Towards reversal of type 3c diabetes through anti-fibrotic therapy with marketed therapeutics

Diabetes secondary to chronic pancreatits (CP) has been relatively neglected but incidence may be as high as type 1 diabetes. It is characterised by progressive loss of β-cell function without absolute loss of β-cell mass. Up to 50% of those affected require insulin therapy and glucose levels can be highly unpredictable.

CP pancreatitis primarily affects the exocrine pancreas leading to fibrosis mediated by activated stellate cells which are believed to be activated by TGF-β1. We propose that: 1.

TGF-β1 drives loss of β-cell functional mass by direct signalling to endocrine cells and/or indirectly via activated stellate cells. 2. Treatment with marketed anti-fibrotic therapeutics, pirfenidone and nintedanib, will restore normal β-cell function.

We aim to test these hypotheses in: activated pancreatic stellate cells derived from primary human islets (ISCs); EndoC-βH1 human β-cells; and viable precision-cut pancreatic slices obtained from CP donors undergoing surgical resection.

ISC collagen secretion / profibrotic secretome will be characterised and impact of TGF-β1 activation and ISC-conditioned medium on EndoC-βH1 phenotype/function evaluated.

ISC (collagen secretion) and β-cell (glucose-stimulated insulin secretion) function will be studied in CP pancreatic slices.

Impact of chemical TGF-β inhibition and pirenidone/nintedanib incubation in inducing stellate cell quiescence and restoring β-cell function will be tested.