The 1921 discovery of
insulin was a Big Bang from which a vast and expanding universe of research into
insulin action and resistance has issued. In the intervening century, some discoveries have matured, coalescing into solid and fertile ground for clinical application; others remain incompletely investigated and scientifically controversial. Here, we attempt to synthesize this work to guide further mechanistic investigation and to inform the development of novel
therapies for
type 2 diabetes (T2D). The rational development of such
therapies necessitates detailed knowledge of one of the key pathophysiological processes involved in T2D:
insulin resistance. Understanding
insulin resistance, in turn, requires knowledge of normal
insulin action. In this review, both the physiology of
insulin action and the pathophysiology of
insulin resistance are described, focusing on three key
insulin target tissues: skeletal muscle, liver, and white adipose tissue. We aim to develop an integrated physiological perspective, placing the intricate signaling effectors that carry out the cell-autonomous response to
insulin in the context of the tissue-specific functions that generate the coordinated organismal response. First, in section II, the effectors and effects of direct, cell-autonomous
insulin action in muscle, liver, and white adipose tissue are reviewed, beginning at the
insulin receptor and working downstream. Section III considers the critical and underappreciated role of tissue crosstalk in whole body
insulin action, especially the essential interaction between adipose lipolysis and hepatic gluconeogenesis. The pathophysiology of
insulin resistance is then described in section IV. Special attention is given to which signaling pathways and functions become
insulin resistant in the setting of chronic
overnutrition, and an alternative explanation for the phenomenon of ‟selective hepatic
insulin resistanceˮ is presented. Sections V, VI, and VII critically examine the evidence for and against several putative mediators of
insulin resistance. Section V reviews work linking the bioactive
lipids diacylglycerol,
ceramide, and
acylcarnitine to
insulin resistance; section VI considers the impact of nutrient stresses in the endoplasmic reticulum and mitochondria on
insulin resistance; and section VII discusses non-cell autonomous factors proposed to induce
insulin resistance, including inflammatory mediators,
branched-chain amino acids,
adipokines, and hepatokines. Finally, in section VIII, we propose an integrated model of
insulin resistance that links these mediators to final common pathways of metabolite-driven gluconeogenesis and ectopic
lipid accumulation.