In the last decade, the treatment of type 2 Diabetes has evolved with the identification of new therapeutic targets and a better understanding of the disease itself. The two recent blogs posted on Eureka by Dr. Joe Cornicelli and Dr. Cliff Rosen shed some light on the cross talk between energy metabolism and bone. This blog will focus on the currently available treatments for Diabetes along with new therapeutic targets and their potential for effects on bone.
Diabetes can be managed in a number of ways, by:
- Preventing the absorption of glucose from the GI system,
- Inhibiting production and release of glucose from the liver,
- Increasing insulin production by the pancreas,
- Inhibiting glucose reabsorption from the kidney; and
- Reducing insulin resistance.
The main classes of antidiabetics are summarized below. Combinations of some of these compounds have also been successfully used to treat diabetes.
- Biguanides (ex: Metformin) normalize blood glucose by decreasing the production of glucose from the liver. There are contradictory reports on the effects of metformin on osteoclasts (bone resorbing cells) and osteoblasts (bone forming cells). One clinical study suggested metformin treatment is associated with reduced fracture risk.
- Thiazolidinediones (Glitazones or TZDs) reduce insulin resistance by activating PPAR-γ in muscle and fat tissues. The negative effects of these compounds on bone are well documented in preclinical and clinical studies.
- Secretagogues stimulate insulin production by inhibiting the KATP channel (ATP-sensitive potassium ion channel) on the plasma membrane of pancreatic beta-cells. Insulin secretagogues consist of two subclasses: Sulfonylureas (ex: Glipizide) and Nonsulfonylureas (ex:Mitiglinide). The effects of this class of antidiabetics on bone require further investigation. The results from one clinical study suggest that the treatment with glibenclamide decreases fracture risk in Type 2 diabetic patients.
- Incretin mimetics increase incretin levels (GLP-1 and GIP), which inhibit glucagon release. Animal studies suggest that increased incretin levels are beneficial for bone however these findings need to be confirmed by large clinical studies.
- DPP-4 inhibitors include the oral drugs Januvia, Nesina, Onglyza, and Tradjenta. These compounds prevent the degradation of incretins (GLP-1 and GIP). Similar to incretin mimetics, preclinical studies indicate positive effects on bone, however, clinical data supporting this outcome is lacking.
- G-protein coupled receptor agonists (GPR119): This class also modulates incretin levels and their effects on bone are similar to DPP-4 inhibitors or incretin mimetics.
- Alpha glucosidase inhibitors reduce the digestion of carbohydrates and therefore decrease intestinal glucose absorption. This class of compound has been also shown to increase calcium absorption from the GI system making it a potential treatment for osteoporosis as well as diabetes.
- Amylin analogs: Amylin is a member of the calcitonin family secreted along with insulin from the pancreatic beta-cells. Investigative studies suggest that Amylin increases the proliferation of osteoblasts while it inhibits bone resorption. These findings suggest a potentially positive effect on bone.
- SGLT-2 (Sodium-Glucose Transporter type 2) inhibitors decrease reabsorption of glucose from the kidney. Studies in rodents have shown increases in bone strength and bone density however their effect on bone in large species or human has not been reported.
- Fibroblast growth factor 21 (FGF21) stimulates glucose uptake in adipocytes. Animal studies show that treatment with FGF21 is associated with increased energy expenditure, decrease bone growth and cortical bone acquisition.
Recent studies suggest that bone quality is compromised in diabetic patients. The reported effects of antidiabetics on bone in clinical studies are associated with either a direct effect of treatment on bone cells or an indirect effect by improving bone quality by better management of energy metabolism and blood glucose; or possibly a combination of both. We have so much to learn from well-designed integrated physiology studies about the balance between controlling glucose homeostasis and maintaining bone quality with the ultimate aim to one day treat both diabetes and osteoporosis simultaneously.