Mechanisms of Hepatic Insulin Resistance and Its Contribution to the Pathogenesis of Type 2 Diabetes

In hepatocytes, the main parenchymal liver cells, insulin binding to its receptor leads to activation of protein kinase B (AKT), which stimulates glycogen synthesis and lipogenesis but inhibits glucose production (glycogenolysis and gluconeogenesis). Hepatic insulin resistance (HIR) is expected to increase glucose production and decrease lipogenesis, and this occurs in animal knockout models of proximal insulin signaling components and in humans with insulin receptor mutations or anti‐insulin receptor autoantibodies. Paradoxically, HIR more commonly involves increases in both glucose production and lipogenesis, and this has been termed (pathway) selective HIR. Selective HIR is involved in Type 2 diabetes (T2D), but its mechanisms of pathogenesis or its contributions to T2D are not fully understood. Different forms of prediabetes including impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) precede T2D, and HIR is widely regarded to contribute to IFG but not IGT. This article reviews mechanisms of insulin action in the liver and mechanisms of HIR, including selective HIR. It provides some hypothesis‐driven extensions of the latter, including mechanisms of increased gluconeogenesis independently of the inhibition of AKT. Literature showing that selective HIR is involved in both IFG and IGT is presented, and the potential mechanisms proposed. Cross‐talk between the liver and other organs during the pathogenesis of selective HIR and (pre)diabetes is discussed. Worsening HIR and beta cell dysfunction are discussed as key factors for the progression from prediabetes to diabetes, and the contribution of HIR to beta cell dysfunction is highlighted. Implications of these mechanisms for antidiabetic interventions are discussed.