What’s wrong with the pancreas in diabetes?

25th April 2026, A/Prof Chee L Khoo

pancreas

When we think about diabetes, we think about the shrinkage of beta cell mass and its inability to keep up with the insulin demand. We have lots of information of what the islet cells can or cannot do in diabetes but we don’t actually know much of pathogenesis of the pancreatic endocrine (or exocrine) dysfunction in diabetes. There is now increasing data on the role of exocrine pancreatic cellular fibrosis and profibrotic signalling as a potential common pathway in the pathogenesis of beta cell insufficiency in diabetes across the spectrum of aetiologies. This may open up avenues for rescuing or resurrecting the poor beta cells and actually treat the underlying cause of diabetes.

We did discuss type 3c diabetes as the disease of the exocrine pancreas. 75% of DEP is caused by chronic pancreatitis. The other causes of DEP include acute pancreatitis, cystic fibrosis, pancreatic adenocarcinoma, pancreatic surgical resections and autoimmune pancreatitis. Less common causes of DEP are hereditary hemochromatosis, transfusion overload, and thalassemia major. Chronic pancreatitis-associated diabetes is not only characterised by insufficient insulin secretion but also by alpha cell dysfunction causing blunted response to hypoglycaemia and reduction in pancreatic polypeptide secretion which is thought to contribute to hepatic insulin resistance.

By understanding the pathophysiology in these conditions, we can learn about the pathogenesis of diabetes in these conditions. Let’s look at the evidence:

Chronic pancreatitis

Pancreatic exocrine fibrosis, initially between lobules and surrounding ducts and then replacing areas of intralobular acinar parenchyma in parallel with pancreatic ductal pathology, is ubiquitously present in chronic pancreatitis of all aetiologies (1-4). The fibrosis is associated with activated PSCs which deposit collagen and other extracellular matrix components in the progressive fibrotic process in chronic pancreatitis. It has been proposed that conversion from tissue repair to scarring fibrosis in chronic pancreatitis may be mediated by a perpetual cycle involving activated PSCs, macrophages and pancreatic duct cells (5-7).

While there is definite reduction in the endocrine cell ratios, electron microscopy did not reveal degenerative lesions within beta cells, although insulin granule numbers appeared reduced. Fibrotic disruption of endocrine cell vascularisation and cell-to-cell connectivity or vascular pathology not associated with fibrosis may be indirect mediators of beta cell dysfunction and ultimately diabetes in chronic pancreatitis. It is thought that perpetual profibrotic signalling cycle within the islet niche in chronic pancreatitis in the presence of elevated tissue TGF-β levels that may drive islet dysfunction and ultimately diabetes.

Cystic fibrosis related diabetes (CFRD)

Progressive loss of beta cell function occurs in those with pancreatic exocrine insufficiency, with fewer than 10% of those with cystic fibrosis developing CFRD before the age of 10 years compared with a prevalence of 20% in adolescents, 50% in adults and up to 80% in those aged over 50 years with the most severe CFTR genotype (8-12).

Just like in chronic pancreatitis, there is evidence of peri-islet fibrosis from activated PSCs and macrophages in and around islets (13,14). It is though that there is a second fibrotic wave which leads to CFRD through a paracrine effect that alters the islet cell phenotype and function and/or through a mechanical effect on vascularisation and endocrine cell communication (as exemplified in chronic pancreatitis in disorganised islets.

Pancreatic ductal adenocarcinoma (PDAC)

In a UK Biobank study, PDAC diagnosis was associated with worsening of glucose levels in established diabetes (15). The relationship between new-onset diabetes and PDAC is striking, with diabetes detected a median of 10 months before cancer diagnosis (16). An eightfold increased risk of PDAC in older individuals with new-onset diabetes compared with the non-diabetic population has been proposed, suggesting a common aetiology (17).

Diabetes does not appear to be caused by physical destruction of a large proportion of islet mass (18). New-onset diabetes is thus believed to be a paraneoplastic phenomenon where one or more tumour-secreted factors interfere with insulin secretion. In a study of 104 individuals who underwent PDAC resection, 57% with new-onset diabetes had resolution of their diabetes postoperatively, supporting a paraneoplastic mechanism enabling recovery of normal glucose homeostasis even after surgical reduction of overall pancreatic endocrine mass (19).

It would seem from the evidence we have thus far, that diabetes is more about beta cell dysfunction rather beta cell death. TGF-β is a key driver of fibrosis across a wide range of human tissues. Within these tissues this cytokine directly activates resident fibroblasts inducing collagen synthesis and secretion and leading to extracellular matrix deposition and fibrosis. Administration of a TGF-β inhibitor in a mouse model of PDAC inhibited beta cell apoptosis. 

Potential candidates

Pirfenidone has become established as an antifibrotic therapy for IPF, reducing lung function decline (20,21). It is a synthetic pyridine that acts primarily through inhibition of TGF-β signalling through a range of mechanisms [139]. In animal studies, Pirfenidone has been shown to reduce islet fibrosis but has not been shown to have any impact on beta cell mass or function.

Nintedanib is also licensed for IPF therapy and has been shown to reduce the rate of pulmonary function decline. It has also shown to regress fibrosis in animal studies.

The first randomised clinical trial using antifibrotic therapy in pancreatic disease is currently underway in the USA comparing pirfenidone with placebo in acute pancreatitis (22).

References

  1. Klöppel G, Detlefsen S, Feyerabend B (2004) Fibrosis of the pancreas: the initial tissue damage and the resulting pattern. Virchows Arch 445:1–8.
  2. Schrader H, Menge BA, Schneider S et al (2009) Reduced pancreatic volume and beta-cell area in patients with chronic pancreatitis. Gastroenterology 136:513–522.
  3. Shi C, Washington MK, Chaturvedi R et al (2014) Fibrogenesis in pancreatic cancer is a dynamic process regulated by macrophage–stellate cell interaction. Lab Investig 94:409–421.
  4. Webb MBA, Chen JJ, James RFL, Davies MJ, Dennison AR (2018) Elevated levels of alpha cells emanating from the pancreatic ducts of a patient with a low BMI and chronic pancreatitis. Cell Transplant 27:902–906.
  5. Klöppel G (2007) Chronic pancreatitis, pseudotumors and other tumor-like lesions. Mod Pathol 20:S113–S131. https://doi.org/10.1038/modpathol.3800690
  6. Kong F, Pan Y, Wu D (2024) Activation and regulation of pancreatic stellate cells in chronic pancreatic fibrosis: a potential therapeutic approach for chronic pancreatitis. Biomedicines 12:108. https://doi.org/10.3390/biomedicines12010108
  7. Detlefsen S, Sipos B, Feyerabend B, Klöppel G (2006) Fibrogenesis in alcoholic chronic pancreatitis: the role of tissue necrosis, macrophages, myofibroblasts and cytokines. Mod Pathol 19:1019–1026
  8. Gaskin K, Gurwitz D, Durie P, Corey M, Levison H, Forstner G (1982) Improved respiratory prognosis in patients with cystic fibrosis with normal fat absorption. J Pediatr 100:857–862. https://doi.org/10.1016/s0022-3476(82)80501-5
  9. Cystic Fibrosis Trust (2024) UK Cystic Fibrosis Registry 2023 Annual Data Report. Cystic Fibrosis Trust, London
  10. Cystic Fibrosis Foundation (2024) Cystic Fibrosis Foundation Patient Registry 2023 Annual Data Report. Cystic Fibrosis Foundation, Bethesda, MA, USA
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  12. Lewis C, Blackman SM, Nelson A et al (2015) Diabetes-related mortality in adults with cystic fibrosis. Role of genotype and sex. Am J Respir Crit Care Med 191:194–200.
  13. Löhr M, Goertchen P, Nizze H et al (1989) Cystic fibrosis associated islet changes may provide a basis for diabetes. Virchows Arch A Pathol Anat Histopathol 414:179–185.
  14. Al-Selwi Y, Tiniakos D, Richardson SJ et al (2026) Generation of a pseudo-timeline describing progressive human exocrine and endocrine pancreatic pathology in cystic fibrosis through novel semi-quantitative scoring and AI-driven quantitative image analysis. Diabetologia 69:157–172.
  15. McDonnell D, Cheang AWE, Wilding S et al (2023) Elevated glycated haemoglobin (HbA1c) is associated with an increased risk of pancreatic ductal adenocarcinoma: a UK Biobank Cohort Study. Cancers 15:4078–4078 
  16. Pelaez-Luna M, Takahashi N, Fletcher JG, Chari ST (2007) Resectability of presymptomatic pancreatic cancer and its relationship to onset of diabetes: a retrospective review of CT scans and fasting glucose values prior to diagnosis. Am J Gastroenterol 102:2157–2163
  17. Chari ST, Leibson CL, Rabe KG, Ransom J, De Andrade M, Petersen GM (2005) Probability of pancreatic cancer following diabetes: a population-based study. Gastroenterology 129:504–511
  18. Tsuchiya R, Noda T, Harada N et al (1986) Collective review of small carcinomas of the pancreas. Ann Surg 203:77–81
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  20. Lopez-de la Mora DA, Sanchez-Roque C, Montoya-Buelna M et al (2015) Role and new insights of pirfenidone in fibrotic diseases. Int J Med Sci 12:840–847. 
  21. Schaefer C, Ruhrmund D, Pan L, Seiwert S, Kossen K (2011) Antifibrotic activities of pirfenidone in animal models. Eur Respir Rev 20:85–97.
  22. Bava EP, Jain T, Al-Obaidi M et al (2025) Safety, tolerability and therapeutic efficacy of anti-inflammatory drug pirfenidone in acute pancreatitis patients: Protocol for a randomized pilot clinical trial. Pancreatology 25:214–220.