Systemic and renal growth hormone-IGF1 axis involvement in a mouse model of type 2 diabetes.
OBJECTIVE
In previous studies we have shown a significant involvement of the growth hormone (GH)-IGF axis in animal models of type 1 diabetes mellitus, but the role of this endocrine system in type 2 diabetes mellitus is less well characterised. We therefore examined the endocrine and renal GH-IGF axis changes in db/db mice, a model of type 2 diabetes mellitus and nephropathy.


METHODS
Obese and lean animals were followed, beginning at hyperglycaemia onset, for 4 weeks. Albuminuria and creatinine clearance, as well as kidney and glomerular morphology were assessed. Tissue protein levels were determined by western blotting and mRNA levels by RT-PCR.


RESULTS
Serum GH and IGF1 levels immediately prior to killing were decreased and liver mRNA levels of insulin-like growth factor binding protein 1 (Igfbp1) were increased in obese animals. Kidney weight was increased in obese animals, associated with hyperfiltration, albuminuria and glomerular hypertrophy. Administration of a somatostatin analogue (PTR-313) did not improve any of these parameters of diabetic renal involvement. Renal Igf1 mRNA was decreased and renal Igfbp1 mRNA and protein were significantly increased in obese animals. Renal insulin-driven levels of phosphorylated forkhead box O1 (FOXO1) were decreased in obese animals.


CONCLUSIONS
Diabetic db/db mice show significant renal changes (and IGFBP1 renal accumulation), similar to the findings in models of type 1 diabetes mellitus. A decreased signalling through the insulin receptor and decreased FOXO1 phosphorylation may allow Igfbp1 gene transcription. These renal changes are associated with low circulating IGF1 and GH levels and unchanged hepatic growth hormone receptor expression, unlike the condition in type 1 diabetes mellitus. This suggests that further GH inhibition to modulate renal complications in type 2 diabetes mellitus is not indicated.
Segev
Y
Y
Department of Microbiology and Immunology, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel.
Eshet
R
R
Yakir
O
O
Haim
N
N
Phillip
M
M
Landau
D
D
D000419:Albuminuria; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000235:genetics / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D013006:Growth Hormone / Q000097:blood* / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000502:physiology*; D007678:Kidney Glomerulus / Q000473:pathology; D008099:Liver / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D011986:Receptors, Somatotropin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D012333:RNA, Messenger; D011986:Receptors, Somatotropin; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone