Background: Prevalence of Type 2 Diabetes Mellitus (T2DM) has reached pandemic levels
in the Western societies. T2DM begins with the development of peripheral insulin resistance which
prior research suggests may commonly originate within the skeletal muscle. A number of mechanisms
have been proposed for the development of muscle insulin resistance including those of classical
glucose handling, and also other cellular derangements observed in this disease which include
mitochondrial degeneration, alterations in muscle protein turnover and early evidences for
dysregulation of the microRNAs. The purpose of the current review is to examine the current findings
on these latter aspects of mitochondrial maintenance, protein turnover and microRNA dysregulation
along with the potential implications for these derangements in the development of insulin resistance
and hence T2DM. We summarize multiple evidences for the degeneration of mitochondria and known
elements of the processes regulating mitochondrial quality. Subsequently, we examine current findings
of the alterations in muscle protein synthesis and autophagic protein degradation in T2DM and
potential feedback of these systems onto canonical insulin signaling. Finally, evidences have emerged
for the dysregulation of microRNAs in muscle insulin resistance. Of note early data point to several
microRNAs altered by the insulin resistant state which exhibit relations to classic insulin signaling and
the other processes discussed here.
Conclusion: Considering that T2DM may be initiated with muscle insulin resistance, improved
understanding of the dysregulation of these metabolic parameters of skeletal muscle in the
pathogenesis of T2DM may be key to developing efficacious therapeutic modalities to prevent and
treat this condition.
Keywords: Autophagy, mitochondria, microRNA, mitochondrial quality, protein synthesis, insulin resistance.
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