Agonists of
growth hormone-releasing hormone (GHRH) have been previously reported to promote growth, function, and engraftment of islet cells following
transplantation. Here we evaluated recently synthesized GHRH agonists on the proliferation and
biological functions of rat pancreatic β-cell line (INS-1) and islets. In vitro treatment of INS-1 cells with GHRH agonists increased cell proliferation, the expression of cellular
insulin,
insulin-like growth factor-1 (IGF1), and
GHRH receptor, and also stimulated insulin secretion in response to
glucose challenge. Exposure of INS-1 cells to GHRH agonists,
MR-356 and
MR-409, induced activation of ERK and AKT pathways. Agonist
MR-409 also significantly increased the levels of cellular cAMP and the phosphorylation of
cAMP response element binding protein (CREB) in INS-1 cells. Treatment of rat islets with agonist,
MR-409 significantly increased cell proliferation, islet size, and the expression of
insulin. In vivo daily s.c. administration of 10 μg
MR-409 for 3 wk dramatically reduced the severity of
streptozotocin (STZ)-induced diabetes in nonobese diabetic
severe combined immunodeficiency (NOD/SCID) mice. The maximal therapeutic benefits with respect to the efficiency of engraftment, ability to reach normoglycemia, gain in
body weight, response to high
glucose challenge, and induction of higher levels of serum
insulin and IGF1 were observed when diabetic mice were transplanted with rat islets preconditioned with GHRH agonist,
MR-409, and received additional treatment with
MR-409 posttransplantation. This study provides an improved approach to the
therapeutic use of GHRH agonists in the treatment of
diabetes mellitus.