Glucose transporters in adipose tissue, liver, and skeletal muscle in metabolic health and disease

Abstract

A family of facilitative glucose transporters (GLUTs) is involved in regulating tissue-specific glucose uptake and metabolism in the liver, skeletal muscle, and adipose tissue to ensure homeostatic control of blood glucose levels. Reduced glucose transport activity results in aberrant use of energy substrates and is associated with insulin resistance and type 2 diabetes. It is well established that GLUT2, the main regulator of hepatic hexose flux, and GLUT4, the workhorse in insulin- and contraction-stimulated glucose uptake in skeletal muscle, are critical contributors in the control of whole-body glycemia. However, the molecular mechanism how insulin controls glucose transport across membranes and its relation to impaired glycemic control in type 2 diabetes remains not sufficiently understood. An array of circulating metabolites and hormone-like molecules and potential supplementary glucose transporters play roles in fine-tuning glucose flux between the different organs in response to an altered energy demand.

Keywords: Crosstalk; Exercise; Insulin resistance; NAFLD; Type 2 diabetes.

Fig. 1

Integrative physiology of glucose transporters (GLUTs) in the liver, skeletal muscle, and adipose tissue. Expression levels of main GLUT isoforms are regulated by a diversity of metabolic stimuli including fasting and physical activity (exercise) and by certain pathophysiological conditions such as type 2 diabetes (T2DM). A complex inter-organ network is necessary to maintain whole-body energy metabolism in balance. This interaction is regulated by secretion of various factors into the circulation to facilitate tissue crosstalk. The distinct trigger mechanisms for the secretion of these factors are indicated by the respective arrow color (gray, fasting conditions; blue, exercise/physical activity; red, T2DM). In addition, the impact of these three (patho)physiological conditions on gene and/or protein expression of the diverse GLUTs as well as transport of GLUT substrates (e.g., glucose, fructose) is presented by small colored arrows next to the respective GLUT. TGs, triglycerides; FGF-21, fibroblast growth factor 21; TGF-β2, transforming growth factor β2; RBP4, retinol binding protein 4; FAHFAs, fatty acid esters of hydroxy fatty acids

Fig. 2

Major facilitative glucose transporters of the GLUT family in the liver, skeletal muscle, and adipose tissue. Several glucose transporters of the SLC4A2 family are involved in cellular uptake of hexoses. Entry of glucose into hepatocytes is mainly catalyzed by the low-affinity, high-capacity GLUT2 transporter which is localized on the cell surface. Following insulin stimulation, glucose is stored as glycogen or released through an ER-dependent mechanism. Other hepatic GLUTs may have accessory functions such as transporting fructose or uric acid. GLUT4 is the principal glucose transporter in adipose and muscle cells and recycles between the plasma membrane and intracellular storage vesicles. Its steady-state distribution is regulated through insulin- and/or contraction-dependent signaling cascades that involve the RabGAP proteins TBC1D1 and TBC1D4. Rab8 and Rab10 have been identified as major GTPases involved in GLUT4 translocation in muscle and fat cells, respectively. In muscle cells, GLUT12 has been described to undergo regulated traffic in response to metabolic stimuli, similar to GLUT4, whereas GLUT8 recycles in adipose cells through endosomal compartments without a known stimulus for translocation. GLUT10 has been shown to facilitate entry of oxidized vitamin C into mitochondria. At least in skeletal muscle, RabGAPs are involved in the regulated entry of fatty acids (FAs) through fatty acid transporters. Arrows indicate flow of substrates, signaling. AKT, protein kinase B; AMPK, 5′ AMP-activated protein kinase; DHA, dehydroascorbic acid; E, endosomal vesicles; ER, endoplasmic reticulum; FAT, fatty acid transporters; GSK3, glycogen synthase kinase 3; GSV, glucose transporter storage vesicles; TGN, trans-Golgi network