Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are a relatively newer class of antihyperglycemic medications that reduce blood glucose by inhibition of renal glucose re-uptake, thereby increasing urinary glucose excretion. Although glycosuria is the primary mechanism of action of these agents, there is some evidence suggesting they can reduce insulin resistance and induce peripheral insulin sensitivity. Identifying the molecular mechanisms by which these medications improve glucose homeostasis can help us to develop newer forms of SGLT2i with lesser side effects. We have reviewed the molecular mechanisms and signaling pathways by which SGLT2i therapy improve insulin sensitivity and ameliorates insulin resistance.

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The modern lifestyle has a negative impact on health. It is usually accompanied by increased stress levels and lower physical activity, which interferes with body homeostasis. Diabetes mellitus is a relatively common metabolic disorder with increasing prevalence globally, associated with various risk factors, including lower physical activity and a sedentary lifestyle. It has been shown that sedentary behavior increases the risk of insulin resistance, but the intermediate molecular mechanisms are not fully understood. In this mechanistic review, we explore the possible interactions between physical inactivity and insulin resistance to help better understand the pathophysiology of physical inactivity-dependent insulin resistance and finding novel interventions against these deleterious pathways.

C-peptide is a small peptide connecting two chains of proinsulin molecule and is dissociated before the release of insulin. It is secreted in an equimolar amount to insulin from the pancreatic beta-cells into the circulation. Recent evidence demonstrates that it has other physiologic activities beyond its structural function. C-peptide modulates intracellular signaling pathways in various pathophysiologic states and, could potentially be a new therapeutic target for different disorders including diabetic complications. There is growing evidence that c-peptide has modulatory effects on the molecular mechanisms involved in the development of diabetic nephropathy. Although we have little direct evidence, pharmacological properties of c-peptide suggest that it can provide potent renoprotective effects especially, in a c-peptide deficient milieu as in type 1 diabetes mellitus. In this review, we describe possible molecular mechanisms by which c-peptide may improve renal efficiency in a diabetic milieu.