Sclerostin Resistance Protects Bone Mass and Retards the Onset of Metabolic Abnormalities in a Mouse Model of Type 1 Diabetes

Abstract

Type 1 diabetes (T1D) is characterized by bone fragility and increased risk of fracture. In humans and preclinical models of T1D, serum markers of bone formation are decreased suggesting reduced bone turnover rates. In a preliminary study, we found high circulating levels of the Wnt inhibitor sclerostin (Scl) in T1D patients. To test the potential role of Scl and Wnt in T1D bone disease, we introduced the Scl-resistant Lrp5A214V mutation, associated with high bone mass (HBM), in mice carrying the Ins2Akita mutation (Akita), which causes hypoinsulinemia and hyperglycemia at age 4-5 week. Both Akita and Akita/HBM mutants developed diabetes (non-fasting blood glucose >300 mg/dl), albeit with different onset timing. At 6 weeks, only 30% of Akita/HBM mice had developed hyperglycemia, compared to 90% of Akita mice (n=10); and at 8 weeks only 40% of Akita/HBM were hyperglycemic vs. 90% in the Akita group. Only at 12 weeks was the majority of Akita/HBM mice hyperglycemic, as the Akita group. Furthermore, Akita mice exhibited a significant impairment in glucose tolerance in an intraperitoneal glucose tolerance test relative to Akita/HBM mice at 6 and 8 weeks (p<0.for difference in areas under the curve; n=3-6). Thus, Wnt signaling hyperactivation in Scl resistant mice may slow the onset of T1D, although it does not prevent it. No significant differences in weight and nose-tail length were found in Akita/HBM mutants and controls. Importantly, bone mass was 18% higher in Akita/HBM relative to Akita littermates at 12 weeks (p<0.001; n=3-6), a difference that persisted up until at least 18 weeks of age, despite prolonged hyperglycemia. Bone mass in compound mutants was not different relative to HBM mice. Thus, the metabolic changes caused by T1D do not alter the consequence of Scl resistance and Wnt hyperactivation on bone. In summary, even though we have not yet measured bone strength, Wnt stimulation protects bone mass and may retard the onset of metabolic abnormalities in T1D. Disclosure G. Leanza: None. R. Strollo: None. P. Pozzilli: Research Support; Self; Sanofi. Speaker's Bureau; Self; Eli Lilly and Company. Research Support; Self; Merck Sharp & Dohme Corp.. R. Civitelli: None. N. Napoli: None.