Step 1 · Biochemistry

Metabolic Fuel Use & Insulin/Glucagon Signaling

Name: Metabolic Fuel Use & Insulin/Glucagon Signaling
Creator: Veli Bakalov, MD

How the fed-fasting switch routes fuel through the body

Biochemistry·Bioenergetics & Lipid Metabolism·4 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Insulin (receptor tyrosine kinase → IRS-1 → PI3K/Akt → GLUT4) is anabolic; glucagon (Gs → cAMP → PKA, mainly liver) is catabolic; the insulin-to-glucagon ratio sets fed vs fasting.
Only GLUT4 (skeletal muscle, adipose) needs insulin; GLUT1 (RBC, blood-brain barrier), GLUT2 (beta cells, liver, kidney, gut), and GLUT3 (neurons) are insulin-independent.
Fasting: hepatic glycogenolysis supplies glucose for ~12–24 h, then gluconeogenesis from lactate, alanine, and glycerol; muscle glycogen cannot release glucose (no glucose-6-phosphatase).
Prolonged starvation: adipose FFA and hepatic ketones dominate and spare protein; the brain shifts to ketones after about 3 days (it cannot use FFA), while RBCs use only glucose (no mitochondria).
Pathways in BOTH mitochondria and cytoplasm = HUG: heme synthesis, urea cycle, gluconeogenesis.
The Cori cycle returns lactate carbon to the liver for gluconeogenesis (net cost 4 ATP per turn); the glucose-alanine (Cahill) cycle carries amino nitrogen to the liver for urea.
Hormone-sensitive lipase (PKA-activated, insulin-inhibited) releases FFA and glycerol from adipocytes; lipoprotein lipase (insulin-activated, needs ApoC-II) clears triglyceride after meals.
Fructose-2,6-bisphosphate activates PFK-1 and inhibits fructose-1,6-bisphosphatase; insulin raises it (PFK-2), glucagon lowers it (FBPase-2).
Pyruvate dehydrogenase is activated by insulin and inhibited by ATP, NADH, and acetyl-CoA; acetyl-CoA activates pyruvate carboxylase instead.

The fed–fasting switch: insulin and glucagon

Fed builds up, fasting breaks down. Insulin (fed, anabolic) drives glycogen, fat, and protein synthesis. Glucagon (fasting, catabolic) drives glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis. Neither acts alone: the insulin-to-glucagon ratio sets the switch.

Insulin signaling. Insulin binds a receptor tyrosine kinase, which autophosphorylates and recruits IRS-1, then PI3K/Akt, to insert GLUT4 transporters into the membranes of muscle and adipose cells. Its anabolic effects are glycogenesis, lipogenesis, protein synthesis, and cellular K⁺ uptake (the basis for insulin in treating hyperkalemia). It also inhibits lipolysis, glycogenolysis, and gluconeogenesis.

Glucagon signaling. Glucagon from pancreatic alpha cells binds a Gs-coupled receptor, activating adenylyl cyclase to raise cAMP and activate protein kinase A (PKA), which drives hepatic glycogenolysis, gluconeogenesis, and ketogenesis. Its main target is the liver; muscle lacks glucagon receptors. Epinephrine mimics glucagon via beta-adrenergic receptors (Gs, cAMP) and, unlike glucagon, also mobilizes muscle glycogen.

Insulin vs glucagon

Feature	Insulin	Glucagon
Source	Pancreatic beta cells	Pancreatic alpha cells
State	Fed (anabolic)	Fasting (catabolic)
Receptor	Receptor tyrosine kinase → IRS-1 → PI3K/Akt	Gs → adenylyl cyclase → cAMP → PKA
Key tissues	Muscle and adipose (GLUT4), liver	Liver
Actions	Glycogenesis, lipogenesis, protein synthesis, K⁺ into cells	Glycogenolysis, gluconeogenesis, lipolysis, ketogenesis

Only GLUT4 needs insulin. GLUT4 in skeletal muscle and adipose is the insulin-responsive transporter; exercise can also recruit GLUT4 in muscle independently of insulin. The others work without insulin:

GLUT1 — RBCs, blood-brain barrier.
GLUT2 — beta cells, liver, kidney, gut; bidirectional, low-affinity glucose sensor.
GLUT3 — neurons.

Insulin-independent glucose uptake: Brain, RBC, Intestine, Cornea, Kidney, Liver.

Fuel use from the fed state to starvation

Fed / absorptiveGlucose is the fuel; insulin stores glycogen and fat
Fasting (~12–24 h)Hepatic glycogenolysis maintains blood glucose
Early starvationGlycogen exhausted; gluconeogenesis from lactate, alanine, glycerol
Prolonged starvationAdipose FFA and hepatic ketones dominate; ketones fuel the brain; protein spared

Fuel use over time

Fasting. For roughly the first 12–24 hours, hepatic glycogenolysis is the main source of blood glucose. Muscle glycogen cannot supply blood glucose because muscle lacks glucose-6-phosphatase; it fuels only the muscle itself. Gluconeogenesis then takes over, using lactate, alanine, and glycerol. Even-chain fatty acids cannot make net glucose, because their acetyl-CoA cannot be converted back to pyruvate.

Starvation. Over days, adipose-derived free fatty acids and hepatic ketones dominate, sparing muscle protein. Muscle and liver shift to burning fatty acids so that glucose is reserved for the tissues that need it.

Brain and red cells. The brain runs on glucose but, after about 3 days of starvation, increasingly switches to ketones (beta-hydroxybutyrate, acetoacetate); it cannot use free fatty acids. RBCs lack mitochondria, so they have no beta-oxidation or ketone use and rely exclusively on glucose, which they metabolize anaerobically to lactate.

Mobilizing fat. Hormone-sensitive lipase (HSL) inside adipocytes hydrolyzes stored triglyceride to free fatty acids plus glycerol (a gluconeogenic substrate). It is activated by PKA downstream of catecholamines and glucagon, with cortisol also promoting lipolysis, and it is inhibited by insulin. Contrast lipoprotein lipase on capillary endothelium, which insulin activates and which needs ApoC-II to clear chylomicron and VLDL triglyceride in the fed state.

Two lipases, opposite hormones: HSL (inside fat cells) releases fat during fasting; LPL (on capillaries) loads fat into tissues after a meal.

Inter-organ cycles

Cori cycle. Anaerobic muscle and RBCs export lactate to the liver, which regenerates glucose by gluconeogenesis and returns it, shifting the ATP burden to the liver. The liver spends 6 ATP equivalents to rebuild one glucose from two lactates, while anaerobic glycolysis yields only 2 ATP, so each turn costs a net 4 ATP.

Muscle / RBC glycolysisGlucose → lactate (anaerobic)
Lactate travels to liverVia the bloodstream
Liver gluconeogenesisLactate → glucose; costs 6 ATP
Glucose returns to muscleSustains anaerobic work

Cori (lactate) cycle

Glucose-alanine (Cahill) cycle. Muscle transaminates pyruvate to alanine to ship amino nitrogen to the liver, which converts alanine back to glucose and disposes of the nitrogen as urea.

Cori moves carbon (lactate); Cahill moves nitrogen (alanine).

Compartments and committed steps

Where pathways run.

Mitochondria — beta-oxidation, TCA cycle, oxidative phosphorylation, ketogenesis.
Cytoplasm — glycolysis, HMP shunt, fatty acid and cholesterol synthesis.
Both — gluconeogenesis, urea cycle, heme synthesis.

Both compartments = HUG: Heme synthesis, Urea cycle, Gluconeogenesis. Fatty acid OXIDATION is mitochondrial; fatty acid SYNTHESIS is cytoplasmic.

Fructose-2,6-bisphosphate, the fed/fasting switch. Glycolysis is committed at PFK-1 and gluconeogenesis at fructose-1,6-bisphosphatase (FBPase-1); F2,6-BP activates the first and inhibits the second. In the fed state, insulin dephosphorylates the bifunctional enzyme so its PFK-2 activity raises F2,6-BP, favoring glycolysis. In fasting, glucagon (PKA) phosphorylates it, activating FBPase-2, lowering F2,6-BP, and favoring gluconeogenesis.

Committed-step enzymes

Pathway	Enzyme	Activated by	Inhibited by
Glycolysis	PFK-1	AMP, F2,6-BP	ATP, citrate
Gluconeogenesis	Fructose-1,6-bisphosphatase	Glucagon, indirectly (by lowering F2,6-BP)	AMP, F2,6-BP
Pyruvate → acetyl-CoA	Pyruvate dehydrogenase	Insulin; NAD⁺, ADP, Ca²⁺ (exercise)	ATP, NADH, acetyl-CoA
Fatty acid synthesis	Acetyl-CoA carboxylase	Insulin, citrate	Glucagon, palmitoyl-CoA
Cholesterol synthesis	HMG-CoA reductase	Insulin	Glucagon, cholesterol, statins

Acetyl-CoA activates pyruvate CARBOXYLase (gluconeogenesis) while inhibiting pyruvate DEHYDROGENase — in fasting, pyruvate is steered toward glucose rather than burned.