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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. 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 IR l°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.

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SGLT2 inhibitors reduce insulin resistance and may improve beta-cell function in humans with T2D. We studied the effects of Canagliflozin (Cana) on glucose homeostasis, islet architecture and endocrine cell fate in male TallyHO/JngJ (TH) mice, a new model of T2D, which mimics many aspects of polygenic T2D in humans. By 8 weeks of age, all TH mice developed moderate obesity and hyperglycemia compared to control SWR/J mice; ∼60% of TH mice converted quickly to overt diabetes, characterized by elevated BG values (>400mg/dL) (HG mice), while the remaining cohort maintained lower BG values (250-400mg/dL) until the end of the study (LG mice). Mice from both groups (HG, LG) were then randomized to receive Chow or Chow-containing Cana (100ppm) diet for 10 weeks, prior to sacrifice. Cana treatment significantly decreased the fasting BG levels only in the HG mice (HG/Cana) compared with untreated HG/Chow mice (207.7±34.6 vs. 452.2±163.4mg/dL, p<0.0001), improved glucose and insulin excursion curves during an ipGTT (p<0.0001 for AUC values) and decreased HbA1c values (4.3±0.7 vs. 6.2±0.93%, p<0.0001). Non-fasting plasma insulin and C-peptide levels, pancreatic insulin content and HOMA-B index were all significantly higher in HG/Cana than in HG/Chow mice, suggesting improved beta-cell function by Cana. Immunofluorescence staining for islet hormones showed that, compared to untreated animals, Cana reestablished the islet area and the beta-cell number/islet in HG mice (possibly due to reduced apoptosis of beta-cells), in addition to decreased number of alpha- and delta-cells/islet. In HG/Cana mice, the majority of Ins+ cells expressed the glucose transporter Glut2, while its expression was undetectable in Ins+ cells of the HG/Chow mice, further suggesting an improvement in glucose sensing capability of beta-cells with Cana treatment. Our study shows that Cana has beneficial effects on preserving beta-cell mass, identity and function in a model of early onset T2D. Disclosure I. Popescu: None. G.M. Mussman: None. C.B. Hughes: None. T.J. Janes: None. P. Ray: None. R. Bunn: None. J. Fowlkes: None. K.M. Thrailkill: None.

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