The overlap in signaling functions between insulin and IGF-1 likely also contributes to the well-established relationship between hyperinsulinemia and several cancers ( 631). However, the blurriness of these functional distinctions is highlighted by the high homology between the insulin and IGF-1 receptors, which form hybrid heterodimers in many cell types and share many downstream effectors ( 41, 770). IGF-1 and IGF-2 promote cell growth and differentiation in mammals in contrast, insulin primarily controls metabolic fluxes ( 204). Leveraging gene duplication events through evolutionary time, mammals developed specialized functions for the related peptide hormones insulin, insulin-like growth factor (IGF)-1 and IGF-2 ( 120). In invertebrates, ILPs provide mitogenic signaling input, but their effects on metabolic processes and fuel selection are less significant ( 917). In all animals, insulin or insulin-like peptides (ILPs) have been identified ( 120). Insulin is an endocrine peptide hormone that binds plasma membrane-bound receptors in target cells to orchestrate an integrated anabolic response to nutrient availability. Understanding the mechanisms of insulin action is therefore essential for the continued development of effective therapeutic strategies to combat T2D. The fasting hyperglycemia that defines T2D is largely secondary to inadequate action of the major glucose-lowering hormone: insulin. Although only a subset of obese people develops T2D, obesity is a major risk factor for T2D, and rates of T2D prevalence have paralleled those of obesity ( 381). In the United States, the combined prevalence of diabetes and prediabetes is over 50% ( 538). Overconsumption of relatively inexpensive, calorically dense, inadequately satiating, highly palatable food in industrialized nations has led to unprecedented increases in obesity. Type 2 diabetes mellitus (T2D) is one of the defining medical challenges of the 21st century ( 960). 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. 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. Sections V, VI, and VII critically examine the evidence for and against several putative mediators of insulin resistance. 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 вЂџselective hepatic insulin resistanceЛ® is presented. The pathophysiology of insulin resistance is then described in section IV. 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. 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. 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. 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. Understanding insulin resistance, in turn, requires knowledge of normal insulin action. The rational development of such therapies necessitates detailed knowledge of one of the key pathophysiological processes involved in T2D: insulin resistance. 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). In the intervening century, some discoveries have matured, coalescing into solid and fertile ground for clinical application others remain incompletely investigated and scientifically controversial.

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.

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