Diabetes mellitus has been increasing in prevalence and imposes serious economic burdens on both the developed as well as the developing world. Understanding pathobiological underpinning of chronic progressive disease like diabetes is an imperative that we cannot escape. For several decades now, the focus has remained on a two hit theory which begins with insulin resistance and is followed thereafter by the β cell failure. Therapies have revolved around this concept with only limited success. Reorientation in our understanding of "islet pathology" should help rethink strategies that would yield better dividends in terms of effective therapy. Role of Glucagon needs to be revisited and incorporated to create treatment regimens addressing the concept of bi-hormonal defect rather than remaining stuck in standalone "insulinopathy." This brief review hopes to initiate/continue that dialogue.
Keywords: glucagon; hypothalamus; insulin; islet mass; liver; β-cell.