The centenary of insulin discovery represents an important opportunity to transform diabetes from a fatal diagnosis into a medically manageable chronic condition. Insulin is a key peptide hormone and mediates the systemic glucose metabolism in different tissues. Insulin resistance (IR) is a disordered biological response for insulin stimulation through the disruption of different molecular pathways in target tissues. Acquired conditions and genetic factors have been implicated in IR. Recent genetic and biochemical studies suggest that the dysregulated metabolic mediators released by adipose tissue including adipokines, cytokines, chemokines, excess lipids and toxic lipid metabolites promote IR in other tissues. IR is associated with several groups of abnormal syndromes that include obesity, diabetes, metabolic dysfunction-associated fatty liver disease (MAFLD), cardiovascular disease, polycystic ovary syndrome (PCOS), and other abnormalities. Although no medication is specifically approved to treat IR, we summarized the lifestyle changes and pharmacological medications that have been used as efficient intervention to improve insulin sensitivity. Ultimately, the systematic discussion of complex mechanism will help to identify potential new targets and treat the closely associated metabolic syndrome of IR.
The discovery of insulin in 1921 was a milestone event1 that introduced the possibility of systematic research of insulin action (Fig. 1). Frederick Sanger (1918-2013) sequenced bovine insulin in 1955, identifying its exact amino-acids composition,2,3 and was awarded with the Nobel Prize for Chemistry in 1958. In 1965, a large team in the People’s Republic of China successfully synthesized the crystalline bovine insulin with full biological activity, immunogenicity and chemical property for the first time in the world.4 Subsequently, human insulin was produced using recombinant DNA methods and genetic modification of bacteria.5 Insulin therapy and understanding its mechanisms of action become important later research targets. Insulin is a peptide hormone that is produced and released by islets pancreatic β cells, that finely regulates the glucose uptake from blood into liver, fat, and skeletal muscle cells.6 Insulin also promotes several other cellular processes, in addition to glucose homeostasis, including regulation of glycogen synthesis, lipid metabolism, DNA synthesis, gene transcription, amino acid transport, protein synthesis and degradation7.
Under normal physiological conditions, increased plasma glucose levels lead to increased insulin secretion and circulating insulin levels, thereby stimulating glucose transfer into peripheral tissues and inhibiting hepatic gluconeogenesis. Individuals with defected insulin-stimulated glucose uptake into muscle and adipocytes tissues, in addition to impaired insulin suppression of hepatic glucose output, are described as having ‘insulin resistance’(IR).8 Several diseases are clinically associated with IR includes obesity, type 2 diabetes mellitus (T2DM), metabolic syndrome, cardiovascular disease, MAFLD, PCOS, and cancer.9,10,11,12,13 Thus, there is an urgent need to identify the mechanisms of IR and effective interventions for treating these metabolic diseases. A relatively safe and well accepted approach in the prevention and treatment of IR is via lifestyle interventions. Nutritional intervention is an important first step that emphasizes a low-calorie and low-fat diet that stimulates excessive insulin demands. In addition, increased physical activity is recommended to help increase energy expenditures and improve muscle insulin sensitivity, this two approach represent the fundamental treatment for IR.14,15 The second step is the use of pharmacologic medications, including metformin, oral sulphonylureas, oral sodium-glucose cotransporter 2 (SGLT2) inhibitors, oral dipeptidyl peptidase 4 (DPP-4) inhibitors, oral α-Glucosidase, injectable glucagon-like peptide 1 (GLP1) receptor agonists, or injectable insulin.16,17
In this review, the mechanism of insulin action and IR are first described to promote the development of new therapeutic strategies. Further, the direct and indirect effects of insulin on target tissues are discussed to better understand the pivotal role of tissue crosstalk in systemic insulin action. Lastly, diseases associated with IR are discussed and summarized. Many methods and multiple surrogate markers have been developed to calculate the IR. We then summarize the current measurements and potential biomarkers of IR to facilitate the clinical diagnosis. Finally, we provide the general approaches including lifestyle intervention, specific pharmacologic interventions and clinical trials to reduce IR.
Insulin is an endocrine peptide hormone with 51 amino acids and composed of an α and a β chain linked together as a dimer by two disulfide bridges18 along with a third intrachain disulfide bridge in the α chain.19,20 Insulin is released by pancreatic beta cells and is essential for glucose and lipid homeostasis.21 Insulin binds the insulin receptor (INSR) on the plasma membrane of target cells, leading to the recruitment/phosphorylation of downstream proteins, that primarily including insulin receptor substrate (IRS), PI3-kinase(PI3K), and AKT isoforms, that are largely conserved among insulin target tissues and that initiate the insulin response.22,23 The pathway diversification of insulin signaling downstream targets of Akt activation leads to different distal signaling in target tissues response to insulin (Fig. 2). (1) AKT substrates include the inactive glycogen synthase kinase 3 (GSK3) and active protein phosphatase 1 (PP1) that promote glycogen synthesis.24,25,26 In addition, the transcription factor forkhead box O1 (FOXO1) is phosphorylated by AKT and is transported from the nucleus, thereby disabling its transcription factor activity and inhibiting gluconeogenesis.27,28 (2) Tuberous sclerosis complex 1/2 (TSC1/2) and proline-rich Akt substrate 40 (PRAS40) are inhibitors of mTORC1, thereby inducing protein synthesis and adipogenesis.29,30 (3) The upregulation of sterol regulatory element binding protein 1c (SREBP-1c), de-phosphorylation of ACC1/2 through inhibition of AMP-dependent protein kinase (AMPK), and the phosphorylation of ATP citrate lyase (ACLY) lead to constitutive increases in de novo lipogenesis (DNL);31,32,33 (4) Phosphodiesterase 3B (PDE3B) and the abhydrolase domain containing 15 (ABHD15) protein are involved in suppression of lipolysis in adipocytes by inhibiting adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL).34,35
Accumulation of reports have demonstrated that IR is a complex metabolic disorder with integrated pathophysiology. The exact causes of IR has not been fully determined,36,37,38 but ongoing research seeks to better understand how IR develops. Here, we focus on the underlying mechanism of IR including direct defective of insulin signaling, epidemiological factors, interorgan metabolic crosstalk, metabolic mediators, genetic mutation, epigenetic dysregulation, non-coding RNAs, and gut microbiota dysbiosis.
As has been mentioned, the proper modulators acting on different steps of the signaling pathway ensure appropriate biological responses to insulin in different tissues. Thus, the diverse defect in signal transduction contributes to IR.
Insulin exerts its biological effects by binding to its cell-surface receptors, therby activating specific adapter proteins, such us the insulin receptor substrate (IRS) proteins (principally IRS1 and IRS2), Src-homology 2 (SH2) and protein-tyrosine phosphatase 1B (PTP1B), eventually promoting downstream insulin signaling involving glucose homeostasis.39 Thus, changes in insulin receptor expression, ligand binding, phosphorylation states, and/or kinase activity accounts for many IR phenotypes.
Most individuals that are obese or diabetic exhibit decreased surface INSR content and INSR kinase (IRK) activity.40 Defective IRK activity is also implicated by decreased IRS1 tyrosine phosphorylation which is consistently observed in insulin-resistant skeletal muscles.41 In addition, the specific knockout or ablation of INSR in livers prevents insulin suppression of hepatic glucose production (HGP),42,43 suggesting a direct role for INSR in hepatic IR. Second, decreased expression or serine phosphorylation of IRS proteins44,45 can reduce their binding to PI3K, thereby down-regulating PI3K activation and inducing apparent IR. Third, homozygous mice of IRS1 or IRS2 gene leading to peripheral IR and diabetes, and impaired insulin secretion through restrained PI3K/AKT signal transduction.46 Thus, pharmacological inhibitors, blocking antibodies and knockdown of PI3K abolishes the insulin stimulation of glucose transport, GLUT4 translocation and DNA synthesis.47,48,49 Additionally, deletion of Pik3r1 and Pik3r2 that encode PI3K subunit isoforms in skeletal muscle inhibits insulin-stimulated glucose transport.50 Similarly, interfering Akt mutant suppresses insulin-stimulated GLUT4 translocation,51 and inhibition of AKT expression, or impairment in AKT Ser473 phosphorylation are certainly detected in both muscle and liver IR.52,53 Further, there are three known isoforms of Akt1/2/3 in insulin sensitive tissues, the present study showed that the Akt2 and Akt3 defects impaired insulin-stimulated glucose transport in IR.54 In addition, elevated plasma nonesterified fatty acid (NEFA) levels impaired the insulin-induced increase in IRS-1-associated PI3K activity, but no defect in Akt phosphorylation was observed.55 Together, the combined actions of various disorders in the proximal signaling components leads to impaired glucose metabolism and IR, and a major challenge remains for understanding IR mechanisms regarding how to distinguish the causes from insulin effects or primary defects from their consequences.
It is generally accepted that diverse downstream targets of Akt activation lead to different distal signaling in target tissues response to insulin. As mentioned above, there are more than 100 Akt substrates mainly including GLUT4, FOXO1, GSK3, mTORC1, SREBP-1c, TSC1/2, PRAS40, ABHD15, PDE3B.56 Among them, GLUT4 is the best characterized and mediates glucose uptake in skeletal muscle and white adipose cells after insulin stimulation.57,58 Impaired translocation of intracellular GSV (GLUT4 storage vesicles) caused decreased insulin-stimulated glucose uptake which are associated with IR in muscle and adipose tissues.59 This proved that heterozygous deletion of Glut4 mice reduce glucose uptake and develop metabolic disease in adipocytes.60 Similarly, defection of insulin-stimulated GLUT4 translocation to the cell surface occurs in skeletal muscle in various IR mice models61,62 and humans with T2DM.63,64 In addition, loss of Tbc1d4 in mice that phosphorylated by Akt leads to the attenuation of downstream target activation of Rab-GTPase proteins associated with GLUT4 vesicles, and completely abolishes insulin-stimulated adipocyte glucose uptake.65 Mice homozygous for the physiologically important AKT substrate TBC1D4 Thr649 knock-in exhibit impaired insulin-stimulated myocellular GLUT4 translocation and induction of glucose intolerance.66 In summary, continued discovery of novel AKT substrates involved in GLUT4 translocation indicates that many but not all of the same effectors are involved in the glucose uptake of different tissues, and further studies should be conducted to identify the molecular mediators in all phases of insulin-stimulated glucose uptake.
Different investigations have indicated that premenopausal women exhibit many less metabolic disorders than men, including lower incidence of IR, although this effect diminishes severely when women reach the postmenopausal situation.67,68 Specifically, female sex hormones including estradiol (e.g., 17β-oestradiol)69 protect female proopiomelanocortin (POMC) neurons from IR by enhancing POMC neuronal excitability and coupling insulin receptors to transient receptor potential (TRPC) channel activation. Concomitantly, clinical and experimental observations70,71 have revealed that endogenous estrogens can protect against IR primarily through ER-α activation in multiple tissues, including in the brain, liver, skeletal muscle, and adipose tissue, in addition to pancreatic β cells. Further, female hormone estrogens are determinants that mediate body adiposity levels and body fat distribution in addition to glucose metabolism and insulin sensitivity. Specifically, insulin sensitivity and capacities for insulin responses in women is significantly higher than men.72
