our responses have adequately addressed the issues raised and provide enhanced clarity regarding the interpretation and clinical relevance of our study.

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CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

REFERENCES

1. Kim YE, Yu MH, Nam CM, Kang ES. Effects of pancreatitis and type 2 diabetes mellitus on the development of pancreatic cancer: a nationwide nested case-control study. Diabetes Metab J 2025;49:252-63.Article PubMed PMC PDF
2. Hu C, Chen Y, Yin X, Xu R, Yin C, Wang C, et al. Pancreatic endocrine and exocrine signaling and crosstalk in physiological and pathological status. Signal Transduct Target Ther 2025;10:39.Article PubMed PMC PDF
3. Alhobayb T, Peravali R, Ashkar M. The relationship between acute and chronic pancreatitis with pancreatic adenocarcinoma: review. Diseases 2021;9:93.Article PubMed PMC
4. Cui Y, Andersen DK. Diabetes and pancreatic cancer. Endocr Relat Cancer 2012;19:F9-26.Article PubMed

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Effects of Pancreatitis and Type 2 Diabetes Mellitus on the Development of Pancreatic Cancer: A Nationwide Nested Case-Control Study (Diabetes Metab J 2025;49:252-63)

Diabetes Metab J. 2025;49(3):522-523. Published online May 1, 2025

DOI: https://doi.org/10.4093/dmj.2025.0314

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Effects of Pancreatitis and Type 2 Diabetes Mellitus on the Development of Pancreatic Cancer: A Nationwide Nested Case-Control Study (Diabetes Metab J 2025;49:252-63)

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Kim Ye, Yu MH, Nam CM, Kang ES. Effects of Pancreatitis and Type 2 Diabetes Mellitus on the Development of Pancreatic Cancer: A Nationwide Nested Case-Control Study (Diabetes Metab J 2025;49:252-63). Diabetes Metab J. 2025;49(3):522-523.

DOI: https://doi.org/10.4093/dmj.2025.0314.

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