Exendin-4 treatment of nonobese diabetic mice increases beta-cell proliferation and fractional insulin reactive area.
OBJECTIVE
The notion of combining immunomodulatory agents with the incretin exendin-4 (Ex-4) has seen considerable favor as a potential therapy for the reversal of type 1 diabetes in man. While the addition of Ex-4 provides modest improvement to the effectiveness of immunological-based monotherapies in reversing hyperglycemia in the nonobese diabetic (NOD) mouse, the mechanism of action underlying this effect remains controversial and formed the basis for this investigation.


METHODS
Female NOD mice with new onset diabetes received either Ex-4 (0.2 microg) or saline via daily intraperitoneal injection for 30 days. To maintain viability after diagnosis of diabetes, animals also received subcutaneous insulin pellets. When persistent hyperglycemia returned, animals were sacrificed and histological studies performed to assess beta-cell proliferation (BrdU+/insulin+; Ki67+/insulin+) and fractional insulin reactive area.


RESULTS
Ex-4-treated animals experienced diabetes reversal rates no better than controls. Despite this, Ex-4-treated mice demonstrated increased fractional insulin area (P=.035) and beta-cell proliferation as evidenced by elevated BrdU (P=.0001) and Ki67 staining (P=.04) with insulin co-localization. Also noteworthy, Ex-4-treated mice had poor weight gain following diagnosis in comparison to saline-treated animals (P=.003).


CONCLUSIONS
Ex-4 monotherapy (0.2 microg daily-10 microg/kg per day) in NOD mice with new onset diabetes increases beta-cell proliferation and fractional insulin area. Ex-4 remains a promising component of combination therapies for type 1 diabetes. Additional studies are needed to identify a dose that maximizes beta-cell proliferation and minimizes potential side effects.
Xue
Song
S
Department of Pathology, University of Florida, Gainesville, FL 32610, USA.
Wasserfall
Clive
C
Parker
Matthew
M
McGrail
Sean
S
McGrail
Kieran
K
Campbell-Thompson
Martha
M
Schatz
Desmond A
DA
Atkinson
Mark A
MA
Haller
Michael J
MJ
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy*; D000077270:Exenatide; D005260:Female; D006943:Hyperglycemia / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D051379:Mice; D016688:Mice, Inbred NOD; D010455:Peptides / Q000627:therapeutic use*; D014688:Venoms / Q000627:therapeutic use*
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D014688:Venoms; D000077270:Exenatide