Incretins are gastric hormones released by intestinal K-cells in response to food consumption and stimulate insulin secretion from pancreatic beta cells. One of these hormones, glucose-dependent insulinotropic peptide (GIP) is also anabolic in bone. Individuals with diabetes experience diminished bone quality caused by a low bone formation osteopenia. The present study seeks to identify a mechanism for diabetic osteopenia in which diabetes interferes with GIP-stimulated increases in the collagen cross-linking enzyme lysyl oxidase (LOX) in osteoblasts, leading to decreased collagen integrity and the trabecular abnormalities seen in diabetic bone. Micro-CT analysis and picrosirius red histology of long bones from LOX +/- and wild type mice made diabetic by low dose streptozotocin induction revealed a profound exacerbation of the decreased bone volume, impaired trabecular structure, and disorganized collagen matrix seen in diabetic mice when the mice were also haploinsufficient for LOX. Furthermore, qPCR of RNA isolated from diabetic long bones revealed a more than 20 fold decrease in LOX expression in diabetic bone from wild type mice. Treatment of wild type osteoblasts in culture with GIP results in a significant increase in LOX transcript and protein levels. Interestingly in our diabetic mice there is a decrease in osteoblast derived LOX and an abnormal increase in serum levels of the anti-incretin gut-derived dopamine, which is known to inhibit the effects of GIP in the pancreas. Therefore the ability of dopamine to inhibit GIP-stimulated signaling in osteoblasts was examined. Data indicate a strong dose-dependent inhibition of GIP-stimulated LOX expression when primary osteoblast cultures are pretreated with dopamine. Finally, pretreatment of primary osteoblasts with the dopamine receptor inhibitor amisulpride restored the impaired GIP stimulated increases in LOX expression in osteoblasts isolated from diabetic mice. This study defines a potential mechanism for diabetic bone disease and suggests that interference with dopamine signaling would likely restore bone health in diabetes.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/33010 |
| Date | 24 October 2018 |
| Creators | Daley, Eileen |
| Contributors | Trackman, Philip, Mochida, Yoshiyuki |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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