Question

Be able to draw, in detail, the mechanism of signaling in the following examples:

- insulin signaling through the insulin receptor to activate mitogenesis.

- insulin signaling to stimulate glycogen synthesis and glucose uptake.

Answer 1

Insulin signalling through insulin receptor to activate mitogenesis

. Insulin stimulates glucose uptake by binding to the insulin receptor (IR), which promotes autophosphorylation and subsequent activation of insulin receptor substrate 1 (IRS1) and PI3 kinase via SH2 interaction with regulatory p85 and catalytic p110 subunits. This promotes association with phosphatidylinositol 4,5-bisphosphate (PIP2) at the plasma membrane, which is converted to phosphatidylinositol 3,4,5-triphosphate (PIP3), which induces a conformational change in Akt that allows Akt phosphorylation and subsequent phosphorylation and inhibition of the Rab-GAP activating protein tre-2/USP6, BUB2, cdc16 domain family member 4 (TBC1D4). Rac/actin can also promote glucose uptake by promoting actin remodeling. Once glucose is entered to the cell it can be metabolized through glycolysis to produce ATP or utilized for glycogen synthesis. Glycogen synthesis involves phosphorylation and inhibition of glycogen synthase kinase 3 (GSK3) by Akt, which activates glycogen synthase (GS); promoting the conversion of glucose-6 phosphate (G6P) to G1P then uridine diphosphoglucose (UDP-G), which is targeted towards glycogen. AMPK can phosphorylate and inhibit GS; however, G6P can override this inhibitory effect. PTG, protein targeting to glycogen.

Glycogen synthesis and glucose uptake through insulin mechanism

In human body there is insulin-stimulated glucose uptake and glycogen synthesis. Insulin stimulates glucose uptake by binding to the insulin receptor (IR) and this promotes autophosphorylation and subsequent activation of insulin receptor substrate 1 (IRS1) and PI3 kinase via SH2 interaction with regulatory p85 and catalytic p110 subunits. This promotes association with phosphatidylinositol 4,5-bisphosphate (PIP2) at the plasma membrane, which is converted to phosphatidylinositol 3,4,5-triphosphate (PIP3), which induces a conformational change in Akt that allows Akt phosphorylation and subsequent phosphorylation and inhibition of the Rab-GAP activating protein tre-2/USP6, BUB2, cdc16 domain family member 4 (TBC1D4). Rac/actin can also promote glucose uptake by promoting actin remodeling. Once glucose enters the cell it can be metabolized through glycolysis to produce ATP or utilized for glycogen synthesis. Glycogen synthesis involves phosphorylation and inhibition of glycogen synthase kinase 3 (GSK3) by Akt, which activates glycogen synthase (GS); that help in the conversion of glucose-6 phosphate (G6P) to G1P then uridine diphosphoglucose (UDP-G), which is targeted towards glycogen. AMPK can phosphorylate and inhibit GS; however, G6P can override this inhibitory effect. PTG, protein targeting to glycogen.