A pentadecapeptide fragment of islet neogenesis-associated protein increases beta-cell mass and reverses diabetes in C57BL/6J mice.
OBJECTIVE
The objective of this study was to demonstrate that islet neogenesis-associated protein (INGAP) peptide, a pentadecapeptide containing the biologically active portion of native INGAP, increases functional beta-cell mass in normal animals and can be used therapeutically to reverse hyperglycemia in streptozotocin-induced diabetes.


BACKGROUND
INGAP, a 175 amino acid pancreatic acinar cell protein, has been suggested to be implicated in beta-cell mass expansion.


METHODS
In the first part of this study, normoglycemic hamsters were administered either 500 microg INGAP peptide (n = 30) or saline (n = 20) intraperitoneally daily and sacrificed after 10 or 30 days of treatment. Blood glucose and insulin levels were measured, and a histologic and morphometric analysis of the pancreas was performed to determine the effect of INGAP peptide on the endocrine pancreas. In the second part of the study, 6- to 8-week-old C57BL/6J mice (n = 8) were administered multiple low doses of the beta-cell toxin streptozotocin (STZ) inducing insulitis and hyperglycemia. The mice were then injected with INGAP peptide (n = 4) or saline (n = 4) for 39 days and sacrificed at 48 days. Two additional groups of diabetic mice were administered either a peptide composed of a scrambled sequence of amino acids from INGAP peptide (n = 5) or exendin-4 (n = 5), an incretin that has been associated with amelioration of hyperglycemia.


RESULTS
Islet cell neogenesis was stimulated in INGAP-treated hamsters by 10 days. At 30 days, the foci of new endocrine cells had the appearance of mature islets. There was a 75% increase in islet number, with normal circulating levels of blood glucose and insulin. Administration of INGAP peptide to diabetic mice reversed the diabetic state in all animals, and this was associated with increased expression of PDX-1 in duct cells and islet cell neogenesis with a reduction of insulitis in the new islets. Diabetic mice treated with exendin-4 or a scrambled INGAP peptide did not revert from hyperglycemia.


CONCLUSIONS
Because there is a deficiency of beta-cell mass in both type-1 and type-2 diabetes, INGAP peptide stimulation of fully functional neoislet differentiation may provide a novel approach for diabetes therapy.
Rosenberg
Lawrence
L
Department of Surgery, McGill University, Montreal, Quebec, Canada. lawrence.rosenberg@mcgill.ca
Lipsett
Mark
M
Yoon
Ji-Won
JW
Prentki
Marc
M
Wang
Rennian
R
Jun
Hee-Sook
HS
Pittenger
Gary L
GL
Taylor-Fishwick
David
D
Vinik
Aaron I
AI
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects*; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000378:metabolism; D000073718:Pancreatitis-Associated Proteins; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use; D011506:Proteins / Q000494:pharmacology / Q000627:therapeutic use*
D001786:Blood Glucose; D007328:Insulin; D000073718:Pancreatitis-Associated Proteins; D010446:Peptide Fragments; D011506:Proteins; C000612141:REG3A protein, human; C490253:Reg3b protein, mouse