Distinct mTORC1 pathways for transcription and cleavage of SREBP-1c

Abstract

In recent years, it has become increasingly apparent that common polygenic diseases generally do not result from accumulated defects in a single pathway but, rather, present as complex interactions among multiple environmental and inherited factors. Nowhere is this more obvious than in diabetes mellitus, which is classified into at least two groups, type 1 and type 2 (T2DM), that share hyperglycemia but differ in the initiating primary immune destruction of the β-cells or insulin resistance, respectively. Although much literature has emphasized the dissimilarities in the progression of β-cell failure in type 1 diabetes mellitus vs. T2DM, only recently have investigators focused on how the peripheral metabolic profile of T2DM differs from that predicted to be the consequence of an insulin deficiency state (i.e., simple global “insulin resistance”). As a result of these studies, the idea has emerged that the “insulin-resistant” liver, for example, remains sensitive to action of the hormone on lipid metabolism while developing resistance to the control of glucose metabolism, a state that has been termed “selective insulin resistance” (1). One consequence of this revised model has been an emphasis on examining downstream signaling pathways as possible sites of insulin insensitivity as well as potential targets for therapeutic intervention (2). In PNAS, Owen et al. (3) describe a unique “branch point” in the pathway by which insulin works in concert with nutritional signals to regulate hepatic lipid synthesis positively.