Abstract:
The liver has been suggested as a suitable target organ for reversing type 1
diabetes by gene therapy. Whilst gene delivery systems to the hepatocyte have
yet to be optimized in vivo, whether insulin-secreting hepatocytes are resistant
to the autoimmune process that kills pancreatic B-cells has never been
addressed. One of the mechanisms by which B-cells are killed in type 1
diabetes is by the release of the cytokines interleukin-If (IL-1B), tumour
necrosis factor-a (TNF-a)and interferon-y (IFN-y)by immune cells.To test the
effectof the cytokines on insulin-secreting hepatocytes in vitro we exposed the
betacyte, also called the HEP C2ins/g cell which possesses cytokine receptors
and can synthesize, store and secrete insulin in a regulated fashion to a glucose
stimulus, to the above mentioned cytokines for 14 days. Viability of the HEP
C2ins/g cells was similar to that of other liver cell lines/primary cells which
were more resistant to the cytokines than the B-celliine NIT-I. The cytokines
had no adverse effect for the first six days on insulin secretion, content and
mRNAlevels of the HEP C2ins/ g cells and insulin secretion in response to l-h
exposure to 20mM glucose was enhanced 14-fold. Our results indicate that
genetically engineered hepatocytes and primary liver cells are more resistant
than pancreatic B-cells to the adverse effects of cytokines offering hope that
insulin secreting hepatocytes in vivo made by gene therapy are less likely to be
destroyed by cytokines released during autoimmune destruction.
