Insulin Treatment Restores Diabetic Bone Morphology in an Animal Model of Insulinopenia, after a Period of Poor Glycemic Control

Presentation Number: SUN 600
Date of Presentation: April 2nd, 2017

Evangelia Kalaitzoglou*1, Jeffry S Nyman2, Sasidhar Uppuganti2, Philip D Ray1, R. Clay Bunn1, Kathryn M Thrailkill1 and John L Fowlkes1
1University of Kentucky, Lexington, KY, 2Vanderbilt University Medical Center, Nashville, TN

Abstract

Type 1 diabetes impedes bone mass accrual and is associated with increased risk of cortical porosity and fracture. Insulin can prevent the development of diabetic bone disease in streptozotocin (STZ)-induced diabetes but its effects on restoring bone abnormalities after a period of uncontrolled diabetes are not well established. To study the role of insulin treatment in restoring the bone phenotype of an insulinopenic animal model, twelve week old DBA/2J male mice were injected with citrate (non-diabetic, non-D) (n=12) or STZ (diabetic, D) (n=21). After 4 weeks of overt diabetes confirmed by blood glucose measurements, the diabetic group was implanted with Alzet minipumps containing either saline (Ds) (n=11) or insulin (Di) (n=10) and the non-D group was implanted with pumps containing saline, to continue for an additional 4 weeks (8 week time-point). Body weight and blood glucose levels were measured weekly. Dual-energy X-ray absorptiometry (DXA) for body composition and bone mineral density analysis was performed at baseline, and at 4 and 8 weeks. At 8 weeks, serum was collected for analysis of bone formation (P1NP) and bone resorption (RatLaps), whole blood was collected for measurement of glycated hemoglobin (HbA1c) and the left femur was collected for micro-CT analysis. After 4 weeks of diabetes, diabetic mice (D) had developed a decrease in their % body fat (p<0.0001) and their bone mineral density (BMD) (p<0.0001) as measured by DXA compared to non-D mice. At study end, differences were seen between saline-treated Ds mice and non-D mice in terms of glycemic control (elevated HbA1c and blood glucose levels, p<0.0001 for both), body composition (% body fat- p<0.0001, lean mass- p=0.0104 and BMD- p=0.0006) and bone structure (trabecular bone volume fraction- p<0.0001, cortical bone area- p<0.0001, average cortical thickness- p=0.0089, cortical porosity- p<0.0001 and rigidity- p=0.0001). In comparison, at study end, insulin-treated Di mice had improved HbA1c (p<0.0001), % body fat (p=0.0045) and a trend for improved BMD compared to Ds mice. In addition, their bone volume fraction and cortical bone area were increased (p=0.0005 and p=0.01, respectively) whereas their cortical porosity was decreased (p=0.0014) compared to Ds mice. Improvements were also seen in trabecular thickness and trabecular tissue mineral density with insulin treatment (p<0.01). Finally, the resorption marker RatLaps was significantly decreased whereas bone formation marker P1NP was significantly increased in Di mice compared to Ds mice. In conclusion, delayed insulin treatment resulted in improvement of body composition and partial restoration of bone structure through an increase in bone formation and suppression of bone resorption in our animal model. Our findings highlight the potential benefits of insulin therapy in reversing diabetic bone disease even after a history of poorly controlled Type 1 diabetes.

 

Nothing to Disclose: EK, JSN, SU, PDR, RCB, KMT, JLF