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Review
. 2018 Oct 1;98(4):2133-2223.
doi: 10.1152/physrev.00063.2017.

Mechanisms of Insulin Action and Insulin Resistance

Max C Petersen  1 , Gerald I Shulman  1
Affiliations
Review

Mechanisms of Insulin Action and Insulin Resistance

Max C Petersen et al. Physiol Rev. .

Abstract

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.

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Figures

FIGURE 1.
FIGURE 1.
Proximal insulin signaling. Upon insulin binding, the insulin receptor (INSR) autophosphorylates and recruits diverse substrates. The two major arms of insulin signaling are mitogenic (initiated by GRB2 and SHC) and metabolic [initiated by insulin receptor substrate (IRS) proteins and SH2B2/APS]. Insulin signaling is also characterized by feedback mechanisms, both positive [GIV potentiation of phosphoinositide-3-kinase (PI3K)-AKT signaling, and phosphatase inhibition by NAD(P)H oxidase 4 (NOX4)-derived H2O2] and negative (stabilization and recruitment of GRB10 to the INSR, and activation of S6 kinase 1 (S6K1) to phosphorylate and inhibit IRS proteins). Green circles and arrows represent activating events; red circles and arrows represent inhibitory events.
FIGURE 2.
FIGURE 2.
The insulin signaling cascade in skeletal muscle. Insulin receptor (INSR) activation has two major metabolic functions in the skeletal myocyte: glucose uptake and glycogen storage. Insulin stimulation of glucose uptake occurs through translocation of GLUT4-containing storage vesicles (GSVs) to the plasma membrane. The resultant increase in intracellular glucose-6-phosphate production, together with a coordinated dephosphorylation of glycogen metabolic proteins, enables net glycogen synthesis. Green circles and arrows represent activating events; red circles and arrows represent inhibitory events. GSK3, glycogen synthase kinase 3; PI3K, phosphoinositide-3-kinase; PP1, protein phosphatase 1.
FIGURE 3.
FIGURE 3.
Sources of hepatic glucose production during fasting in humans. During the early postprandial period (not shown), the liver performs net glucose uptake as ingested glucose is stored as liver glycogen. Gluconeogenic flux continues but is diverted into glycogen storage. After this period, gluconeogenic flux contributes to hepatic glucose production and continues at a relatively constant rate for ~48 h, eventually decreasing due to declining substrate availability. Net hepatic glycogenolysis, in contrast, initially contributes about half of hepatic glucose production, but its rate decreases exponentially in concordance with hepatic glycogen content. Hepatic glycogenolysis still contributes appreciably to hepatic glucose production after 24 h of fasting, but is nearly depleted by 48 h. Because plasma glucose concentrations reflect rates of hepatic glucose production during a fast, the plasma glucose concentration is a systemic signal of hepatic glycogen content during fasting. [Data from Rothman et al. (704).]
FIGURE 4.
FIGURE 4.
Hepatic insulin signaling. AKT signaling is central to hepatocellular insulin action. Fast effects include activation of the glycogen and protein synthetic machinery. Slower transcriptionally mediated effects include upregulation of glucokinase, dimunition of gluconeogenic capacity, and stimulation of de novo lipogenic capacity. Green circles and arrows represent activating events; red circles and arrows represent inhibitory events. IRS, insulin receptor substrate; GSK3, glycogen synthase kinase 3; PI3K, phosphoinositide-3-kinase; PP1, protein phosphatase 1; GPAT, glycerol-3-phosphate acyltransferase; G6PC, glucose-6-phosphatase; PCK1, phosphoenolpyruvate carboxykinase; SREBP1c, sterol regulatory element binding protein 1c; FAS, fatty acid synthase.
FIGURE 5.
FIGURE 5.
Insulin signaling in the white adipocyte. The most critical physiological functions of insulin action in white adipose tissue are suppression of lipolysis and stimulation of glucose uptake. Suppression of lipolysis requires phosphodiesterase 3B (PDE3B) and occurs largely through attenuation of cAMP-stimulated events such as perilipin (PLIN) and hormone-sensitive lipase (HSL) phosphorylation. Insulin stimulation of glucose uptake occurs through phosphoinositide-3-kinase (PI3K)-dependent [left insulin receptor (INSR)] and PI3K-independent (right INSR) pathways using numerous effectors to promote translocation, docking, and fusion of GLUT-containing storage vesicles (GSVs) with the plasma membrane. Green circles and arrows represent activating events; red circles and arrows represent inhibitory events. IRS, insulin receptor substrate; PP, protein phosphatase; SREBP-1c, sterol regulatory element binding protein 1c; LPL, lipoprotein lipase.
FIGURE 6.
FIGURE 6.
The adipocyte-hepatocyte axis and insulin suppression of gluconeogenesis. A: in the fasted state, the adipocyte releases nonesterified fatty acids (NEFA) into the circulation. Within the hepatocyte, NEFA are oxidized to mitochondrial acetyl CoA, an allosteric activator of pyruvate carboxylase (PC). PC drives gluconeogenic flux. This, together with net glycogenolysis, facilitates hepatic glucose production (HGP) during fasting. B: during insulin stimulation (e.g., postprandially), both direct and indirect effects of insulin suppress HGP. Adipocyte insulin signaling suppresses lipolysis, decreasing plasma NEFA concentrations, hepatic mitochondrial acetyl CoA concentrations, PC activity, and gluconeogenic flux. Simultaneously, direct insulin action on the hepatocyte promotes net glycogen synthesis. Both processes enable insulin to rapidly and potently suppress net HGP.
FIGURE 7.
FIGURE 7.
Insulin resistance in dose-response curves. A: in a hypothetical cell with decreased surface insulin receptor (INSR) content, the dose-response curve is right-shifted but the maximal biological response is not decreased unless >90% of surface receptors are lost. B: in a cell with an insulin signal transduction (“post-receptor”) defect, or a combined receptor/post-receptor defect, both a right shift and decreased maximal response are observed. The right graph typifies human obesity-associated insulin resistance in muscle, liver, and adipose tissues.
FIGURE 8.
FIGURE 8.
Functional consequences of skeletal muscle insulin resistance. A: an insulin-sensitive skeletal myocyte activates the metabolic insulin receptor substrate 1 (IRS1)-phosphoinositide-3-kinase (PI3K)-AKT arm of the insulin signaling cascade to increase glucose uptake and glycogen synthesis. B: an insulin-resistant myocyte exhibits impairments in proximal insulin signaling events, blunting insulin’s ability to stimulate GLUT4 translocation and glycogen synthesis.
FIGURE 9.
FIGURE 9.
Mechanisms for the development of nonalcoholic fatty liver disease (NAFLD) despite hepatic insulin resistance. A: insulin normally activates de novo lipogenesis through sterol regulatory element binding protein 1c (SREBP-1c). B: the seemingly paradoxical coexistence of NAFLD and hepatic insulin resistance has spawned the hypothesis of selective hepatic insulin resistance, wherein insulin activation of lipogenesis is preserved despite impaired insulin regulation of glucose metabolism. However, hepatic de novo lipogenesis has multiple inputs, including ChREBP and mTORC1/SREBP-1c, both of which are activated in states of chronic overnutrition. Additionally, the primary pathway for hepatic triglyceride synthesis is re-esterification of preformed fatty acids, which are readily available in states of chronic overnutrition owing both to dietary supply and to adipose insulin resistance. Even if insulin receptor (INSR) activation of SREBP-1c is impaired by hepatic insulin resistance, these other inputs are likely capable of supporting the lipogenic fluxes that lead to NAFLD. NEFA, nonesterified fatty acid; WAT, white adipose tissue.
FIGURE 10.
FIGURE 10.
Interpretation of glucose tolerance tests requires measurement of plasma insulin concentrations. A: diet-induced obese and prediabetic nonobese diabetic (NOD) mice both display glucose intolerance compared with lean chow-fed control mice, but the causes differ. The diet-induced obese mice mount a normal or even heightened insulin secretory response but are hyperglycemic owing to insulin resistance. The prediabetic NOD mice are glucose intolerant owing to defective insulin secretion. B: improved glucose tolerance can similarly result from increased insulin sensitivity [fibroblast growth factor 21 (FGF21)-treated mice] or from increased insulin secretion (sulfonylurea-treated mice).
FIGURE 11.
FIGURE 11.
Isotope tracer methods to assess insulin resistance in vivo. Six example methods are illustrated. The experimental protocol and mode of tracer delivery are italicized, the tracer is bolded, and the effect of insulin resistance is at bottom right. A: several glucose isotopomers can be used to trace whole-body glucose turnover, Rd. During a hyperinsulinemic-euglycemic clamp, where Rd and the glucose infusion rate F are both known, endogenous glucose production can be calculated by subtracting F from Rd. Insulin suppression of endogenous glucose production is impaired in insulin-resistant subjects. B: under hyperinsulinemic-euglycemic clamp conditions, 70–80% of Rd is accounted for by skeletal muscle glucose uptake, so skeletal muscle insulin resistance is often accompanied by decreased Rd. C: the nonmetabolizable glucose analogue 2-deoxyglucose (2-DG) is phosphorylated and trapped inside tissues which lack glucose-6-phosphatase (e.g., skeletal muscle and adipose tissue, but not liver). Tissue 2-DG-6-phosphate levels can thus be used to estimate insulin-stimulated glucose uptake, which is decreased in insulin resistance. D: the negligible natural abundance of m+6 glucose makes [U-13C]glucose a useful tracer of hepatic glycogen synthesis, which is decreased in hepatic insulin resistance. To stimulate net hepatic glycogen synthesis, both hyperinsulinemia and hyperglycemia are necessary. E: the incorporation of deuterated or tritiated water into hepatic palmitate yields a measurement of hepatic de novo lipogenesis (DNL) but requires several days of administration to reach isotopic steady state. DNL is decreased in some models of insulin resistance, such as the high-fat-fed rodent. Because insulin regulation of DNL is a slow, transcriptionally mediated process, this method is compatible with the physiology being studied. F: several palmitate and glycerol tracers, including [U-13C]palmitate and [1,1,2,3,3-2H]glycerol, can be used to trace lipolysis. Insulin suppression of lipolysis from white adipose tissue is impaired in adipose insulin resistance. Notably, Ra glycerol under fasting conditions is likely a more accurate measure of lipolysis than Ra palmitate, because palmitate can be re-esterified within the adipocyte.
FIGURE 12.
FIGURE 12.
The Randle hypothesis and lipid-induced skeletal muscle insulin resistance. A: Randle and co-workers proposed that lipid-induced impairments in muscle glucose oxidation are secondary to substrate competition with fatty acids. Increased fatty acid oxidation would increase the mitochondrial acetyl CoA/CoA and NADH/NAD+ ratios. This would allosterically inhibit pyruvate dehydrogenase (PDH) and phosphofructokinase (PFK; through increases in its allosteric inhibitor citrate), decreasing glycolytic flux. The ensuing increase in glucose-6-phosphate concentration would in turn allosterically inhibit hexokinase (HK), leading to increased intracellular glucose concentrations. B: measurements of intramyocellular glucose and glucose-6-phosphate during acute lipid infusions revealed that concentrations of these metabolites are decreased, not increased, in this setting. Together with studies linking muscle insulin resistance with impaired GLUT4 translocation, these data implicated impaired glucose transport as the chief defect in lipid-induced muscle insulin resistance.
FIGURE 13.
FIGURE 13.
Ectopic lipid hypothesis of liver and muscle insulin resistance. The central organizing principle is that lipid storage in white adipose tissue, especially in subcutaneous depots, is physiologically appropriate, but lipid storage in liver and skeletal muscle is inappropriate and metabolically harmful. Lipid accumulation at these ‟ectopicˮ sites is associated with insulin resistance. Human phenotypes are listed above silhouettes, and corresponding mouse models, described in the main text, are below.
FIGURE 14.
FIGURE 14.
Rodent models of perturbed hepatic triglyceride synthesis. Various genetic loss-of-function and gain-of function rodent models have been generated to test the role of diacylglycerol (DAG) in lipid-induced hepatic insulin resistance. These models are broadly consistent with the DAG/protein kinase C (PKC)ε hypothesis of lipid-induced hepatic insulin resistance. TAG, triacylglycerol; HFD, high-fat diet, KO, knockout. See text for details and references.
FIGURE 15.
FIGURE 15.
Subcellular localization and stereoisomers of diacylglycerol (DAG). DAG is produced by the action of various enzymes at multiple intracellular sites, only a few of which are depicted. At the plasma membrane, phospholipase C (PLC) generates sn-1,2-DAG from phosphatidylinositol-4,5-bisphosphate (PIP2); this DAG is particularly critical for the activation of the classical protein kinase C (PKC) isoforms that also require the Ca2+ liberated downstream of PLC activity. The lipogenic enzymes of the Kennedy pathway are localized to the endoplasmic reticulum (ER) and produce sn-1,2-DAG. The novel PKC isoforms display significant localization to the Golgi. For PKCε in particular, this partially owes to the Golgi localization of its adapter protein RACK2. RACK2 also participates in vesicle transport between the ER and Golgi, and Golgi DAGs regulate protein trafficking to the plasma membrane. Notably, lipolytic DAG generated by the action of adipose triglyceride lipase (ATGL) at the lipid droplet is of the sn-1,3 stereoisomer and would not be predicted to activate PKC isoforms.
FIGURE 16.
FIGURE 16.
The diacylglycerol (DAG)/protein kinase C (PKC)ε axis in lipid-induced hepatic insulin resistance. Chronic overnutrition promotes intrahepatic lipid accumulation. Although this lipid is primarily stored as relatively inert triglyceride, levels of the bioactive lipid DAG, the penultimate intermediate in triglyceride synthesis, increase as well. DAG activates PKC isoforms by promoting PKC translocation to cellular membranes, and PKCε translocation in particular is chronically and reproducibly increased in the setting of lipid-induced hepatic insulin resistance. PKCε impairs insulin action by directly phosphorylating and inhibiting the insulin receptor (INSR) at Thr1160 in the activation loop of its tyrosine kinase domain.
FIGURE 17.
FIGURE 17.
Proposed molecular mechanisms of lipid-induced skeletal muscle insulin resistance. A: diacylglycerol (DAG) has been proposed to cause muscle insulin resistance by activating protein kinase C-θ (PKCθ). The targets of PKCθ within the insulin signaling cascade are incompletely defined but may include insulin receptor substrate 1 (IRS1) and GIV. PI3K, phosphoinositide-3-kinase. B: ceramides have been proposed to mediate skeletal muscle insulin resistance by decreasing AKT activity through at least two mechanisms. PP2A, protein phosphatase 2A. C: incomplete mitochondrial fatty acid oxidation has been proposed to mediate skeletal muscle insulin resistance, either through direct effects of the resultant acylcarnitine species or through production of reactive oxygen species, which modulate various cellular processes.
FIGURE 18.
FIGURE 18.
Nutrient stress and insulin resistance. A: endoplasmic reticulum (ER) stress, manifested as the unfolded protein response (UPR), is activated in multiple models of liver insulin resistance. Accumulation of misfolded proteins in the ER lumen initiates the UPR, activating PKR-like eukaryotic initiation factor 2α kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). Key effectors of the UPR include c-Jun NH2-terminal kinase (JNK) and the mRNA splice variant of X-box binding protein 1 (XBP1s). JNK may directly impair proximal insulin signaling, although this is controversial. XBP1s transcriptionally activates the de novo lipogenic program and promotes hepatic steatosis, which may in turn drive hepatic insulin resistance through diacylglycerol (DAG)/protein kinase C (PKC)ε signaling. B: muscle insulin resistance is associated with mitochondrial dysfunction, although cause and effect relationships are not clearly defined. The red pathway describes observations made in humans: older adults and the young lean insulin-resistant offspring of parents with type 2 diabetes (T2D) display reduced mitochondrial ATP synthesis in skeletal muscle, probably reflective of reduced ATP demand as resting mitochondria operate at submaximal ATP synthetic rates. This decrease in substrate oxidation promotes lipid storage, increasing intramyocellular lipid (IMCL). IMCL accumulation may then impair proximal insulin signaling through activation of the DAG/PKCθ axis, accounting for the reduced insulin-stimulated glucose uptake observed in these individuals. Alternatively, chronic overnutrition and/or lipid oversupply increases the mitochondrial capacity for fatty acid oxidation. However, because ATP demand is relatively inflexible, this increase is not enough to match supply, leading to IMCL accumulation and increased rates of incomplete fatty acid oxidation. Incomplete fatty acid oxidation produces acylcarnitine species and reactive oxygen species (ROS). Acylcarnitines have been hypothesized to impair insulin signaling through undefined mechanisms, and ROS have broad cellular effects, including impairment of mitochondrial function. ROS-induced mitochondrial damage would then exacerbate these effects, further promoting IMCL accumulation and ROS production.
FIGURE 19.
FIGURE 19.
An integrated physiological perspective on tissue insulin resistance. Chronic overnutrition is the ultimate cause of systemic insulin resistance and promotes insulin resistance by both tissue-autonomous and crosstalk-dependent mechanisms. Chronic overnutrition promotes lipid accumulation in skeletal muscle and liver, which causes insulin resistance in those tissues. Additionally, chronic overnutrition poses a nutrient stress to adipocytes, resulting in adipocyte insulin resistance and adipocyte death. Increases in the adipokine RBP4 and other proinflammatory signals lead to the recruitment of macrophages to white adipose tissue. Inflammatory signaling in macrophages, including activation of c-Jun NH2-terminal kinase (JNK), leads to the elaboration of paracrine mediators such as tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β), and others. These inflammatory cytokines may increase adipocyte lipolysis either directly or indirectly by impairing insulin signaling. The increased adipocyte lipolysis of inflammation increases nonesterified fatty acid (NEFA) and glycerol turnover. This has direct (glycerol conversion to glucose) and indirect [NEFA-derived acetyl CoA activation of pyruvate carboxylase (PC)] stimulatory effects on gluconeogenesis, and also promotes accumulation of intrahepatic triglyceride (IHTG) and consequent lipid-induced hepatic insulin resistance, which impairs insulin stimulation of net hepatic glycogen synthesis. Together, these effects increase hepatic glucose production. Chronically increased lipolysis may also facilitate the accumulation of intramyocellular lipid (IMCL) and consequent lipid-induced muscle insulin resistance. The decreased glucose disposal of muscle insulin resistance increases glucose availability for the liver, which in turn promotes IHTG accumulation and worsens hepatic insulin resistance.
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