Insulin Resistance Induced by Loop Diuretics and Hyperosmolarity in Perfused Rat Liver

Abstract

Insulin-induced cell swelling was recently suggested to reflect an independent signal for metabolic insulin effects such as inhibition of hepatic proteolysis, which is transmitted at the level of autophagosome formation via p38MAPK activation [Häussinger et al., Gastroenterology 116 (1999), 921-935]. Here, the role of insulin-induced cell swelling in the overall context of insulin signalling towards proteolysis inhibition was studied in perfused rat liver. Loop diuretics and hyperosmolarity, which impair insulin-stimulated cell swelling, strongly blunt Erk-2 and p38MAPK activation as well as proteolysis inhibition by insulin, but are without effect on insulin-induced tyrosine phosphorylation of IR-beta and IRS-1. Inhibitors of phosphatidylinositol-3-kinase (PI3-kinase) also block insulin-induced cell swelling, MAP kinase activation and proteolysis inhibition, but the antiproteolytic response to hypoosmolarity remains unaffected. We suggest that PI3-kinase-mediated cell swelling induced by insulin is required to amplify the insulin signal to MAP kinases and thus proteolysis regulation. The perturbation of insulin-induced cell swelling may be of pathophysiological relevance for the development of insulin resistance in clinical situations associated with hyperosmotic dehydration and loop diuretic treatment.

Involvement of Integrins and Src in Insulin Signaling toward Autophagic Proteolysis in Rat Liver

“…Rather, the data suggest that cell swelling triggers integrin-dependent insulin signaling in hepatocytes anchored to the extracellular matrix. This is further supported by the finding that in perfused rat liver hypoosmotic swelling is sufficient to activate ␤ 1 integrin (this study) and to trigger p38 MAPK activation and proteolysis inhibition as downstream events of integrin-dependent osmosensing and Src activation (11,12,15,16). Further, inhibition of insulin-induced cell swelling by furosemide prevents activation of ␤ 1 integrin and integrin-dependent activation of Src (this study), p38 MAPK , and proteolysis inhibition (16).…”

“…Moreover, in isolated, suspended hepatocytes without contact with an extracellular matrix, insulin potently induces swelling but not proteolysis inhibition (28). This indicates that integrins are probably not involved in the PtdIns-3-kinase-dependent signaling, which was recently located upstream of insulin-induced K ϩ retention and cell swelling (16). Rather, the data suggest that cell swelling triggers integrin-dependent insulin signaling in hepatocytes anchored to the extracellular matrix.…”

“…Loop diuretics inhibit the sodium potassium chloride cotransport and thereby prevent insulin-induced hepatocyte swelling (27,28) and p38 MAPK activation but not IR␤ tyrosine phosphorylation by insulin in the perfused rat liver (16). As shown in Fig.…”

“…Hepatocyte swelling by insulin depends on PtdIns-3-kinase and mediates p38 MAPK activation, which triggers inhibition of autophagic proteolysis (15,16). Equipotent hypoosmotic swelling mimics the insulin effect on p38 MAPK and proteolysis inhibition, whereas prevention of insulin-induced cell swelling abolishes p38 MAPK activation and proteolysis inhibition by insulin (16). Adipocyte swelling by insulin was considered to feed forward MAP-kinase activation and glutamine uptake triggered by the hormone (17).…”

Enhanced insulin sensitivity of gene-targeted mice lacking functional KCNQ1

“…This effect contributes to the metabolic effects of the hormone (19,45). Accordingly, the influence of insulin on cell volume and cell volume-sensitive metabolic functions (27) should be attenuated by activation of cell volume-regulatory K ϩ channels.…”