Cell Hydration and Insulin Signalling

Abstract

Changes in cell hydration are critically important for the signalling towards metabolic responses to hormones, substrates and reactive oxygen intermediates. In liver insulin-induced cell swelling is due to a net K⁺-uptake resulting from the concerted activation of Na⁺/K⁺/2Cl^- cotransport, Na⁺/H⁺ exchange and the Na⁺/K⁺-ATPase. Insulin-induced swelling is essential for generating the antiproteolytic response to the hormone, which depends on activation of the MAP-kinase p38. Recent investigations show, that cell swelling induced by either hypoosmolarity or insulin triggers the activation of signalling cascades. Cell swelling by insulin is Ptdins-3-kinase mediated and contributes to the activation of Erk- and p38-type MAP-kinases. Conditions dehydrating insulin target tissues such as hyperosmolarity or amino acid deprivation are frequently associated with insulin resistance. In liver, hyperosmolarity impairs the Ptdins-3-kinase-dependent K⁺ uptake and cell swelling in response to insulin, leading to resistance of MAP-kinases and proteolysis to regulation by insulin. Likewise, a reduction of insulin-induced swelling by the loop diuretics furosemide and bumetanide cause insulin resistance shown by the levels of cell swelling, MAP-kinase activation and proteolysis control. Blockage of the cell volume response to insulin may be the common denominator in dehydration-induced insulin resistance found in clinical settings such as sepsis, burn injury and diabetes mellitus.

Higher plain water intake is associated with lower type 2 diabetes risk: a cross-sectional study in humans

“…have proposed more direct mechanisms, such as the role of water in cell metabolism [30], which if disrupted may lead to insulin resistance [31], along with its roles in nutrient transportation and hydrolysis [10]. Although further research needs to be conducted, it is fair to conclude that dehydration could negatively impact these functions, thus increasing T2D risk; a mechanism which supports the findings of the first regression analysis in this study.…”

Liver Cell Volume Regulation: Size Matters

“…8 Because primary increases in cell volume in the absence of insulin reproduce many of these effects, and inhibition of the cell volume increase partially blocks many insulin responses, there is emerging evidence that cell volume per se represents a signal influencing insulin signaling, as well as many other liver cell and organ functions. 3,6,9 In general, increases in cell volume represent an anabolic signal, stimulating protein and glycogen synthesis, exocytosis, and bile flow, while simultaneously inhibiting proteolysis and glycogenolysis. Decreases in cell volume have opposite effects, leading to catabolic changes in protein and glycogen processing.…”

“…Several excellent articles summarizing the relationship between cell volume and different liver functions are available. 3,6,9,14 …”

Volume-sensitive Tyrosine Kinases Regulate Liver Cell Volume through Effects on Vesicular Trafficking and Membrane Na+ Permeability

“…These findings suggest that volume-sensitive tyrosine kinases serve as critical intermediary signals that couple cell volume to changes in membrane Na ϩ permeability through effects on NSC channels. These findings are of interest because insulin also stimulates an increase in liver cell volume through activation of NSC-like channels (2,20), and cell volume per se may represent a signal regulating antiproteolytic and other insulin-like responses (39). Thus, although tyrosine kinases have established roles in the regulation of cell growth, cell cycle, and mitogenic signaling (8 -10), they also appear capable of rapid modulation of membrane transport and membrane recycling.…”