Insulin Action, Metabolism, and Energy Pathways in Cells

Hormone Action and Effects

Hormone action: interaction between hormone and receptor. Effect: the hormonal response generated by the action of the hormone: what it produces (insulin → lower glucose).

Historical Milestones in Insulin

Banting and Best (1920): Insulin isolated. Nobel: MacLeod and Banting. 1945: Sanger purifies protein.

Pancreatic Cells and Insulin Biosynthesis

Cell delta: somatostatin; cell PP: pancreatic polypeptide. Preproinsulin: preproinsulin → proinsulin [1 chain] - (removal of C‑peptide) → insulin (2 chains).

Insulin Receptor and Signaling

Insulin binds receptor (alpha subunit) → tyrosine autophosphorylation on kinase (beta subunit).

Glucose Transporters and Utilization

GLUT1: blood–brain barrier. GLUT3: nerve cells. Arrival of glucose → brain (transport dependent on concentration).
Utilization of glucose: glycogen synthesis, via the pentose phosphate pathway (producing NADPH + H⁺) for lipid metabolism.

Ketone Body and Lipid Metabolism

BLOOD: 3-OH-butyrate; ACAC (acetoacetate).
CYTOSOL: 3-OH-butyrate; ACAC → AcAcCoA → 2 x Acetyl-CoA → ... AcAcCoA + Acetyl-CoA → 3-hydroxy-methylglutaryl-CoA → ... cholesterol / Metabolism.
MITOCHONDRIAL: 3-OH-butyrate <- (NAD⁺ <-> NADH + H⁺) → ACAC.
MITOCHONDRIA: ACAC <- (succinyl-CoA <-> succinate) → ...
AcAcCoA → Acetyl-CoA → Krebs cycle (requires a minimum of glucose for the Krebs cycle: OAA).

NADH Shuttle and Malate–Aspartate Cycle

NADH + H⁺ shuttle from cytosol to mitochondria
CYTOSOL: alpha-KG → OAA (using Asp → Glu). OAA - (MDH) -> malate (using NADH + H⁺ → NAD⁺).
MITOCHONDRIA: malate → OAA (using NAD⁺ → NADH + H⁺). OAA → alpha-KG (using Glu → Asp).

Energy Transfer and Creatine Phosphate

Energy: creatine phosphate (Creatine‑P) - (creatine kinase + ADP/ATP) → creatine; AMP + ATP <- (adenylate kinase) -> 2 ADP.

Neurotransmitter Synthesis Pathways

Tyr → DOPA → dopamine → noradrenaline → adrenaline.
Trp → serotonin.
Glu → GABA; also glutamic acid, beta‑alanine, taurine.

Insulin: Carbohydrate, Lipid and Protein Metabolism

Insulin: carbohydrate metabolism
Liver: active glycogenesis and increased glucose utilization. Muscle: increased glucose utilization by increasing transport via GLUT4 and activating glycogenesis and glycolysis.
Fat: increased uptake of glucose. Insulin facilitates glucose metabolism to enable uptake in adipose and muscle tissue. By providing glycerol, it is linked to lipid metabolism.

Metabolic effects on lipids: increased synthesis of fatty acids and triglycerides in adipose and liver tissue (lipogenesis). Inhibition of lipolysis and of the lipolytic action of adrenaline, growth hormone and glucagon.

Metabolic effects on protein: Liver: decreased protein catabolism. Muscle: decreased protein catabolism: increased protein synthesis and uptake of amino acids. Inhibition of oxidation of hepatic amino acids.

Consequences of Hyperglycemia

Hyperglycemia:

1. Activates glucose uptake through GLUT (especially GLUT4 in fat and skeletal muscle, which is very insulin sensitive).
2. Activates glycolysis.
3. Inhibits gluconeogenesis.
4. Facilitates synthesis of glycogen.
5. Inhibits degradation of glycogen (glycogenolysis).
6. Facilitates lipogenesis.
7. Inhibits lipolysis.