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Difficulty: HardEndocrine and Metabolic Mechanisms

A 28-year-old critically ill patient is admitted to the intensive care unit with profound acidemia, hyperglycemia, and elevated serum beta-hydroxybutyrate. The medical team initiates a continuous intravenous infusion of a hormone that binds to a transmembrane receptor with intrinsic enzymatic activity. In addition to halting lipolysis, this intervention aggressively stimulates the storage of glucose as a highly branched polymer in the liver. Arrange the following intracellular signaling events in the correct chronological sequence to describe the hepatocyte response to this continuous infusion.

  1. 1Ligand-induced autophosphorylation of receptor beta-subunit tyrosine residues
  2. 2Recruitment and tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1)
  3. 3Phosphoinositide 3-kinase (PI3K) catalyzed formation of phosphatidylinositol 3,4,5-trisphosphate (PIP3)
  4. 4Membrane docking and subsequent activation of protein kinase B (Akt)
  5. 5Phosphorylation-mediated inactivation of glycogen synthase kinase-3 (GSK-3)

Answer

The correct chronological sequence begins with receptor autophosphorylation, followed by IRS-1 phosphorylation, generation of PIP3, activation of Akt, and finally the phosphorylation and inactivation of GSK-3.
The question requires tracing the molecular mechanism of insulin signaling that leads to increased glycogen synthesis in hepatocytes. Insulin binds to its receptor tyrosine kinase, causing autophosphorylation of the beta subunits. This activated kinase phosphorylates insulin receptor substrate (IRS) proteins. Phosphorylated IRS recruits phosphoinositide 3-kinase (PI3K), which converts PIP2 to PIP3 at the cell membrane. The accumulation of PIP3 recruits protein kinase B (Akt) and phosphoinositide-dependent kinase-1 (PDK1), leading to the activation of Akt. Activated Akt then phosphorylates glycogen synthase kinase-3 (GSK-3), which inhibits it. Because GSK-3 constitutively inhibits glycogen synthase through phosphorylation, the inhibition of GSK-3 leads to a net decrease in glycogen synthase phosphorylation, thereby increasing its activity and promoting glycogen synthesis.

Step-by-Step Solution

1
Identify the primary hormone and targeted physiological pathway based on the clinical presentation.
The patient has diabetic ketoacidosis and is receiving continuous intravenous insulin. The targeted pathway in hepatocytes is the stimulation of glycogen synthesis.
Recognizing the hormone allows for the identification of its specific receptor type (a receptor tyrosine kinase).
2
Determine the initial receptor activation event.
Ligand-induced autophosphorylation of receptor beta-subunit tyrosine residues.
Insulin does not use G-protein coupled receptors. It binds to extracellular alpha subunits, causing the transmembrane beta subunits to cross-phosphorylate each other.
3
Trace the proximal intracellular adapter and lipid kinase steps.
Recruitment and phosphorylation of IRS-1, followed by PI3K activation and PIP3 formation.
The activated receptor kinase uses IRS-1 as a primary docking protein, which in turn recruits and activates PI3K to generate PIP3 at the cell membrane.
4
Sequence the downstream kinase cascade leading to the final metabolic effect.
Akt activation followed by the inactivation of GSK-3.
PIP3 serves as a membrane anchor for Akt, allowing it to be activated. Akt then phosphorylates GSK-3, turning it off. Because GSK-3 normally inhibits glycogen synthase, turning off GSK-3 disinhibits glycogen synthase, allowing glycogen formation.

Key Concept

The metabolic effects of insulin, including hepatic glycogen synthesis, are mediated by a receptor tyrosine kinase signaling cascade involving IRS-1, PI3K, and Akt, which ultimately disinhibits glycogen synthase by phosphorylating and inactivating GSK-3.
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Topics

Endocrine and Metabolic Mechanisms

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