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High fracture rate and high circulating levels of the Wnt inhibitor, sclerostin, have been reported in diabetic patients. We studied the effects of Wnt signaling activation on bone health in a mouse model of insulin‐deficient diabetes. We introduced the sclerostin‐resistant  Lrp5   A214V   mutation, associated with high bone mass, in mice carrying the  Ins2   Akita   mutation (Akita), which results in loss of beta cells, insulin deficiency, and diabetes in males. Akita mice accrue less trabecular bone mass with age relative to wild type (WT). Double heterozygous  Lrp5   A214V  /Akita mutants have high trabecular bone mass and cortical thickness relative to WT animals, as do  Lrp5   A214V   single mutants. Likewise, the  Lrp5   A214V   mutation prevents deterioration of biomechanical properties occurring in Akita mice. Notably,  Lrp5   A214V  /Akita mice develop fasting hyperglycemia and glucose intolerance with a delay relative to Akita mice (7 to 8 vs. 5 to 6 weeks, respectively), despite lack of insulin production in both groups by 6 weeks of age. Although insulin sensitivity is partially preserved in double heterozygous  Lrp5   A214V  /Akita relative to Akita mutants up to 30 weeks of age, insulin‐dependent phosphorylated protein kinase B (pAKT) activation in vitro is not altered by the  Lrp5   A214V   mutation. Although white adipose tissue depots are equally reduced in both compound and Akita mice, the  Lrp5   A214V   mutation prevents brown adipose tissue whitening that occurs in Akita mice. Thus, hyperactivation of Lrp5‐dependent signaling fully protects bone mass and strength in prolonged hyperglycemia and improves peripheral glucose metabolism in an insulin independent manner. Wnt signaling activation represents an ideal therapeutic approach for diabetic patients at high risk of fracture. © 2021 The Authors.  Journal of Bone and Mineral Research  published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Gain‐of‐Function Lrp5 Mutation Improves Bone Mass and Strength and Delays Hyperglycemia in a Mouse Model of Insulin‐Deficient Diabetes