Insulin signalling activates PI3K → PIP3 → PDK1 → Akt (PKB) pathway. Akt phosphorylates and inactivates glycogen synthase kinase-3 (GSK-3), thereby activating glycogen synthase. The additional mechanism by which insulin simultaneously promotes glycogen synthesis via protein phosphatase-1 (PP1) activation is:

• A Akt directly phosphorylates and activates PP1
• B Insulin activates phosphodiesterase that degrades cAMP, reducing PKA activity and thereby reducing phosphorylation of protein phosphatase inhibitor-1 (Inhibitor-1), allowing PP1 to remain active ✓
• C Insulin activates adenylate cyclase via Gi, increasing cAMP which activates PP1
• D Insulin receptor directly phosphorylates glycogen synthase on serine residues, activating it

Explanation

Insulin activates a phosphodiesterase (PDE3B in adipocytes and hepatocytes via Akt phosphorylation) that degrades cAMP. Reduced cAMP decreases PKA (protein kinase A) activity. PKA normally phosphorylates Inhibitor-1 (of PP1) at Thr35, activating it to inhibit PP1. When PKA activity falls, phosphorylated Inhibitor-1 decreases, releasing PP1 inhibition. Active PP1 then dephosphorylates (and activates) glycogen synthase while simultaneously dephosphorylating (and inactivating) glycogen phosphorylase. This mechanism coordinates glycogen synthesis with inhibition of glycogenolysis in response to insulin, acting in opposition to glucagon's cAMP-mediated effects.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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