Biomolecular basis of the role of diabetes mellitus in osteoporosis and bone fractures

Figure 4 Diabetes mellitus induced regulation of skeletal muscle. Diabetes mellitus (DM) induced elevated blood glucose is the major source of advance advance glycation end product (AGE) which binds with its receptor advance glycation end product (RAGE) to activate the signal cascade into myocyte. RAGE activation enhances the generation of reactive oxygen species (ROS) through the activation of nicotinamide adenine diphosphate hydrogen (NADPH) oxidase. Ang-II also induce the production ROS not only by activating NADPH oxidase but also by inducing the mitochondria. ROS may exert its effects on nuclear factor kappa B (NF-κB) through Rac1-Mkk6 and Ras mediated pathway or accelerate the damage of muscle protein through Ca²⁺ depended pathway. Beyond the generation of ROS, RAGE also activates PI3K which in turn activates NF-κB through Csp3- PKR and Akt mediated pathway. Activated PKR may induce the activation of eIF2α that inhibits protein synthesis. DM induced Proinflammatory cytokines interleukin 6 (IL-6) activates the gene through JAK-STAT signaling pathway and TNF activates the factor NF-κB via IKK or MAPKP38 induced pathway. Ang-II induced GC also have role in muscle atrophy and GC exerts its effect through GC-GCR complex mediated pathway. Insulin signaling is also important for muscle growth because it sequesters the activity of Csp3 through inducing the production of cIAP-1 and MEK which are potential inhibitor of Cap3. Type 1 DM reduces the production of insulin and type 2 DM makes the cell insulin resistance, so due to the deficiency of insulin it limits the functioning of cIAP-1 and MEK.