Insulin Resistance: From Mechanisms to Therapeutic Strategies

Abstract

Insulin resistance is the pivotal pathogenic component of many metabolic diseases, including type 2 diabetes mellitus, and is defined as a state of reduced responsiveness of insulin-targeting tissues to physiological levels of insulin. Although the underlying mechanism of insulin resistance is not fully understood, several credible theories have been proposed. In this review, we summarize the functions of insulin in glucose metabolism in typical metabolic tissues and describe the mechanisms proposed to underlie insulin resistance, that is, ectopic lipid accumulation in liver and skeletal muscle, endoplasmic reticulum stress, and inflammation. In addition, we suggest potential therapeutic strategies for addressing insulin resistance.

Keywords: Diabetes mellitus, type 2; Insulin resistance; Metabolic syndrome; Therapeutics.

Fig. 1.

Role of insulin signaling in liver, skeletal muscle, and adipose tissue. (A) Insulin binds to insulin receptor tyrosine kinase (IRTK), and activate insulin receptor substrate-1 (IRS-1), which recruits phosphatidylinositol-3-OH kinase (PI3K) and activate Akt. In skeletal muscle, Akt promotes glucose uptake via the translocation of glucose transporter type 4 (GLUT4) storage vesicles (GSVs) to the plasma membrane, which is mediated by inactivation of GTPase-activating protein (GAP) AKT substrate of 160 kDa (AS160) and promotion of GTP-bound form of Ras-related C3 botulinum toxin substrate 1 (RAC1). Insulin stimulate glycogen synthesis via glycogen synthase kinase 3 (GSK3)-inhibition mediated glycogen synthease (GYS) activation and glycogen phosphorylase inactivation via the dephosphorylation of phosphorylase kinase. (B) In liver, Akt decreases gluconeogenesis by suppressing of forkhead box O1 (FOXO1)-mediated gluconeogenic gene expressions. In addition, insulin increases hepatic glycogen synthesis by regulating GYS2 and glycogen phosphorylase through GSK3 and protein phosphatase 1 (PP1). Also, insulin increases hepatic de novo lipogenesis by upregulating sterol regulatory element-binding protein 1c (SREBP-1c). (C) In white adipocyte, insulin suppress lipolysis, which in turn suppresses hepatic glucose production by reducing gluconeogenic substrates, which is believed to be mediated by phosphodiesterase 3B (PDE3B), PP1, and protein phosphatase-2A (PP2A). Insulin also promotes glucose transport, lipogenesis, and adipogenesis. PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5-trisphosphate; PKB, protein kinase B; mTORC1, mechanistic target of rapamycin complex 1; G6PC, glucose-6-phosphatase; PCK1, phosphoenolpyruvate carboxykinase 1 (PEPCK); GCK, glucokinase; GPAT1, glycerol-3-phosphate acyltransferase 1; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase.

Fig. 2.

The glucose-fatty acid cycle hypothesis in insulin resistance. Randle et al. [52] proposed that lipid-induced insulin resistance in skeletal muscle is attributed to limited insulin-stimulated glucose utilization caused by increased fatty acid oxidation. Fatty acid oxidation might increase mitochondrial acetyl-CoA levels and subsequently inactivate pyruvate dehydrogenase (PDH), which in turn, would increase intracellular citrate levels and inhibit phosphofructokinase 1 (PFK-1), and lead to the accumulation of intramyocellular glucose-6-phosphate (G6-P), which inhibits hexokinase activity and causes the accumulation of intramyocellular glucose and reduced glucose uptake. FFA, free fatty acid; GLUT4, glucose transporter type 4; GSV, GLUT4 storage vesicle; ATP, adenosine triphosphate; CPT1, carnitine palmitoyltransferase 1; NADH, reduced nicotinamide adenine dinucleotide; TCA, trichloroacetic acid.

Fig. 3.

Hexosamine biosynthesis pathway (HBP) in insulin resistance. In HBP, fructose-6-phosphate (F-6-P) is converted to glucosamine-6-phosphate (Glucosamine-6-P) by glutamine:fructose-6-phosphate amidotransferase (GFAT), and glucosamine-6-P is converted to uridine 5’-diphosphate N-acetylglucosamine (UDP-GlcNAc), which serves as the donor sugar nucleotide for the O-GlcNAcylation of lipids and proteins. O-GlcNAcylation could affect target proteins by regulating gene expressions or enzyme activities. Insulin signaling pathway components, mammalian uncoordinated-18c (Munc18-c), and forkhead box O1 (FOXO1) are modified with O-GlcNAc. PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5-trisphosphate; IRS-1, insulin receptor substrate-1; PKB, protein kinase B; GSK3, glycogen synthase kinase 3; GSV, GLUT4 storage vesicle; GLUT4, glucose transporter type 4; GYS, glycogen synthease; OGT, O-GlcNAc transferase; OGA, O-GlcNAcase; ATP, adenosine triphosphate; PFK-1, phosphofructokinase 1; PDH, pyruvate dehydrogenase; NADH, reduced nicotinamide adenine dinucleotide; TCA, trichloroacetic acid.

Fig. 4.

Diacylglycerol (DAG)-protein kinase C (PKC) hypothesis in insulin resistance. Fatty acids are rapidly esterified in cells to fatty acyl-CoA, which form lysophosphatidic acid (LPA), DAG, and triacylglycerol (TAG) through lipogenesis. Increased hepatic DAG levels induced the translocation of nPKC (PKCε and PKCθ in liver and skeletal muscle, respectively) to the plasma membrane and inhibited insulin receptor tyrosine kinase (IRTK) tyrosine kinase activity by phosphorylating it at Thr1160, which inactivate insulin receptor substrate 2 (IRS-2), phosphatidylinositol-3-OH kinase (PI3K), and Akt2. PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5-trisphosphate; PKB, protein kinase B; PLC, phospholipase C; FFA, free fatty acid; MGL, monoacylglycerol lipase; MAG, monoacylglycerol; HSL, hormone-sensitive lipase; ATGL, adipose triglyceride lipase; CGI-58, comparative gene identification-58; GPAT, glycerol-3-phosphate acyltransferase; AGPAT, acylglycerolphosphate acyltransferase; PA, phosphatidic acid; PAP, phosphatidic acid phosphatases; DGAT, diacylglycerol acyltransferase; ACS, acyl-CoA synthetases; FAS, fatty acid synthase; ACC, acetyl-CoA carboxylase; CPT1, carnitine palmitoyltransferase 1; TCA, trichloroacetic acid.

Fig. 5.

Other potential mechanisms for insulin resistance. Other hypotheses, such as endoplasmic reticulum (ER) stress, reactive oxygen species (ROS), and inflammation, have been proposed to explain the mechanism responsible for obesity-induced insulin resistance. PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5-trisphosphate; PKB, protein kinase B; IKK, inhibitor of nuclear factor κ-B kinase; JNK, c-Jun N-terminal kinase; PKC, protein kinase C; LIPIN2, phosphatidic acid phosphatases; DAG, diacylglycerol; HFD, high-fat diet.

Fig. 6.

Schematic mechanism of type 2 diabetes mellitus (T2DM) and therapeutic strategies for insulin resistance. The main strategies of present (blue) treatment for T2DM and possible future (red) treatments for insulin resistance are summarized. Many T2DM drugs, such as sulfonylureas, glucagon-like peptide 1 (GLP-1) agonists, and dipeptidyl peptide-4 (DPP-4) inhibitors, target the ability of β-cells to secrete insulin. In addition, thiazolidinediones (TZDs) and metformin are insulin-sensitizing antidiabetic drugs, targeting fat storage capacity of adipose tissue and glucose production in liver, respectively. Key strategies of potential future treatment for insulin resistance suggested in this study are targeting enhancement of β oxidation in liver and skeletal muscle and stimulation of muscle quality. FFA, free fatty acid; ACC, acetyl-CoA carboxylase; GPAT, glycerol-3-phosphate acyltransferase; DGAT2, diacylglycerol acyltransferase 2; UCP3, uncoupling protein 3; MSTN, myostatin; PPARγ, peroxisome proliferator-activated receptor-γ; SGLT2, sodium-glucose cotransporter 2.