Incretin dysregulation of lysyl oxidase: a new mechanism for diabetic bone disease
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The American Diabetes Association has determined that the number of people with diabetes in America was 30.3 million in 2015, and it is becoming increasingly more prevalent. Diabetes is a condition characterized by chronic hyperglycemia due to either insufficient insulin or reduced insulin sensitivity. Diabetes comes with a host of complications; one major complication is osteopenia, which increases fracture risks in both type 1 and type 2 diabetics14. The changes in diabetic bone may be due to reductions in lysyl oxidase (LOX) levels leading to decreased amounts of insoluble type 1 collagen fibers, which are necessary for bone strength28. LOX catalyzes oxidative deamination of the hydroxylysine and lysine side chains of the collagen molecules to create reactive aldehyde groups9,14,17. These aldehyde groups rapidly react with the lysine or hydroxylysine on the helical region of neighboring molecules of collagen fibrils, creating crosslinks between molecules leading to a mature cross-linked collagen matrix9,15,18. Our lab has now linked the LOX reductions in diabetes to incretins such as glucose-dependent insulinotropic peptide (GIP), which directly increases LOX, and anti-incretins such as dopamine, which reduces LOX by inhibiting GIP. Incretins and anti-incretins are gastric hormones released by the intestine in response to nutrient consumption4. Generally, incretins are hormones that stimulate insulin secretion from the pancreas where as anti-incretins inhibit that insulinotropic effect13,23. GIP is an incretin that also has an anabolic effect on bone in addition to its insulinotropic effect23. In diabetes there is an impaired cellular response to GIP in the pancreas, but its effects on the bone as related to diabetes are unknown. Additionally, it was observed in our lab that bone-derived LOX levels were decreased in diabetes while the serum level of anti-incretin gut-derived dopamine was vastly increased. Dopamine is known to inhibit GIP in the pancreas, but its effect on the bone was unknown. Prior to this experiment our lab had already started exploring a potential mechanism for diabetic osteopenia, where diabetes leads to an increase in gut-derived anti-incretin (dopamine), which interferes with GIP-stimulated LOX in osteoblasts. The decreased levels of LOX lead to lowered collagen integrity and a loss in trabecular bone structure. The current work is a sub-study within the larger aim to elucidate the mechanism for diabetic osteopenia. The aim of this study was to further verify the effects of dopamine by using amisulpride, a dopamine receptor antagonist, to determine if amisulpride could restore bone health in streptozotocin (STZ) induced diabetic mice. For this study C57BL/6 wild type mice were used. The mice were divided at random into three groups (N=10 per group) as follows: control (no STZ, no amisulpride), STZ diabetic (STZ, no amisulpride), and STZ + amisulpride. Twenty of the mice had low dose intraperitoneal injections of STZ for five days to induce diabetes and ten mice received vehicle injections for the control group. The mice were maintained diabetic or normal for 8 weeks, after which ten of the STZ mice received intraperitoneal injections of amisulpride daily for a month. It was found that STZ induced diabetic mice had a significant decrease in LOX levels and insulin levels. Amisulpride was able to rescue the decreases in LOX levels but did not alter insulin levels. Furthermore, micro-CT analysis and picrosirius red histology of long bones indicated that there is a decrease in bone volume, impaired trabecular structure, and disorganized collagen matrix in the STZ diabetic group. These impairments could be rescued by amisulpride administration, giving further evidence to the new mechanism for diabetic osteopenia. The increase in anti-incretin gut-derived dopamine signaling could be the cause of diabetic osteopenia. Inhibition of the anti-incretin gut-derived dopamine may possibly provide a therapeutic target for diabetic osteopenia.
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