• Insulin
• Diabetes Mellitus

• Insulin
• Endocrinology
• Diabetes & Metabolic Syndrome
• Diabetes Mellitus

Skeletal muscle is the major site for insulin-dependent glucose utilization, and insulin resistance in skeletal muscle is thought to be integral in the pathogenesis of type 2 diabetes mellitus (T2DM). Kyong Soo Park, MD, PhD, Seoul National University, Seoul, South Korea, discussed some emerging insights into the molecular basis of skeletal muscle insulin resistance, highlighting the role of peroxisome proliferator activated receptor-gamma (PPAR-γ), a nuclear transcription factor.

PPAR-γ is implicated in the regulation of fat metabolism in skeletal muscle, and is activated by the binding of specific ligands, including thiazolidinediones (TZDs), such as troglitazone, rosiglitazone, and pioglitazone, which are used for the treatment of T2DM [Chung SS et al. Mol Cell Biol 2009]. Although PPAR-γ is mostly expressed in fat tissue where it is critically involved in lipogenesis and adipocyte differentiation, low levels are also expressed in skeletal muscle where it enhances insulin sensitivity [Chung SS et al. Biochem J 2011].

Oxidative stress plays a central role in the pathogenesis of insulin resistance, T2DM, and its vascular complications. Production of reactive oxygen species is increased in T2DM, and antioxidant activity is simultaneously reduced. TZDs, however, have been shown to prevent oxidative stress-induced insulin resistance in skeletal muscle. They activate PPAR-γ, stimulating glutathione peroxidase 3 (GPx3) gene expression leading to reduction of extracellular hydrogen peroxide (H₂O₂) levels that contribute to insulin resistance in skeletal muscle cells. Since inhibition of GPx3 expression prevents this TZD-induced antioxidant effect, GPx3 is thought to be essential for the regulation of PPAR-γ-mediated antioxidant activity. And since lower GPx3 levels have also been demonstrated in patients with T2DM and in diabetic diet-induced obese mice, the antioxidant effect of PPAR-γ is considered to be completely mediated by GPx3 [Chung SS et al. Mol Cell Biol 2009].

More recently, the function of PPAR-γ has been shown to be regulated by various posttranslational modifications, including SUMOylation, which involves binding of a small ubiquitin-like modifier (SUMO) protein to target proteins. SUMOylation is catalyzed by SUMO-specific proteases (SENPs). In one study of C2C12 cells in a primary line of mouse myoblasts, the critical role of SENP2 in lipogenesis as a desumoylating enzyme was demonstrated. SENP2 effectively removed SUMO from PPAR-γ-SUMO conjugates, while also increasing PPAR-γ transcriptional activity. In addition, SENP2 overexpression selectively enhanced the expression of the PPAR-γ target genes FABP3 (fatty-acid-binding protein 3) and CD36 (fatty acid translocase), in the presence and absence of rosiglitazone, but had no effect on ADRP (adipose differentiation-related protein) [Chung SS et al. Biochem J 2011].

Prof. Park emphasized the important role that GPx3 plays in regulating oxidative stress, and its potential as a therapeutic target for both insulin resistance and T2DM. In addition, he also noted the potential for SENP2 as a potential therapeutic target to deal with excess fatty acids in skeletal muscle.

• © 2013 MD Conference Express®