Step by Step
Ins
Insulin — the fed-state hormone
Insulin is secreted by pancreatic β-cells in response to high blood glucose (and amino acids, GIP, GLP-1). Mechanism: binds receptor tyrosine kinase → activates PI3K/Akt pathway. Effects: GLUT4 translocation to muscle/fat cell membranes (glucose uptake). Glycogen synthesis ↑ (activates glycogen synthase). Fatty acid synthesis ↑ (activates ACC). Protein synthesis ↑. Gluconeogenesis ↓. Beta-oxidation ↓.
Memory trick: Insulin = 'INvite glucose IN.' Everything to store fuel.
Glu
Glucagon — the fasting hormone
Glucagon is secreted by pancreatic α-cells when blood glucose falls. Mechanism: binds GPCR → activates adenylyl cyclase → cAMP → PKA → phosphorylation cascade. Effects: Glycogenolysis ↑ (activates phosphorylase). Gluconeogenesis ↑ (activates PEPCK, inhibits PFK-2). Beta-oxidation ↑ (lowers malonyl-CoA). Ketogenesis ↑. Glycogen synthesis ↓. Fatty acid synthesis ↓.
Memory trick: Glucagon = 'GLUCose Gone — send it out!' Everything to release fuel.
Ratio
The insulin:glucagon ratio
What matters is the RATIO of insulin to glucagon, not their absolute levels. High ratio (fed): anabolism dominates. Low ratio (fasted): catabolism dominates. In Type 1 diabetes: no insulin → ratio is always low → uncontrolled catabolism → hyperglycemia + DKA (diabetic ketoacidosis). In Type 2 diabetes: insulin resistance → cells don't respond to insulin even when levels are high.
DKA
Diabetic ketoacidosis — metabolic emergency
Without insulin: GLUT4 not translocated → cells can't take up glucose → hyperglycemia. Glucagon unopposed → massive beta-oxidation → huge acetyl-CoA excess → ketone body synthesis (acetoacetate, β-hydroxybutyrate, acetone) → metabolic acidosis. Symptoms: fruity breath (acetone), hyperventilation (Kussmaul breathing — compensates for acidosis), dehydration, altered consciousness.
Applied Walkthrough
1
Fed state (1 hour after a meal): insulin:glucagon ratio = 10:1. GLUT4 on muscle/fat cell surfaces. Liver synthesizing glycogen and fatty acids. Gluconeogenesis suppressed.
2
Overnight fast (8 hours): ratio falls to ~2:1. Liver glycogen being mobilized. GNG starting. Mild beta-oxidation.
3
Prolonged starvation (3+ days): ratio = ~0.5:1. Glucagon dominates. Massive beta-oxidation. Ketone bodies become the primary brain fuel (replaces glucose). Muscle protein catabolism provides amino acids for GNG.
4
Type 1 diabetes: ratio = 0 (no insulin). Untreated: hyperglycemia + massive ketogenesis → DKA → coma and death without insulin therapy.
Exam Application
Exams test insulin's mechanisms (GLUT4, glycogen synthesis, fatty acid synthesis) vs glucagon's mechanisms (glycogenolysis, GNG, beta-oxidation, ketogenesis), the cAMP/PKA pathway for glucagon, the PI3K/Akt pathway for insulin, and the pathophysiology of DKA. The insulin:glucagon ratio concept is highly testable.
⚠ Common Trap
Students think insulin only lowers blood glucose — it has many anabolic effects beyond glucose transport. Also: glucagon does NOT directly stimulate muscle — muscle lacks glucagon receptors. Glucagon acts primarily on the LIVER. Epinephrine (not glucagon) is the hormone that mobilizes muscle glycogen.
✓ Quick Self-Check
1. What cells secrete insulin and glucagon?
Insulin: pancreatic β-cells. Glucagon: pancreatic α-cells.
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2. What are three major anabolic effects of insulin?
Any three of: GLUT4 translocation (glucose uptake), glycogen synthesis, fatty acid synthesis, protein synthesis, inhibition of gluconeogenesis.
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3. What signaling pathway does glucagon use?
Glucagon binds GPCR → activates adenylyl cyclase → cAMP → PKA → phosphorylation cascade.
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4. Why does Type 1 diabetes lead to DKA?
Without insulin, glucagon is unopposed → massive beta-oxidation → acetyl-CoA excess → ketone body synthesis → metabolic acidosis.
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5. Why doesn't glucagon act on muscle?
Muscle lacks glucagon receptors — epinephrine (via β-adrenergic receptors) is the hormone that stimulates muscle glycogenolysis.
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