Excessive Intrapancreatic Fat Deposition: A Missing Metabolic Driver of Pancreatic Carcinogenesis in Type 2 Diabetes?

Intrapancreatic fat deposition (IPFD) is characterised by ectopic fat in the pancreas, notably distinct from visceral or hepatic adiposity 1. With advances in abdominal imaging for fat quantification (e.g., magnetic resonance imaging MRI), the excess form of IPFD, known as fatty pancreas disease, has gained increasing recognition as a pathologic state associated with endocrine dysfunction and susceptibility to pancreatic injury 1-5. While IPFD is physiologically present in a normal pancreas, individuals with type 2 diabetes (T2D) exhibit considerably higher IPFD than their healthy counterparts 6, 7. This raises the possibility that IPFD represents not merely a marker of metabolic dysfunction 8, 9, but a modifiable trait with implications for pancreatic carcinogenesis 10. Against this background, the population-based study by Tan et al. 11 provides compelling evidence connecting long-term glycaemic control with pancreatic cancer (PC) incidence in individuals with T2D. In a cohort of more than 450 000 patients, followed for nearly a decade, they provide evidence of a strong relationship between worsening dysglycaemia and increasing PC risk 11. Remarkably, each 1% increase in HbA1c was associated with a 46% higher long-term risk of PC 11. Notably, individuals who maintained optimal glycaemic control during the follow-up (defined as time-weighted mean HbA1c 10%), followed over a median of 4.5 years. However, this relatively short follow-up may be insufficient to fully capture the long latency period of pancreatic carcinogenesis 18, likely underestimating the long-term impact of sustained exposure to high IPFD. The observed association was further supported as potentially causal in Mendelian randomisation analyses. Similarly, Chatterjee et al. 19 demonstrated that patients with FPD (with computed tomography CT-based IPFD quantification) had a significantly higher risk of PC in a propensity-matched cohort. Importantly, IPFD measurement varies across imaging modalities. MRI provides precise fat fraction quantification of IPFD, while CT-based assessments rely on attenuation values and may be influenced by fibrosis and/or technical factors; this heterogeneity may affect threshold definitions and limit comparability across studies. Notably, there is no longitudinal evidence specifically evaluating whether IPFD modifies PC risk within the T2D population 20, representing an unmet need for future research. Collectively, these considerations raise the question of whether IPFD may represent a missing mechanistic link in the observed association between chronic dysglycaemia and pancreatic carcinogenesis in T2D. Prospective longitudinal studies incorporating MRI-quantified IPFD are needed to address this hypothesis. Such evidence could strengthen future PC prevention strategies in people with T2D, and open avenues for refined risk stratification and targeted therapeutic interventions in this population. From a translational perspective, potential intervention strategies to reduce IPFD include sustained glycaemic control, glucose-lowering medications, bariatric surgery and structured lifestyle interventions, as suggested in prior meta-analyses and observational studies 21-23. However, whether IPFD modification translates into a reduction in subsequent PC incidence remains unknown and warrants prospective investigation in future trials with serial MRI-based IPFD quantification. In conclusion, as the global burden of T2D and PC continues to rise 16, 24, unveiling modifiable upstream drivers of pancreatic carcinogenesis is a critical priority. IPFD, long overshadowed by hepatic and visceral adiposity, may be an overlooked yet actionable piece of this metabolic puzzle. M.S. wrote the manuscript. ChatGPT (OpenAI) was used only for language editing. The author takes full responsibility for the content of this manuscript. The author has nothing to report. The author declares no conflicts of interest. The author has nothing to report. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.70645.