Type 2 diabetes (T2D), along with obesity, is one of the leading health problems in the world which causes other systemic diseases, such as cardiovascular diseases and kidney failure. Impairments in glycemic control and insulin resistance plays a pivotal role in the development of diabetes and its complications. Since skeletal muscle constitutes a significant tissue mass of the body, insulin resistance within the muscle is considered to initiate the onset of diet-induced metabolic syndrome. Insulin resistance is associated with impaired glucose uptake, resulting from defective post-receptor insulin responses, decreased glucose transport, impaired glucose phosphorylation, oxidation and glycogen synthesis in the muscle. Although defects in the insulin signaling pathway have been widely studied, the effects of cellular mechanisms activated during metabolic syndrome that cross-talk with insulin responses are not fully elucidated. Numerous reports suggest that pathways such as inflammation, lipid peroxidation products, acidosis and autophagy could cross-talk with insulin-signaling pathway and contribute to diminished insulin responses. Here, we review and discuss the literature about the defects in glycolytic pathway, shift in glucose utilization toward anaerobic glycolysis and change in intracellular pH [pH] within the skeletal muscle and their contribution towards insulin resistance. We will discuss whether the derangements in pathways, which maintain [pH] within the skeletal muscle, such as transporters (monocarboxylate transporters 1 and 4) and depletion of intracellular buffers, such as histidyl dipeptides, could lead to decrease in [pH] and the onset of insulin resistance. Further we will discuss, whether the changes in [pH] within the skeletal muscle of patients with T2D, could enhance the formation of protein aggregates and activate autophagy. Understanding the mechanisms by which changes in the glycolytic pathway and [pH] within the muscle, contribute to insulin resistance might help explain the onset of obesity-linked metabolic syndrome. Finally, we will conclude whether correcting the pathways which maintain [pH] within the skeletal muscle could, in turn, be effective to maintain or restore insulin responses during metabolic syndrome.