Insulin signal transduction mechanism

The signal-transduction mechanism for leptin involves phosphorylation of the JAK-STAT system. On phosphorylation by JAK, STATs can bind to regulatory regions in nuclear DNA and alter the expression of genes for the proteins that set the level of metabolic activity and determine feeding behavior. Insulin acts on receptors in the arcuate nucleus, with results similar to those caused by leptin. 

Vanadate stimulates protein kinases in the cytosol, as demonstrated in adipose cells and extracts. The activation of a membrane and cytosolic protein tyrosine kinase have been demonstrated in adipocytes, and the membranous enzyme has been postulated to be a way to involve PI-3K actions without activation of insulin receptor substrate-1 (IRS-1) in the insulin signal transduction pathway [140], It is always difficult to determine if protein kinase activation is direct or the result of stimulation of a protein phosphatase. The fact that kinase stimulation was seen in isolated extracts after cell disintegration in this adipocyte cell system supports the idea that vanadium addition to cells could directly stimulate kinases via an as-yet-undetermined mechanism. In other experiments with 3T3-L1 adipocytes bis(acetylacetonato)oxovana-dium (IV) BMOV and bis(l-N-oxide-pyridine-2thiolato)oxovanadium (TV) caused increased tyrosine phosphorylation of both the insulin receptor and IRS-1 in a synergistic way with insulin, as measured by antibodies to phosphotyrosine residues [141]. 

In addition to the insulin-mimetic effect of vanadium compounds, vanadium affects signal transduction mechanisms and proto-oncogene expression in vitro (Stern etal. 1993). At concentrations > 5 mM, orthovanadate is cytotoxic to proliferating cells, including primary culture and tumor cell lines (Cruz et al. 1995, Djordjevic 1995). 

Figure 1 Insulin signal transduction cascade (simplified). Intracellular kinases affected by tyrosine phosphorylation activation/deactivation under phosphotyrosine phosphatase (PTPase) regulation (vanadium-inhibitable) include (especially) IRS-I, IRS-2, she, and MAPK. V indicates possible sites of vanadium s mechanism of action. Cytosolic protein tyrosine kinase (CytPTK, not shown) stimulation by phosphatase inhibition is independent of the insulin cascade, but is also multi-step, and is particularly susceptible to vanadyl stimulation...

C24H38N7O19P3S 853.587 Involved in control of hepatic fatty acid synthesis and oxidation. Acts as a metabolic coupling factor in pancreatic p-cell signal transduction mechanisms linking insulin secretion and fatty acid metabolism. 236 (H2O). 

Autophosphorylation of the insulin receptor leads to phosphorylation of insulin receptor substrate (IRS). IRS comes in four different forms (IRS-1, IRS-2, IRS-3 and IRS-4). In muscle tissue, IRS-1 is the most important form for mediating insulin-signal transduction and lRS-1 impairment has been observed in muscle tissue of humans with DM-2 (Glund and Zierath, 2005). lRS-1 has many tyrosine phosphorylation sites. When these sites are phosphorylated by the insulin receptor, multiple insulin signals are enabled (Sun et al., 1993). IRS-1 also has several serine phosphorylation sites phosphorylation of serine residue 1101 results in inhibition of insulin signalling and provides a possible mechanism for IR (Li et al., 2004). After IRS is phosphorylated, it recruits and activates phosphatidylinositol 3-kinase (PI3-kinase). PI3-kinase phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2) to... 

It has long been known that insulin ( and other hormones and growth factors) can stimulate protein biosynthesis. The signal transduction pathway linking insulin to the translation apparatus was, imtil recently, imclear. However, insight is now being gained into this mechanism (Pause et al, 1994, review Proud and Denton, 1997). 

As work with vanadium compounds and diabetes in cell system has continued, it has become clear that there are also insulin-independent mechanisms at work. One insulin-independent signal transduction pathway appears to be involved in glycogen metabolism reactions in rat adipocytes [137] that also involve PI-3K. A major difference was that only vanadate promoted glycogenesis through the activation of a cytosolic protein tyrosine kinase, which was mediated in an insulin receptor-independent manner. 

Several studies have attempted to define specific effects of thiazo-lidinediones on aspects of insulin-mediated signal transduction in cultured cells. The most consistent results involve an increase in insulin-mediated PI-3-K activation (81, 82). A potential mechanism for enhanced insulin signaling at this level is an increase in insulin stimulation of IRS-1 phosphorylation, as demonstrated by Liu et al. (83). Since direct effects on insulin signaling have not been carefully correlated with in vivo effects or demonstrated with nonthiazolidinedione PPARy agonists, it is not clear if such effects are PPARy-mediated or if they really contribute to in vivo efficacy. 

Once they are bound to an activated receptor, some signal-transduction proteins are phosphorylated by the receptor s intrinsic or associated kinase to achieve their active form. Binding of other signal-transduction proteins, present in the cytosol in unstimulated cells, positions them near their substrates localized in the plasma membrane. Both mechanisms can trigger downstream signaling. Several cytokine receptors (e.g., the IL-4 receptor) and RTKs (e.g., the insulin receptor)... 

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