Glucose transport and sensing in the maintenance of glucose homeostasis and metabolic harmony

Abstract

Recent data underscore the importance of intertissue communication in the maintenance of normal glucose homeostasis. Important signals are conveyed by hormones, cytokines, and fuel substrates and are sensed through a variety of cellular mechanisms. The ability of tissues to sense and adapt to changes in metabolic status and fuel availability is altered in insulin-resistant states including type 2 diabetes. Here we review the roles of glucose and its metabolites as signaling molecules and the diverse physiologic mechanisms for glucose sensing.

Figure 1. Molecular glucose sensing.

Upon entering cells of various types, numerous glucose-derived metabolites are sensed by a variety of cellular sensors, including glycogen synthase, ChREBP, AMPK, SIRT1–PGC-1α, carnitine palmitoyl transferase 1 (CPT1), and K_ATP channels. Via its diverse metabolites and their sensors, glucose entering the cell changes gene transcription, modulates signal transduction networks, and alters substrate flux through anabolic and catabolic pathways. ACC, acetyl-CoA carboxylase; FA, fatty acid; F6P, fructose-6-phosphate; GLUT, facilitative glucose transporter; GP, glycogen phosphorylase; G6P, glucose-6-phosphate; GS, glycogen synthase; HK/GK, hexokinase/glucokinase; mTOR, mammalian target of rapamycin; OXA, oxaloacetate; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; PPP, pentose phosphate pathway.

Figure 2. Intertissue glucose sensing and communication.

Glucose is sensed in numerous tissues and cell types, including the hypothalamus, hepatocytes, the hepatoportal sensor, pancreatic islets, and possibly muscle and adipose tissue, each of which communicates with other tissues via hormones, neural pathways, or changes in the utilization of substrate. Pink lines represent neural mediated communication. Black lines represent glucose- or hormone-mediated communication.

Figure 3. Substrate cycles as glucose-derived signals.

Carbon that enters muscle and adipose tissue as glucose may be completely oxidized and leave the tissue as CO₂ and H₂O. However, a substantial portion of the carbon that enters these tissues as glucose is recycled back to the liver in the form of various gluconeogenic precursors. These gluconeogenic precursors constitute signals reflecting the intracellular milieu in muscle and adipose tissue, which is determined by the physiologic state of the organism. Amino acids derived from protein breakdown that occurs predominantly in muscle provide nitrogen and carbon for the production of alanine and glutamine in muscle and adipose tissue.

Figure 4. The adipocyte as a glucose sensor.

Physiologic downregulation of GLUT4 in the fasted state, pathologic downregulation in insulin-resistant states, or genetic knockout result in diminished glucose flux. The diminished glucose flux is sensed by the adipocyte, resulting in increased RBP4 secretion. Additionally, the diminished glucose flux may limit the ability to generate glycerol-3-phosphate via glycolysis. The adipocyte becomes reliant on glyceroneogenesis for glycerol-3-phosphate production, which may be limiting for fatty acid re-esterification and contribute to increased fatty acid release. G3P, glycerol-3-phosphate; PEP, phosphoenolpyruvate.