Question

What effect does Epinephrine and Glucagon have on the activity of adenylyl cyclase in adipose cells?

What are three different mechanisms for lowering blood glucose that result from insulin binding to its receptor?

Answer 1

a. In adipose cells, glucagon and epinephrine stimulate the activity of adenylyl cyclase enzyme that converts ATP to cAMP. Epinephrine binds to beta adrenergic receptors on adipose cells. Binding of epinephrine to the beta adrenergic receptor, a GPCR, will trigger the hydrolysis of a G alpha subunit from a G alpha beta gamma trimer. The G alpha subunit ( Gsalpha) will bind GTP and this complex will activate adenylyl cyclase enzyme. Adenylyl cyclase will form cAMP from ATP, which then activates protein kinase activity and downstream signaling. Glucagon binds to its receptor on adipose cells. This also stimulates the release of Gsalpha subunit, which is activated by GTP binding. The GTP-Gsalpha complex then activates adenylyl cyclase enzyme, which produces cAMP. Epinephrine and glucagon stimulate lipase in adipose cells.

b. Insulin binds to insulin receptors on cell membrane. This will cause transphosphorylation of the receptor. The receptor (IR) will then undergo autophosphorylation on tyrosine residues. IR is activated and will then phosphorylate IRS (IRS1-4) substrate, Shc isoforms etc. This will cause recruitment and binding of adapter proteins which have SH2 domains. IRS protein will interact with PI3 Kinase, which phosphorylates PIP2 to PIP3 (phosphatidylinositol 3,4,5-trisphosphate). PIP3 will activate AKT which then activates mTOR signaling. Shc binding to Grb and SOS can stimulate the Ras-MAPK pathways as well.

Insulin signaling will stimulate the lowering of blood glucose in 3 ways.

a) It will increase the expression of GLUT transporters such as GLUT4. GLUTs are involved in the transport of glucose from blood into the cells. As a result, glucose can be broken down via glycolysis in the cell.

b) The liver is stimulated by Insulin to convert glucose to glycogen (Glycogenesis). It activates the hexokinase enzyme, which phosphorylates glucose to glucose -6 phosphate. Other enzymes in glycogen synthesis such as phosphofructokinase and glycogen synthase are also activated by insulin.

c) Insulin also decreases gluconeogenesis by stimulating IL-56 production in hypothalamus which then inhibits gluconeogenesis via STAT3. As a result, formation of glucose from non-carbohydrate sources is decreased. This will in turn decrease blood glucose levels.