Type 1 diabetes (T1D) is characterized by metabolic abnormalities and bone fragility. In humans and preclinical models of T1D, serum markers of bone formation are decreased suggesting reduced bone turnover rates. Moreover, circulating levels of the Wnt inhibitor sclerostin (Scl) are higher in T1D patients. To test the role of Scl 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 weeks. Although both Akita and Akita/HBM mutants developed diabetes (non-fasting blood glucose ≥300 mg/dl), they showed a very different onset timing. At 6 weeks, only 30% of Akita/HBM mice developed hyperglycemia, compared to 90% of Akita mice (n=10), with the majority of Akita/HBM mice becoming hyperglycemic by 12 weeks. At 6 weeks, Akita mice showed a significant impairment in glucose tolerance in an intraperitoneal glucose tolerance test (ipGTT) relative to mild glucose intolerance demonstrated in Akita/HBM mice (p<0.05 for difference in AUC; n=5-7). No differences in serum insulin, glucagon and C-peptide were found between Akita/HBM and Akita mice at time 0 and 30 minutes during the ipGTT (n=2-6). Importantly however, Akita/HBM showed a significant improvement in insulin sensitivity in an ip insulin tolerance test relative to Akita mice at 7 weeks of age, which persisted until 30 weeks (p<0.05 for difference in AUC; n= 4-7). Strikingly, 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 the prolonged hyperglycemia. Together, these results suggest that Scl resistance may improve peripheral glucose metabolism and slow down the onset of T1D, although it does not prevent it. Even though we have not yet measured bone strength, Wnt stimulation protects bone mass and may delay the onset of metabolic abnormalities seen in T1D.
G. Leanza: None. Y. Alippe: None. S. Lee: None. R. Strollo: None. P. Pozzilli: None. R. Civitelli: Stock/Shareholder; Self; Amgen Inc., Eli Lilly and Company, Merck & Co., Inc. N. Napoli: None.