Regulation of glucose uptake in differentiated cells

Abstract

Glucose uptake into the cell is mediated by a family of glycosylated membrane proteins, called glucose transporters (GTs) that are able to facilitate passive hexose transfer across the lipid plasma membrane. The tissue-specific transporter isoforms generally differ in their affinity to the natural substrate D-glucose according to the specific functions of the respective organ. The mechanisms by which external and internal signals regulate glucose uptake into the cells belong to one of the most extensively studied fields of cell physiology. However, in spite of significant progress in identifying the involved molecular components and signaling pathways, the final cellular mechanism responsible for the short-term regulation of glucose uptake is still a matter of intense debate. The widely accepted translocation hypothesis, which explains transport regulation by exo- and endocytic modulation of the number of GTs in the plasma membrane, insufficiently accounts for the whole insulin-induced transport stimulation and is insufficient to integrate the wide variety of different transport-modulating signals in differentiated tissue cells into a common mechanistic concept. Some time ago, a novel type of glucose transport regulation has been proposed prevailing in differentiated tissue cells. This mechanism depends on the presence of glucose transporters on microvilli of differentiated cells. The basic framework for this theory was provided by a recently presented novel concept of ion channel regulation via microvillar structures [Lange, K. (1999): Microvillar Ca++ signaling: A new view on an old problem. J. Cell. Physiol. 180, 19-35; Lange, K. (2000): Regulation of cell volume via microvillar ion channels. J. Cell. Physiol. 185, 21-35; Lange, K. (2000): Microvillar ion channels - Cytoskeletal regulation of ion fluxes. J. Theor. Biol. 206, 561-584], earlier studies on glucose transport regulation and a number actual biochemical findings. Here, a survey on both concepts is given and the ability of the novel mechanism of microvillar transport regulation to integrate a large body of experimental data into the common concept of cellular regulation via microvillar pathways is discussed.

Fundamental role of microvilli in the main functions of differentiated cells: Outline of an universal regulating and signaling system at the cell periphery

“…The concept of microvillar cell regulation opens a surprisingly simple view on the mechanisms of a variety of cellular functions. Cell functions commonly interpreted as independent mechanisms can now be seen as different functional aspects of a common regulatory principle established in differentiated or resting cells (Lange, 2000a,b, 2001; Lange and Gartzke, 2001, 2006a,b; Gartzke and Lange, 2002).…”

“…The diffusion barrier concept, as first formulated by Lange et al (1990), is one of the main cellular principles of the general notion of microvillar regulation of cell functions presented later on (Lange, 1999, 2000a,b, 2001) comprising the regulation of different cell functions such as glucose transport, ion fluxes, and Ca signaling. An essential parameter involved in regulation of cell functions via the microvillar diffusion barrier is the length of microvilli that is equivalent to the effectiveness of the barrier to uncouple channels and transporters on the tip of microvilli from the cytoplasm (Lange and Gartzke, 2006a).…”

“…Later on, exocytic recruitment of additional glucose transporters (GluT4) with a longer half‐life period (∼10 min) can be observed. The exocytic increment of the long‐term insulin action, measurable after 20–30 min of insulin action, has commonly been the matter of studies and has consolidated the assumption that insulin stimulation of transport exclusively depends on exocytosis (discussed by Lange 2001, 2004).…”

“…Proceeding from the above‐discussed regulation of glucose uptake into differentiated cells via an ATP‐regulated microvillar pathway, a plausible theory for all three effects becomes visible (Lange, 2001, 2002; Yang et al, 2008.). According to this approach, the main unresolved problem is how differentiated cells manage to combine glycolysis sequentially with respiration in a perfectly cooperating manner without wasting lactate.…”

Glucose-Transport Regulation in Leukemic Cells: How Can H2O2 Mimic Stem Cell Factor Effects?

“…The mechanisms by which external and internal signals regulate glucose transport have been extensively studied, although the final events responsible for short-term regulation of glucose uptake are still under debate. A large amount of information deals with transport regulation by insulin (15). In the cascade of events leading to the multiple effects of insulin, this hormone activates its receptor tyrosine kinase and stimulates a number of downstream signaling factors.…”