Abstract
The relationship between osteoblast-specific insulin signaling, osteocalcin activation and gluco-metabolic homeostasis has proven to be complex and potentially inconsistent across animal-model systems and in humans. Moreover, the impact of postnatally acquired, osteoblast-specific insulin deficiency on the pancreas-to-skeleton-to-pancreas circuit has not been studied. To explore this relationship, we created a model of postnatal elimination of insulin signaling in osteoprogenitors. Osteoprogenitor-selective ablation of the insulin receptor was induced after ~10 weeks of age in IRl°x/lox/Osx-Cre+/− genotypic male and female mice (designated postnatal-OIRKO). At ~21 weeks of age, mice were then phenotypically and metabolically characterized. Postnatal-OIRKO mice demonstrated a significant reduction in circulating concentrations of undercarboxylated osteocalcin (ucOC), in both males and females compared with control littermates. However, no differences were observed between postnatal-OIRKO and control mice in: body composition (lean or fat mass); fasting serum insulin; HbA1c; glucose dynamics during glucose tolerance testing; or in pancreatic islet area or islet morphology, demonstrating that while ucOC is impacted by insulin signaling in osteoprogenitors, there appears to be little to no relationship between osteocalcin, or its derivative (ucOC), and glucose homeostasis in this model.
Highlights
The relationship between osteoblast-specific insulin signaling, osteocalcin activation and glucometabolic homeostasis has proven to be complex and potentially inconsistent across animal-model systems and in humans
Initial studies proposed that in mice, insulin signaling in osteoblasts, if disrupted prenatally, was linked to a feed-forward mechanism to enhance insulin secretion by activating osteocalcin to undercarboxylated osteocalcin through enhanced osteoclast activity, and in turn, ucOC regulated glucose homeostasis by directly enhancing pancreatic production of insulin via the GPRC6A receptor[2,3,7]
Insulin signaling in osteoblasts has been linked by others to a feed-forward mechanism to “activate” osteocalcin into undercarboxylated osteocalcin, which, in turn, regulates glucose homeostasis by signaling through the GPRC6A on osteogenic cells[2,3,9]
Summary
The relationship between osteoblast-specific insulin signaling, osteocalcin activation and glucometabolic homeostasis has proven to be complex and potentially inconsistent across animal-model systems and in humans. To examine further this potential link between insulin signaling in osteoblastic cells and the generation of ucOC as a regulator of glucose homeostasis, we developed a mouse model designed to mitigate any potential prenatal effects that may impact this metabolic circuit through selectively eliminating the insulin receptor in osteoprogenitors only in mature mice. This model of a postnatally-acquired deficiency in insulin signaling better mimics when insulin deficiency, insulin resistance and/or glucose dysregulation would arise in mice and humans, leading to glucose intolerance and frank diabetes. We hypothesized that disruption of insulin signaling in osteoprogenitors in mature mice would impact production of ucOC and potentially impact body composition and glucose homeostasis
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