Normal bone density obtained in the absence of insulin receptor expression in bone.
Type I diabetes is characterized by little or no insulin production and hyperglycemic conditions. It is also associated with significant bone loss and increased bone marrow adiposity. To examine the role of reduced insulin signaling in type I diabetic bone loss without inducing hyperglycemia, we used genetically reconstituted insulin receptor knockout mice (IRKO-L1) that are euglycemic as a result of human insulin receptor transgene expression in the pancreas, liver, and brain. RT-PCR analyses demonstrated undetectable levels of insulin receptor expression in IRKO-L1 bone, yet IRKO-L1 bones exhibit similar (and trend toward greater) bone density compared with wild-type animals as determined by microcomputed tomography. More detailed bone analyses indicated that cortical bone area was increased in tibias of IRKO-L1 mice. Osteoblast markers (osteocalcin and runx2 mRNA levels) and resorption markers (serum pyridinoline levels) were similar in wild-type and IRKO-L1 bones. When marrow adiposity was examined, we noticed a decrease in adipocyte number and fatty-acid-binding protein 2 expression in IRKO-L1 mice compared with wild-type mice. Bone marrow stromal cell cultures obtained from wild-type and IRKO-L1 mice demonstrated similar adipogenic and osteogenic potentials, indicating that systemic factors likely contribute to differences in marrow adiposity in vivo. Interestingly, IGF-I receptor mRNA levels were elevated in IRKO-L1 bones, suggesting (in combination with hyperinsulinemic conditions) that increased IGF-I receptor signaling may represent a compensatory response and contribute to the changes in cortical bone. Taken together, these results suggest that reduced insulin receptor signaling in bone is not a major factor contributing to bone loss in type I diabetes.
Irwin
Regina
R
Michigan State University, Department of Physiology, 2201 Biomedical Physical Science Building, East Lansing, Michigan 48824, USA.
Lin
Hua V
HV
Motyl
Katherine J
KJ
McCabe
Laura R
LR
D052438:Adipocytes, White / Q000166:cytology; D000818:Animals; D015519:Bone Density / Q000502:physiology*; D001853:Bone Marrow / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism*; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015675:Osteocalcin / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism*
C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D015675:Osteocalcin; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin