Exendin-4 potentiates insulinotropic action partly via increasing beta-cell proliferation and neogenesis and decreasing apoptosis in association with the attenuation of endoplasmic reticulum stress in islets of diabetic rats.
Exendin-4, a long-acting glucagon-like peptide-1-receptor agonist, is known to enhance beta-cell function, but the active mechanism by which it modulates beta-cell mass still remains unclear. We investigated what the long-term effects of exendin-4 (300 pmol/kg body weight per day) on beta-cell function and mass would be in 90% pancreatectomized (Px) Sprague Dawley rats; half of whom were intraperitoneally injected with streptozotocin (STZ, 20 mg/kg body weight) and half of whom were not. Exendin-4 improved glucose tolerance by elevating serum insulin levels in both STZ-treated and untreated Px rats. At hyperglycemic clamp, STZ attenuated both first and second phase insulin secretion in STZ- and saline-treated Px rats, but exendin-4 incompletely reversed the attenuation. Since STZ mostly removed the remaining beta-cells by increasing apoptosis after Px, their regeneration was initiated through neogenesis, which was determined by the number of beta-cells budding from pancreatic duct layers and small clusters. Exendin-4 enhanced beta-cell proliferation and neogenesis in STZ-treated and -untreated Px rats and reduced beta-cell apoptosis partly by attenuating the expression of endoplasmic reticulum stress-response genes such as X-box-binding protein-1, activating transcription factor (ATF)-4, ATF6, and C/EBP-homologous protein. In conclusion, exendin-4 improved glycemic control by potentiating beta-cell function and increasing beta-cell mass by increasing beta-cell neogenesis and proliferation and by decreasing apoptosis in diabetic rats.
Kwon
Dae Young
DY
Emerging Innovative Technology Research Division, Korean Food Research Institutes, Sungnam 463-746, Korea.
Kim
Young Sup
YS
Ahn
Il Sung
IS
Kim
Da Sol
DS
Kang
Suna
S
Hong
Snag Mee
SM
Park
Sunmin
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D002149:Energy Intake / Q000187:drug effects; D000077270:Exenatide; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010180:Pancreatectomy; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000187:drug effects*; D014157:Transcription Factors / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology* / Q000627:therapeutic use
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D014157:Transcription Factors; D014688:Venoms; D000077270:Exenatide