Insulin direct cellular effects

The control of cellular kinases and phosphatases appears to be of undoubted importance to the action of insulin. Whether such effects are determined either directly or indirectly by the receptor tyrosyl kinase, Gins , the second messengers GIP and DAG and by modification of other G-proteins, perhaps even all of these, remains to be determined (Fig. 5). 

Further evidence to support a direct toxic effect of AmB on renal cells is the demonstration of increased apoptosis in proximal tubular and medullary interstitial cell lines [65]. The occurrence of apoptosis has also been confirmed in an in-vivo model in rats in which AmB administration also caused hypokalemia, loss of concentrating ability and dehydration. Interestingly, prevention of apoptosis by recombinant human insulin growth factor-1 (rhIGF-1) ameliorated the tubular toxidly indicating the importance of apoptosis in AmB-induced renal tubular toxicity process. A possible mechanism for this action is suggested by a recent study that has demonstrated that AmB exposure increases cellular ceramide as well as sphingomyelin levels in proximal tubular cells [66]. It is noteworthy that... 

The insulin-enhancing activity of vanadium compounds is likely to be related to their interactions with cellular redox chemistry and ROS formation, in addition to direct inhibition of PTP-1B and other protein phosphatases as a transition-state analogue [100], Differences in the effects of V (III, IV or V)-dipicolinic acid complexes on blood glucose and absorption of V into serum after chronic oral admin-... 

Fatty add synthetase is not controlled directly by phosphorylation however, insulin, glucagon, and thyroxine have an effect on its activity by controlling its cellular concentration. Both insulin and thyroxine increase the biosynthesis of the enzyme, whereas glucagon is inhibitory. Thyroxine and glucagon appear to regulate the biosynthesis at the transcription level, whereas insulin affects the enzyme activity at the translation level. It has no effect on cellular fatty add synthetase mRNA concentration. In summary, fatty add synthetase levels are up in the fed state and down in the fasting state. 

Insulin also exerts a stimulatory effect on the synthesis of cholesterol in the liver. In this tissue, HMG-CoA reductase is activated. HMG-CoA reductase, like hormone-sensitive lipase, can exist in two forms one is phosphorylated (inactive) and the other is dephosphorylated (active). Phosphorylation of the enzyme depends on an increase in the cellular concentration of cAMP and activation of protein kinase. The dephosphorylation (activation) is catalyzed by a phosphatase. In fat cells, a similar phosphatase dephosphorylates (inactivates) hormone-sensitive lipase. Insulin stimulates the activity of the phosphatase in both liver and fat cells. In this way, active HMG-CoA reductase predominates in the liver cell and directs HMG-CoA into cholesterol synthesis, and in the fat cell hormone-sensitive lipase is inactivated. 

Insulin has many direct effects on various cell types from such tissues as muscle, fat, liver, and skin. Which of the following cellular activities is decreased following exposure to physiologic concentrations of insulin ... 

Selective increases in the cellular uptake of certain metabolites. Among this last category are some receptors that serve directly as ion channels, with hormone binding causing a conformational change that opens the channel, and other receptors that stimulate uptake by still-unknown mechanisms, such as the effects of insulin upon glucose uptake. 

The second question concerns the fact that insulin action involves not only effects on glucose uptake, but other effects such as changes in phosphate turnover (Stadie, 1954) and the cellular accumulation of potassium (Verzdr, 1952), as well as effects on protein synthesis (Bouckaert and de Duve, 1947). Are these changes simply the secondary consequence of a primary insulin action upon cell permeability to glucose We do not know. Despite the appeal of a single unitary mechanism for insulin action, the possibility of direct effects of insulin on events other than glucose transfer cannot be ruled out. 

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