Genetic engineering of insulin expression in nonislet cells: implications for beta-cell replacement therapy for insulin-dependent diabetes mellitus.
Insulin-dependent diabetes mellitus (IDDM) occurs as a consequence of autoimmune destruction of the insulin-producing pancreatic beta-cells. Although progress has been made in the field of islet transplantation, an appealing alternative strategy for beta-cell replacement therapy for IDDM is to target insulin expression to non-islet cells. We have recently generated transgenic nonobese diabetic (NOD) mice in which insulin gene expression was targeted to proopiomelanocortin (POMC)-expressing cells of the intermediate lobe (IL) of the pituitary. We have shown that POMC-expressing IL pituitary cells secreted large amounts of mature insulin, similar to islet beta-cells. However, in contrast to the insulin-producing islet beta-cells, the insulin-producing IL pituitary cells were not attacked by the immune system. Remarkably, transplantation of small amounts of the transgenic IL tissues into diabetic NOD mice resulted in the restoration of near-normogylcemia and the complete reversal of diabetic symptoms. In separate experiments, IL allografts showed enhanced viability and were highly vascularized, compared with similarly transplanted islet allografts. These features are highly advantageous in the transplantation setting and demonstrate the considerable potential of these non-islet cell types for insulin-gene delivery in IDDM.
Lipes
M A
MA
Research Division, Joslin Diabetes Center, Boston, MA 02215, USA.
Davalli
A M
AM
Cooper
E M
EM
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy*; D005818:Genetic Engineering / Q000379:methods*; D007328:Insulin / Q000096:biosynthesis* / Q000235:genetics*; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010902:Pituitary Gland / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis
D007328:Insulin; D011333:Pro-Opiomelanocortin