Continuous stimulation of human glucagon-like peptide-1 (7-36) amide in a mouse model (NOD) delays onset of autoimmune type 1 diabetes.
OBJECTIVE
We examined the effect of glucagon-like peptide-1 (GLP-1) on the development of diabetes and islet morphology in NOD mice by administering GLP-1 to prediabetic mice.


METHODS
Eight-week-old female NOD mice were infused subcutaneously with human GLP-1 via a mini-osmotic pump for 4 or 8 weeks. In mice treated with GLP-1 for 4 weeks, blood glucose levels and body weight were measured. An intraperitoneal glucose tolerance test (IPGTT) and evaluation of insulitis score were also performed. Beta cell area, proliferation, apoptosis, neogenesis from ducts and subcellular localisation of forkhead box O1 (FOXO1) were examined by histomorphometrical, BrdU-labelling, TUNEL, insulin/cytokeratin and FOXO1/insulin double-immunostaining methods, respectively.


RESULTS
Mice treated with human GLP-1 for 4 weeks had lower blood glucose levels until 2 weeks after completion of treatment, showing improved IPGTT data and insulitis score. This effect continued even after cessation of the treatment. In addition to the increase of beta cell neogenesis, BrdU labelling index was elevated (0.24 vs 0.13%, p < 0.001), while apoptosis was suppressed by 54.2% (p < 0.001) in beta cells. Beta cell area was increased in parallel with the translocation of FOXO1 from the nucleus to the cytoplasm. The onset of diabetes was delayed in mice treated with GLP-1 for 4 weeks, while mice treated with GLP-1 for 8 weeks did not develop diabetes by age 21 weeks compared with a 60% diabetes incidence in control mice at this age.


CONCLUSIONS
Continuous infusion of human GLP-1 to prediabetic NOD mice not only induces beta cell proliferation and neogenesis, but also suppresses beta cell apoptosis and delays the onset of type 1 diabetes.
Zhang
J
J
Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan.
Tokui
Y
Y
Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan.
Yamagata
K
K
Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan.
Kozawa
J
J
Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan.
Sayama
K
K
Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan.
Iwahashi
H
H
Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan.
Okita
K
K
Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan.
Miuchi
M
M
Division of Diabetes and Metabolism, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
Konya
H
H
Division of Diabetes and Metabolism, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
Hamaguchi
T
T
Division of Diabetes and Metabolism, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
Namba
M
M
Division of Diabetes and Metabolism, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
Shimomura
I
I
Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan.
Miyagawa
J-I
JI
Division of Diabetes and Metabolism, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan. miyagawa@hyo-med.ac.jp.
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002455:Cell Division; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000502:physiology*; D005951:Glucose Tolerance Test; D006801:Humans; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000166:cytology; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000473:pathology; D010446:Peptide Fragments / Q000502:physiology*
D001786:Blood Glucose; D010446:Peptide Fragments; C055453:glucagon-like peptide 1 (7-36)amide; D052216:Glucagon-Like Peptide 1