Electrofusion-derived BRIN-BD11 cells are glucosesensitive
insulin-secreting cells which provide an
archetypal bioengineered surrogate β-cell for
insulin replacement therapy in diabetes mellitus,
5x106 BRIN-BD11 cells were implanted intraperitoneally
into severely hyperglycaemic (>24mmol/l)
streptozotocin-induced insulin-treated diabetic
athymic nude (nu/nu) mice. The implants reduced
hyperglycaemia such that insulin injections were
discontinued by 5–16 days (<17mmol/l) and normoglycaemia
(<9mmol/l) was achieved by 7–20
days. Implanted cells were removed after 28 days
and re-established in culture. After re-culture for 20
days, glucose-stimulated (16.7mmol/l) insulin
release was enhanced by 121% (p<0.001) compared
to non-implanted cells. Insulin responses to
glucagon-like peptide-1 (10−9mol/l), cholecystokinin-8 (10−8 mol/l) and L-alanine (10 mmol/l) were
increased by 32%, 31% and 68% respectively
(p<0.05–0.01). Insulin content of the cells was 148%
greater at 20 days after re-culture than before
implantation (p<0.001), but basal insulin release (at
5.6 mmol/l glucose) was not changed. After re-culture
for 40 days, insulin content declined to 68% of
the content before implantation (p<0.01), although
basal insulin release was unchanged. However, the
insulin secretory responses to glucose, glucagonlike
peptide-1, cholecystokinin-8 and L-alanine
were decreased after 40 days of re-culture to 65%,
72%, 73% and 42% respectively of the values before
implantation (p<0.05–0.01). The functional
enhancement of electrofusion-derived surrogate β-cells that were re-cultured for 20 days after implantation
and restoration of normoglycaemia indicates
that the in vivo environment could greatly assist β-cell engineering approaches to therapy for diabetes.
