Exendin-4 and exercise promotes beta-cell function and mass through IRS2 induction in islets of diabetic rats.
Not only exendin-4 but also exercise has been reported to improve glucose homeostasis by enhancing insulinotropic action, but the nature of its molecular mechanism has not been clarified. We investigated a mechanism to promote insulinotropic action by means of exendin-4 and exercise training in 90% pancreatectomized (Px) rats fed 40% energy fat diets. Px diabetic rats were divided into 4 groups: 1) exendin-4, 2) exendin-4 plus exercise, 3) saline (control), and 4) exercise. During the 8-week experimental period, rats in the exendin-4 groups were subcutaneously administered with 150 pmol/kg exendin-4 twice a day, while those in the exercise groups ran on an uphill treadmill with a 15 degree incline at 20 m/min for 30 min 5 days a week. First phase insulin secretion was elevated by both the administration of exendin-4 and exercise training during hyperglycemic clamp. However, second phase insulin secretion did not differ among the groups. Individual treatment of exendin-4 and exercise expanded beta-cell mass by increasing its proliferation and reducing its apoptosis, but the administration of exendin-4 plus exercise training did not produce any additional, positive effects. Both exendin-4 and exercise enhanced insulin receptor substrate (IRS)-2 expression through the activation of cAMP responding element binding protein in the islets, which potentiated their insulin/insulin like growth factor-1 signaling. The potentiation of the signaling increased the expression of pancreas duodenum homeobox-1, involved in beta-cell proliferation. In conclusion, exendin-4 and exercise equivalently improved glucose homeostasis due to the induction of IRS-2 in the islets of diabetic rats through a cAMP dependent common pathway.
Park
Sunmin
S
Department of Food & Nutrition, College of Natural Science, Hoseo University, Asan-Si, South Korea. smpark@hoseo.edu
Hong
Sang Mee
SM
Sung
So Ra
SR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003920:Diabetes Mellitus / Q000097:blood / Q000503:physiopathology; D002149:Energy Intake / Q000187:drug effects; D000077270:Exenatide; D005786:Gene Expression Regulation / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology; D015151:Immunoblotting; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D010180:Pancreatectomy; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D010805:Physical Conditioning, Animal / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014688:Venoms / Q000008:administration & dosage / Q000494:pharmacology*
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526299:Irs2 protein, rat; D010455:Peptides; D010750:Phosphoproteins; D014688:Venoms; D007334:Insulin-Like Growth Factor I; D000077270:Exenatide