L2 Metabolism Regulation of fuel metabolism

Overview

This lecture covers how insulin and glucagon (with contributions from adrenaline and adiponectin) regulate blood glucose and fuel storage. It moves from the hormones’ secretion (triggers, cell types, incretin amplification), through their receptor signalling and the reversible phosphorylation mechanism that flips glycogen synthase and glycogen phosphorylase between active/inactive states, to their tissue-specific effects on glycogen metabolism, lipid metabolism and gluconeogenesis in the fed versus fasted/stress states. It closes with the clinical consequences of genetic defects in glycogen-metabolising enzymes (glycogen storage diseases).

Glucose homeostasis

• Glucose homeostasis is the balance between glucose intake/production and utilisation. Tissues, especially the brain, require a steady glucose supply, so plasma glucose is closely regulated.
• Regulating hormones: insulin, adiponectin, glucagon, adrenaline.
• Glycogen (liver and muscle) acts as an energy buffer: excess glucose is stored as glycogen in the fed state and mobilised in the fasted state.
• Gluconeogenesis (liver) is an important glucose source in the fasted state.
• Normal plasma glucose midpoint is about 90 mg/dL (5 mmol/L), spanning roughly 18–162 mg/dL (1–9 mmol/L) on the physiological control scale shown.
• Two directions of hormonal control: hypoglycaemic action (insulin, adiponectin) lowers plasma glucose; hyperglycaemic action (glucagon, adrenaline, cortisol, growth hormone) raises it.
• Over a 24-hour cycle: insulin spikes sharply after each meal (food intake pulses); glucagon rises during the fasting gaps between meals, while glucose itself stays relatively stable with only small dips.

Insulin: secretion

• Insulin is a peptide hormone secreted by β cells of the pancreatic islets (glucagon comes from α cells, somatostatin from δ cells — immunohistochemistry shows β-cell insulin staining centrally in the islet core and α-cell glucagon staining peripherally).
• Glucose-stimulated insulin secretion pathway in the β cell (“glucose sensor,” triggered above 5.5 mmol/L glucose):
  1. Glucose enters the β cell via GLUT-2 and is phosphorylated by glucokinase to glucose-6-phosphate (G-6-P).
  2. G-6-P is metabolised via the mitochondria, raising the ATP/ADP ratio.
  3. The rising ATP/ADP ratio closes the $K_{ATP}$ channel, blocking K+ efflux and depolarising the membrane potential above -40 mV.
  4. Depolarisation opens voltage-gated Ca2+ channels, causing Ca2+ influx, which triggers fusion/exocytosis of insulin-containing secretory granules and insulin release.
• Control of insulin secretion:
  • Stimulated by: glucose >5 mmol/L; arginine; alanine; glycine.
  • Potentiated by: gut hormones such as cholecystokinin and other incretins.
  • Inhibited by: adrenaline; glucagon.

Sulfonylurea drugs act directly on the $K_{ATP}$ channel in the β cell, triggering the same depolarisation → Ca2+ influx → insulin release pathway independent of glucose sensing.

Insulin structure

• Preproinsulin has a B-chain (1–30) and A-chain (1–21) joined by disulfide bonds (interchain B7–A7 and B19–A20, plus an intrachain A6–A11 bond), a connecting C-peptide, and an N-terminal signal peptide.
• Processing: preproinsulin (with signal peptide) → proinsulin (signal peptide cleaved, C-peptide still attached in a loop) → mature insulin (A and B chains joined by disulfide bonds) + free C-peptide (final cleavage).
• Insulin is stored in secretory granules as crystals of an insulin hexamer: three dimers assembled around zinc ions (each dimer ~12,000 MW, hexamer ~36,000 MW).
• The A-chain terminal residues (A1 glycine, A19 tyrosine, A21 asparagine) sit on the hexamer surface, are invariant across species, and are not involved in dimer/hexamer aggregation; their deletion or substitution (especially bulky groups at A1 glycine) substantially reduces activity, showing they are important to insulin’s biological activity. The three-dimensional structure was determined by X-ray crystallography (Blundell, Cutfield, Dodson, Hodgkin and colleagues, including Otago/NZ researchers, Diabetes 1972).

The incretin effect

• Oral (intrajejunal) glucose produces a markedly higher insulin response than intravenous glucose for a similar blood glucose rise — this is the incretin effect.
• Incretins are gut hormones that: stimulate insulin release, alter nutrient absorption rates from the gut, and affect appetite. Examples: glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP).
• Native incretins have a very short serum half-life (e.g. GLP-1 ≈ 2 minutes); longer-acting analogues have been developed as therapeutics: exenatide, liraglutide, semaglutide, and others.
• Exenatide (Byetta) is a GLP-1 mimetic, first discovered in Gila Monster venom. In Type 2 diabetics it improves insulin sensitivity and maintains β-cell function; in an IV glucose bolus test it restores a first-phase insulin secretion peak that is otherwise blunted in Type 2 diabetes (approaching the response of healthy controls).
• DPP-4 is the enzyme that breaks down incretins (relevant to why analogues are engineered to resist degradation).
• Long-acting GLP-1 analogue design strategies (illustrating how short native GLP-1 is extended): fatty-acid (palmitoyl) conjugation for albumin binding (semaglutide, liraglutide — liraglutide has 97% amino acid homology to human GLP-1); fusion to an antibody Fc fragment (dulaglutide); fusion to albumin itself (albiglutide).
• GLP-1 receptor mechanism: GLP-1 and mimetics (semaglutide, exendin-4, exenatide/Byetta) bind a GPCR on the β cell, activating adenylate cyclase (AC) → cAMP → PKA. This pathway converges with the glucose/$K_{ATP}$/Ca2+ pathway (which can also be triggered directly by sulfonylurea drugs) to stimulate insulin granule exocytosis. Cryo-EM has resolved the structure of the GLP-1 receptor bound to semaglutide together with a heterotrimeric G-protein (Gαsβ1γ2) (Zhang et al. 2021).

Insulin: overall metabolic effects

Once secreted, insulin binds insulin receptors present on essentially all mammalian cells (liver, muscle, adipose, etc.). The insulin receptor is a tyrosine kinase that phosphorylates specific tyrosines on its substrates, triggering an intracellular signalling cascade that changes enzyme phosphorylation status or gene transcription.

Insulin’s actions, summarised:

• Promotes glucose uptake by activating GLUT4 in muscle and adipose tissue.
• Promotes glycogen synthesis (liver, muscle) and lipogenesis (adipose, liver).
• Promotes glucose utilisation (glycolysis).
• Inhibits gluconeogenesis (liver), glycogenolysis (liver and muscle) and lipolysis (adipose).
• Stimulates lipoprotein lipase (LPL) activity (fatty acid uptake into adipose); inhibits hormone-sensitive lipase.
• Promotes amino acid uptake and protein synthesis.

Tissue-by-tissue (fed state):

• Adipose tissue: insulin binds its receptor, activates GLUT4 for glucose uptake, promotes lipogenesis.
• Muscle: insulin binds its receptor, activates GLUT4 for glucose uptake, promotes glycogen synthesis.
• Liver: insulin binds its receptor, activates GLUT2 for glucose uptake, promotes glycogen synthesis and lipogenesis.

More detailed tissue effects (Figure 20.3):

• Liver: glucose enters via GLUT-2 → stimulates glycogen synthesis and glycolysis (pyruvate → acetyl-CoA → TCA cycle); acetyl-CoA also feeds lipogenesis → fatty acids → glycerol-3-P → triacylglycerol → VLDL; amino acids support protein synthesis.
• Muscle: glucose enters via GLUT-4 → glycogen synthesis and glycolysis → TCA cycle; amino acids → protein synthesis.
• Adipose: glucose enters via GLUT-4 → glycolysis → TCA cycle and glycerol-3-P; VLDL-derived fatty acids taken up via lipoprotein lipase combine with glycerol-3-P to form triacylglycerol for storage.

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Consolidated summary (central “Insulin” diagram):

• Liver: ↑ glycogen synthesis, ↑ lipogenesis, ↓ gluconeogenesis.
• Muscle: ↑ glucose uptake, ↑ glycogen synthesis.
• α-cells (pancreas): ↓ glucagon secretion.
• Adipose tissue: ↑ glucose uptake, ↑ lipoprotein lipase, ↑ TAG storage, ↓ lipolysis.

Reversible phosphorylation as a regulatory mechanism

A general principle underlying much of insulin/glucagon signalling: enzymes are commonly switched between active and inactive forms by phosphorylation and dephosphorylation. A protein kinase adds a phosphate (using ATP → ADP) to alter enzyme activity; a phosphatase removes it (releasing Pi), reversing the change.

Insulin receptor signalling cascade

Insulin binds the insulin receptor (IR), triggering receptor tyrosine autophosphorylation (pY) and branching into two main pathways:

1. Ras/MAPK branch: IR (via Shc, Grb2, Sos) → Ras → Raf1 → MEK → MAPK → Myc/Jun/Fos and p90rsk, driving DNA/RNA/protein synthesis and cell growth/differentiation.
2. PI3K/Akt branch: IR (via IRS proteins, Gab-1, SHP-2, Fyn) → PI3K → PDK1 → PKB/Akt, which branches further to (a) mTOR → S6 kinase → S6, and (b) GSK3β and AS160 — driving glycogen synthesis (via GSK3β inhibition) and glucose transport (via AS160). A separate branch via APS/Cbl, CrkII, C3G, TC10 acting through lipid rafts/caveolae also contributes to glucose transport.

Overall: insulin receptor activation separates into growth/differentiation signalling versus metabolic signalling (glycogen synthesis, glucose transport).

GLUT4 trafficking

GLUT4 is normally stored in intracellular membranous vesicles. Insulin stimulates exocytosis of these vesicles to the plasma membrane, inserting GLUT4 to allow glucose entry. GLUT4 is also removed from the membrane by endocytosis and returned to the vesicle pool — a continuous exocytosis/endocytosis cycle, with insulin shifting the balance toward more surface GLUT4.

Glycogen synthase and glycogen phosphorylase regulation

• In the fed state, insulin activates the phosphatase PP1, which dephosphorylates glycogen synthase (converting it to its active form, promoting glycogen synthesis) and dephosphorylates glycogen phosphorylase (converting it to its inactive form, inhibiting glycogen breakdown). Glycogen synthase is also activated by glucose and glucose-6-phosphate.
• Detailed pathway: insulin receptor tyrosine phosphorylation (Y → Y-(P)) inhibits GSK3 and PKA (both of which would otherwise inhibit glycogen synthase) and activates PP1 (held in a PTG scaffold complex alongside GS/GP kinase). Active PP1 dephosphorylates/activates glycogen synthase and dephosphorylates/inactivates glycogen phosphorylase.
• Glycogen synthase converts UDP-glucose into glycogen; glycogen phosphorylase (when active) breaks glycogen down to glucose-1-phosphate — this breakdown step is inhibited by insulin.
• Glucose entry (via GLUT4, also upregulated by the Y-(P) signal) is phosphorylated by GK/HK (glucokinase/hexokinase) to glucose-6-P, converted via phosphoglucomutase (PGMutase) to glucose-1-P, and via UDP-G-pyrophosphorylase (UDP-G-PP) to UDP-glucose, feeding glycogen synthesis.
• Net effect: insulin promotes glycogen synthesis and blocks glycogen breakdown.

Tissue differences in glucose sensing (GLUT and hexokinase/glucokinase)

Tissue response to glucose depends on which GLUT transporter is present (GLUT2, non-insulin-sensitive, vs GLUT4, insulin-sensitive) and on the affinity of the glucose-phosphorylating enzyme:

• Hexokinase (most tissues, insulin-sensitive tissues via GLUT4): low Km/high affinity — activity rises steeply and saturates already at low glucose concentrations.
• Glucokinase (liver, pancreatic β cell, via GLUT2): high Km/lower affinity — activity rises gradually and near-linearly across the physiological blood glucose range (roughly 4–7 mmol/L), acting as a proportional glucose sensor rather than saturating quickly.

Sites of insulin action, muscle vs liver:

• Muscle: glucose enters from blood via GLUT4 (insulin-activated, ”+”); phosphorylated by hexokinase to G6P (ATP → ADP); can proceed to F6P (glycolysis) or to G1P, then via UDP-glucose (UTP → UDP) into glycogen chain elongation — glycogen synthesis marked ”+” (insulin-activated); the reverse glycogen breakdown step marked ”-” (insulin-inhibited).
• Liver: the same intracellular steps (G6P ↔ G1P ↔ UDP-glucose ↔ glycogen synthesis marked ”+”; breakdown marked ”-”) apply, but glucose uptake itself is not insulin-regulated (liver uses GLUT2, not GLUT4), so the transport step carries no ”+” mark.

Adiponectin

Adiponectin is a peptide hormone produced in adipose tissue that also regulates glucose metabolism:

• Liver: ↓ glucose output, ↓ fat accumulation, ↓ inflammation.
• Muscle: ↑ glucose uptake, ↓ fat accumulation, ↑ energy expenditure.
• Heart: ↓ inflammation, ↓ endothelial adhesion, ↓ foam cell formation.

Adiponectin's actions are protective against insulin resistance, Type 2 diabetes, and coronary artery disease.

Glucagon: secretion and control

• Glucagon is a peptide hormone secreted by pancreatic α cells; it opposes insulin’s effects.
• Secretion is triggered by low glucose. Glucagon binds glucagon receptors on liver and adipocyte cells (not muscle).
• Its effects are mediated by changing the phosphorylation status of key enzymes — often the opposite pattern to insulin.
• Control of glucagon secretion:
  • Stimulated by: lower glucose; anoxia; adrenaline.
  • Inhibited by: insulin; high glucose.

Glucagon: metabolic effects

Glucagon acts on liver and adipose tissue:

• Promotes glycogenolysis (glucose release from glycogen) in the liver.
• Promotes lipolysis (fatty acid release) in adipose tissue.
• Promotes gluconeogenesis in the liver.
• Inhibits glycogen synthesis and glycolysis in the liver.
• Inhibits lipogenesis in adipose tissue.

Pictorial summary of glucagon’s effects on the liver:

• Glycogen synthesis inhibited (”-”); glycogenolysis activated (”+”) → glucose released.
• Glycerol, lactate and alanine feed into pyruvate; gluconeogenesis from pyruvate is activated (”+”), contributing to glucose release; glycolysis is inhibited (”-”), opposing gluconeogenesis.
• Fatty acid oxidation is activated (”+”), producing acetyl-CoA; lipogenesis from acetyl-CoA is inhibited (”-”); acetyl-CoA feeds the TCA cycle and also drives ketogenesis (activated, ”+”) → ketone bodies.

Glucagon signal transduction (cAMP/PKA cascade)

1. Glucagon binds its GPCR-family receptor on liver cell membranes.
2. This activates the G-protein (Gα subunit dissociates from Gβγ).
3. Activated Gα stimulates adenylate cyclase to convert ATP to cAMP (releasing PPi).
4. cAMP activates protein kinase A (PKA): inactive A-kinase → active A-kinase.
5. Active PKA phosphorylates and activates phosphorylase kinase (inactive → active, ATP → ADP).
6. Active phosphorylase kinase phosphorylates and activates glycogen phosphorylase (inactive → active, ATP → ADP).
7. Active glycogen phosphorylase breaks down glycogen to glucose-1-phosphate.

This glucagon → cAMP → PKA → phosphorylase kinase → glycogen phosphorylase cascade is the classic mechanism mobilising glycogen for glucose release.

Glucagon also opposes insulin’s regulation of glycogen synthase/phosphorylase at the same signalling nodes: it (via PKA) activates glycogen phosphorylase (glycogen breakdown) and activates glucose-6-phosphatase (releasing free glucose from glucose-6-P) — the reverse of insulin’s actions on these same components.

Adrenaline

• Adrenaline is released from the adrenal gland in response to stress, trauma, fright, accidents, or surgery.
• Binds adrenaline receptors on liver, muscle and adipocyte cells. Its effects are similar to glucagon’s, but it also acts on muscle (glucagon does not, as muscle lacks glucagon receptors).
• Effects: promotes release of glucose from glycogen in liver and muscle; inhibits glycogen synthesis in liver and muscle; promotes gluconeogenesis in the liver (as does cortisol); promotes lipolysis in adipose tissue; inhibits lipogenesis in adipose tissue; promotes glucagon release and resistance to insulin.

Trauma is often associated with increased adrenaline, which is associated with hyperglycaemia.

Fasted state/stress, tissue summary:

• Adipose tissue: both glucagon receptor and adrenoreceptor promote lipolysis, releasing fatty acids.
• Muscle: adrenoreceptor (adrenaline only — no glucagon receptor) promotes glycogenolysis → glycolysis.
• Liver: both glucagon receptor and adrenoreceptor promote glycogenolysis and gluconeogenesis, producing glucose that exits via GLUT2 into the blood.

Sites of adrenaline/glucagon action in the liver: glycogen phosphorylase step (glycogen → G1P) marked ”+” (activated); the reverse glycogen synthesis step marked ”-” (inhibited); glucose-6-phosphatase step (G6P → glucose released to blood) marked ”+” (activated). Adrenaline produces the same effects in muscle, except muscle lacks glucagon receptors.

Glycogen storage diseases

Rare, serious inherited defects of glycogen-metabolising enzymes. Hepatomegaly and hypoglycaemia recur as common features across several of these diseases.

Type / eponym	Enzyme affected	Primary organ	Manifestations
GSD0a	Glycogen synthase-2	Liver	Hypoglycaemia, hyperketonia
von Gierke, GSD1a	Glucose-6-phosphatase	Liver	Hepatomegaly, kidney failure, hypoglycaemia
GSD1b	Microsomal glucose-6-phosphate translocase	Liver	Like Ia, plus neutropenia, bacterial infections
GSD1c	Microsomal Pi transporter	Liver	Like Ia
Pompe, GSD2	Lysosomal acid α-glucosidase (acid maltase)	Skeletal and cardiac muscle	Infantile form: death by 2; juvenile form: myopathy; adult form: muscular dystrophy-like
Cori/Forbes, GSD3	Liver and muscle debranching enzyme	Liver, skeletal and cardiac muscle	Infant hepatomegaly, myopathy
Andersen, GSD4	Branching enzyme	Liver, muscle	Hepatosplenomegaly, cirrhosis
McArdle, GSD5	Muscle phosphorylase	Skeletal muscle	Exercise-induced cramps and pain, myoglobinuria
Hers, GSD6	Liver phosphorylase	Liver	Hepatomegaly, mild hypoglycaemia, hyperlipidaemia and ketosis, improves with age
Tarui, GSD7	Muscle PFK-1	Muscle, RBCs	Like GSD5, plus haemolytic anaemia
GSD9a/9b	Phosphorylase kinase β-subunit	Liver, leukocytes, muscle	Like GSD6
Fanconi-Bickel	Glucose transporter-2 (GLUT-2)	Liver	Failure to thrive, hepatomegaly, rickets, proximal renal tubular dysfunction

Self-test

1. Describe the four-step pathway of glucose-stimulated insulin secretion in the pancreatic β cell, from glucose entry to insulin release.
2. Define the incretin effect and explain why oral glucose produces more insulin secretion than intravenous glucose for the same blood glucose rise.
3. List the roles of DPP-4 in incretin physiology and explain why this matters for the design of drugs like semaglutide and liraglutide.
4. Describe the processing steps that convert preproinsulin into mature insulin, naming the intermediate forms.
5. Explain the storage form of insulin in secretory granules and which residues on the molecule are essential for its biological activity.
6. List insulin’s overall effects on glucose uptake, glycogen metabolism, lipid metabolism and protein metabolism.
7. Distinguish the two main branches of the insulin receptor signalling cascade (Ras/MAPK vs PI3K/Akt) by their downstream targets and physiological outcomes.
8. Describe the GLUT4 trafficking cycle and how insulin shifts its balance.
9. Describe how insulin regulates glycogen synthase and glycogen phosphorylase via PP1, GSK3 and PKA.
10. Distinguish hexokinase from glucokinase in terms of glucose affinity and tissue distribution, and explain why this difference suits their respective roles.
11. Distinguish how insulin action on hepatic glucose uptake differs from its action on muscle glucose uptake, and explain the transporter basis for this difference.
12. Describe the adiponectin signalling summary: which tissues it acts on and its overall protective role.
13. List the factors that stimulate and inhibit glucagon secretion.
14. Describe the glucagon signal transduction cascade in the liver, from receptor binding to glycogen breakdown.
15. Explain how glucagon opposes insulin’s regulation of glycogen synthase and glycogen phosphorylase at the molecular level.
16. List glucagon’s effects on gluconeogenesis, glycolysis, lipolysis, lipogenesis and ketogenesis in the liver.
17. Distinguish adrenaline’s tissue actions from glucagon’s, explaining why adrenaline but not glucagon affects muscle glycogen.
18. A trauma patient develops hyperglycaemia. Explain the hormonal mechanism most likely responsible.
19. Predict the primary clinical presentation of a patient with a genetic defect in muscle phosphorylase (McArdle disease, GSD5), and distinguish it from a patient with a defect in liver phosphorylase (Hers disease, GSD6).
20. Explain why hepatomegaly and hypoglycaemia recur as shared features across several of the glycogen storage diseases listed.
21. Integrative: using the fed-state and fasted/stress-state diagrams, explain how the same core glycogen-metabolising enzymes (glycogen synthase, glycogen phosphorylase, glucose-6-phosphatase) are regulated in opposite directions by insulin versus glucagon/adrenaline, and why this reciprocal control is necessary for glucose homeostasis.

Answers

Reveal answers

1. Glucose enters the β cell via GLUT-2 and is phosphorylated by glucokinase to G-6-P; G-6-P is metabolised via mitochondria, raising the ATP/ADP ratio; the rising ATP/ADP ratio closes the $K_{ATP}$ channel, depolarising the membrane above -40 mV; depolarisation opens voltage-gated Ca2+ channels, and the resulting Ca2+ influx triggers exocytosis of insulin granules.
2. The incretin effect is the greater insulin response to oral glucose compared with intravenous glucose despite a similar blood glucose rise; it occurs because gut-derived incretin hormones (e.g. GLP-1, GIP), released in response to oral nutrients, amplify insulin secretion beyond what the glucose rise alone would produce.
3. DPP-4 breaks down (degrades) incretins, giving them a very short serum half-life; drugs like semaglutide and liraglutide are engineered (e.g. via fatty-acid conjugation for albumin binding) to resist this degradation and so achieve a much longer half-life than native GLP-1.
4. Preproinsulin (with signal peptide) → proinsulin (signal peptide cleaved, C-peptide still attached in a loop) → mature insulin (A and B chains joined by disulfide bonds) plus free C-peptide (released by final cleavage).
5. Insulin is stored as crystals of a hexamer (three dimers assembled around zinc ions). The A-chain terminal residues (A1 glycine, A19 tyrosine, A21 asparagine) are on the hexamer surface, invariant, and not involved in aggregation; their deletion or substitution substantially reduces biological activity.
6. Insulin promotes glucose uptake (GLUT4), glycogen synthesis and lipogenesis, glycolysis, LPL activity and amino acid uptake/protein synthesis; it inhibits gluconeogenesis, glycogenolysis, lipolysis and hormone-sensitive lipase.
7. The Ras/MAPK branch (Shc/Grb2/Sos → Ras → Raf1 → MEK → MAPK → Myc/Jun/Fos, p90rsk) drives DNA/RNA/protein synthesis and cell growth/differentiation; the PI3K/Akt branch (IRS → PI3K → PDK1 → PKB/Akt → mTOR/S6 kinase, GSK3β, AS160) drives the metabolic effects of glycogen synthesis and glucose transport.
8. GLUT4 is stored in intracellular membranous vesicles; insulin stimulates exocytosis of these vesicles to insert GLUT4 into the plasma membrane, while GLUT4 is continuously removed by endocytosis back to the vesicle pool — insulin shifts the balance toward more surface GLUT4.
9. Insulin receptor signalling (via Y-(P)) inhibits GSK3 and PKA (which would otherwise inhibit glycogen synthase) and activates PP1 (in the PTG scaffold complex); active PP1 dephosphorylates/activates glycogen synthase (promoting glycogen synthesis) and dephosphorylates/inactivates glycogen phosphorylase (inhibiting glycogen breakdown).
10. Hexokinase (most tissues) has low Km/high affinity, saturating at low glucose concentrations, suiting insulin-sensitive tissues that need to take up glucose regardless of blood level once insulin signals; glucokinase (liver, pancreatic β cell) has high Km/lower affinity, rising near-linearly across the physiological glucose range, suiting its role as a proportional glucose sensor.
11. In muscle, glucose entry itself is insulin-regulated via GLUT4 (marked ”+”); in liver, glucose entry via GLUT2 is not insulin-regulated (no ”+” mark on transport) — insulin instead acts only on the intracellular glycogen synthesis/breakdown steps in the liver, downstream of glucose entry.
12. Adiponectin acts on liver (↓ glucose output, ↓ fat accumulation, ↓ inflammation), muscle (↑ glucose uptake, ↓ fat accumulation, ↑ energy expenditure) and heart (↓ inflammation, ↓ endothelial adhesion, ↓ foam cell formation), overall protecting against insulin resistance, Type 2 diabetes and coronary artery disease.
13. Stimulated by: lower glucose, anoxia, adrenaline. Inhibited by: insulin, high glucose.
14. Glucagon binds its GPCR; the G-protein’s Gα subunit dissociates and activates adenylate cyclase, converting ATP to cAMP; cAMP activates PKA (inactive → active A-kinase); active PKA phosphorylates/activates phosphorylase kinase; active phosphorylase kinase phosphorylates/activates glycogen phosphorylase; active glycogen phosphorylase breaks glycogen down to glucose-1-phosphate.
15. Glucagon (via PKA) activates glycogen phosphorylase (promoting glycogen breakdown) and activates glucose-6-phosphatase (promoting release of free glucose from glucose-6-P) — the opposite of insulin’s action at these same nodes, where insulin (via PP1) inactivates glycogen phosphorylase and activates glycogen synthase.
16. Glucagon promotes gluconeogenesis, fatty acid oxidation and ketogenesis in the liver; it inhibits glycolysis and lipogenesis.
17. Adrenaline acts on liver, muscle and adipose tissue (similar effects to glucagon), but glucagon acts only on liver and adipose because muscle lacks glucagon receptors — so only adrenaline can mobilise muscle glycogen.
18. Trauma increases adrenaline release; adrenaline promotes glycogenolysis and gluconeogenesis in the liver (and glycogenolysis in muscle), and promotes glucagon release and insulin resistance, together producing hyperglycaemia.
19. McArdle disease (muscle phosphorylase deficiency) presents with exercise-induced cramps, pain and myoglobinuria, reflecting the muscle’s inability to mobilise glycogen for exercise; Hers disease (liver phosphorylase deficiency) presents with hepatomegaly and mild hypoglycaemia (plus hyperlipidaemia/ketosis), reflecting the liver’s inability to release glucose from glycogen, and tends to improve with age.
20. Hepatomegaly recurs because impaired glycogen breakdown or export in liver-affecting GSDs causes glycogen (or in GSD1a, additional metabolic intermediates) to accumulate in hepatocytes; hypoglycaemia recurs because these same enzyme blocks prevent the liver from releasing glucose from glycogen (or, in GSD1a, from glucose-6-phosphate) to maintain blood glucose during fasting.
21. In the fed state, insulin activates PP1, which dephosphorylates/activates glycogen synthase and dephosphorylates/inactivates glycogen phosphorylase, favouring glycogen storage. In the fasted/stress state, glucagon and adrenaline activate PKA (via cAMP), which phosphorylates/activates phosphorylase kinase and glycogen phosphorylase and activates glucose-6-phosphatase, favouring glycogen breakdown and glucose release. Because the same enzymes are controlled reciprocally by phosphorylation state, the body can rapidly switch between net glucose storage and net glucose release depending on which hormone signal dominates, keeping blood glucose within its narrow normal range.