Mechanisms for insulin resistance: common threads and missing links

Abstract

Insulin resistance is a complex metabolic disorder that defies explanation by a single etiological pathway. Accumulation of ectopic lipid metabolites, activation of the unfolded protein response (UPR) pathway, and innate immune pathways have all been implicated in the pathogenesis of insulin resistance. However, these pathways are also closely linked to changes in fatty acid uptake, lipogenesis, and energy expenditure that can impact ectopic lipid deposition. Ultimately, these cellular changes may converge to promote the accumulation of specific lipid metabolites (diacylglycerols and/or ceramides) in liver and skeletal muscle, a common final pathway leading to impaired insulin signaling and insulin resistance.

Figure 1. Overview of insulin action

Left Panel: In the fed state, dietary carbohydrate (CHO) increases plasma glucose and promotes insulin secretion from the pancreatic β-cells. Insulin has numerous actions to promote storage of dietary calories, but only several are illustrated here. In the skeletal muscle, insulin increases glucose transport, permitting glucose entry and glycogen synthesis. In the liver, insulin promotes glycogen synthesis and de novo lipogenesis while also inhibiting gluconeogenesis. In the adipose tissue, insulin suppresses lipolysis and promotes lipogenesis. Middle Panel: In the fasted state, insulin secretion is decreased. The drop in insulin (as well as the action of other hormones which are not depicted), serve to increase hepatic gluconeogenesis and promote glycogenolysis. Hepatic lipid production diminishes while adipose lipolysis increases. Right Panel: In type 2 diabetes, ectopic lipid accumulation impairs insulin signaling (as depicted by the red “x”). With accumulation of intramyocellular lipid (IMCL), insulin mediated skeletal muscle glucose uptake is impaired. As a result, glucose is diverted to the liver. In the liver, increased liver lipid also impairs the ability of insulin to regulate gluconeogenesis and activate glycogen synthesis. In contrast, lipogenesis remains unaffected, and together with the increase delivery of dietary glucose, leads to increased lipogenesis and worsening NAFLD. Impaired insulin action in the adipose tissue allows for increased lipolysis which will promote re-esterification of lipids in other tissues (e.g. liver) and further exacerbates insulin resistance. Coupled with a decline in pancreatic β-cells (depicted by the smaller lines emanating from the pancreas), hyperglycemia develops.

Figure 2. Schematic representation of pathways involved in muscle insulin resistance

Insulin activates the insulin receptor tyrosine kinase which subsequently tyrosine phosphorylates IRS1. Through a series of intermediary steps, this leads to activation of Akt2. Akt2 activation, via AS160 and Rab-GTPase (not shown), promotes the translocation of GLUT4 containing storage vesicles (GSV’s) to the plasma membrane permitting the entry of glucose into the cell and promotes glycogen synthesis. This central signaling pathway is connected to multiple other cellular pathways that are designated by numbers 1–3. 1) The green shaded areas represent mechanisms for lipid induced insulin resistance, notably diacylglycerol mediated activation of PKCθ and subsequent impairment of insulin signaling, as well as ceramide mediated increases in PP2A and increased sequestration of Akt2 by PKCζ. Impaired Akt2 activation limits translocation of GSV’s to the plasma membrane resulting in impaired glucose uptake. Impaired Akt2 activity also decreases insulin mediated glycogen synthesis. 2) The yellow areas depict several intracellular inflammatory pathways, notably the activation of IKK, which may impact ceramide synthesis and the activation of JNK1, which may impair insulin signaling via serine phosphorylation of IRS1. 3) The pink area depicts that activation of the UPR which under some instances (e.g. acute extreme exercise) may lead to activation of ATF6 and a PGC1α mediated adaptive response. The ER membranes also contain key lipogenic enzymes and give rise to lipid droplets. Proteins that regulate the release from these droplets (e.g. ATGL and PNPLA3) may modulate the concentration of key lipid intermediates in discrete cell compartments.

Figure 3. Schematic representation of pathways involved in hepatic insulin resistance

Insulin activates the insulin receptor tyrosine kinase which subsequently tyrosine phosphorylates IRS1 and 2. Through a set of intermediary steps, this leads to activation of Akt2. Akt2 can promote glycogen synthesis (not shown), suppress gluconeogenesis and activate de novo lipogenesis (DNL). This central signaling pathway is connected to multiple other cellular pathways that are designated by numbers 1–3. 1) The green shaded areas represent mechanisms for lipid induced insulin resistance, notably diacylglycerol mediated activation of PKCε and subsequent impairment of insulin signaling, as well as ceramide mediated increases in PP2A and increased sequestration of Akt2 by PKCζ. Impaired Akt2 activation limits the inactivation of FOXO1 and allows for increased expression of key gluconeogenesis enzymes. Impaired Akt2 activity also decreases insulin mediated glycogen synthesis (not depicted). 2) The yellow areas depict several intracellular inflammatory pathways, notably the activation of IKK, which may impact ceramide synthesis and the activation of JNK1, which may impair lipogenesis. 3) The pink area depicts that activation of the UPR that can lead to increased lipogenesis, via XBP1s and also increased gluconeogenesis via C/EBP. The ER membranes also contain key lipogenic enzymes and give rise to lipid droplets. Proteins that regulate the release from these droplets (e.g. ATGL and PNPLA3) may modulate the concentration of key lipid intermediates in discrete cell compartments.

Figure 4. Inflammation and energy metabolism

Under certain conditions (e.g. adipocyte dysfunction or fasting), the release of chemokines and/or lipolysis from adipose tissue promotes macrophage activation. Activated macrophages can then signal to other tissues via the release of various cytokines (e.g. TFNα, IL-6, etc.). In adipocytes, cytokine signaling promotes lipolysis via a decrease in lipid droplet stabilizing proteins (e.g. perilipin or FSP27). In muscle cells, cytokines can promote increase lipid oxidation, and under extreme situations, may promote muscle atrophy via increased proteolysis. In the liver, cytokine signaling may serve to increase lipogenesis and impair lipid oxidation. The effects on energy balance may largely depend on the specific cytokines that are activated and the extent of activation. However, the changes in energy balance may largely dictate the changes in ectopic lipid accumulation and, ultimately the development of insulin resistance.