Pharmacological treatment of chronic diabetes by stimulating pancreatic beta-cell regeneration with systemic co-administration of EGF and gastrin.
Transgenic expression of gastrin and EGF receptor ligands stimulates islet neogenesis in adult mice, significantly increasing islet mass. The present study aimed to determine whether pharmacological treatment with gastrin and EGF can significantly stimulate beta-cell regeneration in chronic, severe insulin-dependent diabetes. Diabetes was induced by intravenous streptozotocin, resulting in >95% beta cell destruction. Four weeks later, blood glucose levels were restored to normal range by exogenous insulin therapy and rats were treated with EGF/gastrin in combination, gastrin alone, or EGF alone given subcutaneously. After 14 days treatment blood glucose was significantly lower in the EGF/gastrin group compared to the untreated diabetic controls. Along with improved glucose tolerance, EGF/gastrin treatment significantly increased plasma C peptide and pancreatic insulin content compared to diabetic controls. Histological analysis showed that EGF/gastrin treatment significantly increased beta-cell mass as determined by point counting morphometrics. The EGF/gastrin group had a significantly greater number of BrdU labelled beta-cells/section consistent with stimulation of beta-cell replication or neogenesis. An increased number of gastrin receptor positive cells were observed in the EGF/gastrin-treated groups. In contrast to the effectiveness of the EGF/gastrin combination, neither gastrin nor EGF alone improved glucose tolerance in severely streptozotocin-diabetic rats. These studies indicate that physiologically significant improvement in glucose tolerance can be achieved through stimulating beta-cell regeneration with gastrin/EGF administered systemically as conventional pharmacological therapy.
Brand
Stephen J
SJ
Waratah Pharmaceuticals Corp, Woburn, MA 01801, USA. sbrand@attglobal.net
Tagerud
Sven
S
Lambert
Philip
P
Magil
Sheila G
SG
Tatarkiewicz
Krystyna
K
Doiron
Kathryn
K
Yan
Yanhua
Y
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy; D004338:Drug Combinations; D004815:Epidermal Growth Factor / Q000008:administration & dosage / Q000627:therapeutic use*; D005755:Gastrins / Q000008:administration & dosage / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000187:drug effects
D004338:Drug Combinations; D005755:Gastrins; D007328:Insulin; D011949:Receptors, Cholecystokinin; D004815:Epidermal Growth Factor