Regulation of Blood Glucose Level

Introduction

• Glucose is the primary and often the only fuel for the brain, retina, and germinal epithelium of the gonads
• High blood glucose causes osmotic damage to cells and tissues
• Persistently elevated glucose leads to glycosuria, osmotic diuresis, and dehydration
• Very low glucose leads to neuroglycopenia - brain dysfunction, seizures, coma, and death

Normal Blood Glucose Values

Sources of Blood Glucose

1. Dietary absorption - glucose absorbed from the gut after a meal
2. Glycogenolysis - breakdown of liver glycogen (major source during 12-hour fast)
3. Gluconeogenesis - synthesis of glucose from non-carbohydrate precursors (amino acids, lactate, glycerol) - becomes the major source as fasting extends overnight and glycogen is depleted

1. Glycolysis - oxidation of glucose to pyruvate/lactate
2. Glycogenesis - conversion of glucose to glycogen (in liver and muscle)
3. Lipogenesis - conversion of excess glucose to fatty acids and triglycerides
4. Glucose oxidation via the TCA cycle and oxidative phosphorylation

Organs Involved in Blood Glucose Regulation

1. The Liver - the "Glucose Buffer"

• Stores up to ~100g of glycogen after a meal (about two-thirds of absorbed gut glucose)
• Releases glucose back into circulation between meals via glycogenolysis
• Performs gluconeogenesis during prolonged fasting
• Is the only organ (with kidney) that expresses glucose-6-phosphatase, allowing it to release free glucose into blood
• Reduces fluctuations in blood glucose to about one-third of what they would otherwise be

2. The Pancreas

• Beta (β) cells - secrete insulin (in response to high blood glucose)
• Alpha (α) cells - secrete glucagon (in response to low blood glucose)
• Delta (δ) cells - secrete somatostatin (inhibits both insulin and glucagon)

3. Skeletal Muscle and Adipose Tissue

4. Brain (Hypothalamus)

Hormonal Regulation - The Core Mechanism

A. Insulin - The Hypoglycemic Hormone

Source and Stimulus for Secretion

• Secreted by beta cells of the islets of Langerhans, pancreas
• Primary stimulus: rise in blood glucose above ~100 mg/dL
• Insulin secretion rises 10-25 times above basal levels when blood glucose is 400-600 mg/dL
• Secretion turns off rapidly (within 3-5 min) when blood glucose falls back to fasting levels
• Additional stimuli: amino acids (especially arginine, lysine), incretins (GLP-1, GIP) from the gut, glucagon, growth hormone, cortisol, parasympathetic stimulation
• Inhibited by: sympathetic stimulation (epinephrine at alpha receptors), somatostatin

Actions of Insulin on Blood Glucose (Carbohydrate Metabolism)

Actions of Insulin on Fat and Protein

• Fat metabolism: Stimulates lipogenesis; inhibits lipolysis and ketogenesis -> lowers blood fatty acids and ketones
• Protein metabolism: Anabolic - increases amino acid uptake into cells, promotes protein synthesis, inhibits protein catabolism -> lowers blood amino acids
• K+ transport: Promotes K+ uptake into cells alongside glucose (via Na+/K+-ATPase activation)

Mechanism of Insulin Action (Signal Transduction)

1. Insulin binds to its tyrosine kinase receptor on target cell membrane
2. Receptor autophosphorylation activates IRS (insulin receptor substrate) proteins
3. Activates PI3K → AKT pathway
4. AKT → GLUT4 vesicle translocation to membrane → glucose entry
5. AKT → inhibits GSK3 → activates glycogen synthase → glycogen synthesis
6. cAMP-dependent protein kinase and AMP-activated protein kinase (AMPK) coordinate metabolic switching

B. Glucagon - The Hyperglycemic Hormone

Source and Stimulus for Secretion

• Secreted by alpha (α) cells of the islets of Langerhans
• Primary stimulus: fall in blood glucose (hypoglycemia)
• Also stimulated by: amino acids (especially arginine), catecholamines, sympathetic stimulation
• Inhibited by: elevated blood glucose, insulin, somatostatin

Actions of Glucagon

• Stimulates glycogenolysis (breaks down liver glycogen → releases glucose) - major short-term effect
• Stimulates gluconeogenesis (from amino acids, lactate, glycerol)
• Inhibits glycolysis by decreasing fructose-2,6-bisphosphate → inhibits PFK-1
• Net result: rapid rise in blood glucose

• Inhibits fatty acid synthesis (phosphorylates and inactivates ACC)
• Stimulates fatty acid oxidation (removes malonyl-CoA inhibition on CPT-1)
• Promotes ketogenesis during prolonged fasting

Mechanism of Glucagon Action

1. Glucagon binds GPCR on hepatocyte membrane
2. Activates adenylyl cyclase → ↑ cAMP
3. cAMP activates Protein Kinase A (PKA)
4. PKA phosphorylates phosphorylase kinase → activates glycogen phosphorylase → glycogenolysis
5. PKA also phosphorylates and inactivates glycogen synthase → stops glycogen synthesis

C. Counterregulatory Hormones (Glucose-Raising Hormones)

1. Epinephrine (Adrenaline)

• Released from adrenal medulla during stress/hypoglycemia (stimulated by hypothalamus via sympathetic nerves)
• Most potent stimulator of glycogenolysis (both liver and muscle)
• Stimulates gluconeogenesis
• Promotes lipolysis → releases free fatty acids as alternative fuel
• Acts via β-adrenergic receptors → cAMP → PKA
• Also suppresses insulin secretion (via α-adrenergic receptors on beta cells)

2. Cortisol (Glucocorticoid)

• Released from adrenal cortex via ACTH from pituitary (triggered by hypothalamus)
• Acts over hours to days
• Strongly promotes gluconeogenesis (increases substrates - amino acids - by stimulating protein catabolism in muscle)
• Decreases glucose utilization by peripheral tissues
• Causes insulin resistance

3. Growth Hormone

• Secreted by anterior pituitary in response to prolonged hypoglycemia
• Acts over hours to days
• Decreases glucose uptake and utilization by cells
• Promotes lipolysis (fat mobilization) as alternative energy
• Causes insulin resistance at the level of target tissues

4. Somatostatin

• Secreted by delta (δ) cells of the islets of Langerhans
• Inhibits both insulin AND glucagon secretion
• Fine-tunes the hormonal response
• Also secreted by hypothalamus and gut

D. Nervous System Control

1. When blood glucose falls below ~50 mg/dL, hypothalamic glucoreceptors are activated
2. They trigger the sympathetic nervous system → epinephrine release from adrenal medulla
3. They stimulate ACTH from anterior pituitary → cortisol from adrenal cortex
4. They stimulate growth hormone release from anterior pituitary

1. Pancreatic α cells → glucagon release
2. Hypothalamic glucoreceptors → catecholamines (epinephrine/norepinephrine) + ACTH (→ cortisol) + growth hormone

E. Enzyme-Level Regulation (Biochemical Mechanisms)

• cAMP / PKA pathway: Activated by glucagon and epinephrine → promotes glycogenolysis and gluconeogenesis, inhibits glycolysis and glycogenesis
• PI3K/AKT pathway: Activated by insulin → promotes glucose uptake, glycogenesis; inhibits gluconeogenesis

F. The Integrated Response

After a Carbohydrate Meal (Fed State - High Glucose)

1. Blood glucose rises → insulin secreted by beta cells
2. Insulin promotes:
   • Glucose uptake by muscle and adipose (via GLUT4)
   • Liver glycogen synthesis (stores up to 2/3 of absorbed glucose)
   • Glycolysis and lipogenesis
   • Inhibits glycogenolysis and gluconeogenesis
3. Blood glucose falls back to normal within 2 hours
4. Glucagon secretion falls, insulin falls
5. Net: glucose stored as glycogen and fat

During Fasting/Overnight (Low Glucose)

1. Blood glucose falls → glucagon secreted by alpha cells
2. Glucagon promotes:
   • Hepatic glycogenolysis → rapid glucose release (major source for first 8-12 hrs)
   • Gluconeogenesis → sustained glucose production as glycogen depletes (major source overnight)
   • Fatty acid oxidation → ketone body production as alternative fuel
3. Insulin falls → GLUT4 not recruited → peripheral tissues switch to fatty acid oxidation
4. Brain continues to receive glucose (and eventually adapts to use ketone bodies)

During Stress or Exercise

1. Sympathetic activation → epinephrine release
2. Epinephrine stimulates rapid glycogenolysis (liver and muscle)
3. Epinephrine also suppresses insulin release
4. Blood glucose rises to meet increased energy demands

During Prolonged Starvation

1. Glycogen is depleted in 24-48 hours
2. Gluconeogenesis becomes the primary source of blood glucose
3. Cortisol and growth hormone increase
4. They promote muscle protein catabolism → amino acids for gluconeogenesis
5. Ketone bodies (from fatty acid oxidation) become the brain's major fuel, sparing glucose for obligate glycolytic tissues

G. Summary of Regulatory Mechanisms (Guyton & Hall)

1. Liver as glucose buffer - dampens glucose fluctuations by absorbing excess glucose into glycogen after meals and releasing it during fasting
2. Insulin-glucagon feedback loop - the most important mechanism: high glucose → insulin release → glucose uptake and storage; low glucose → glucagon release → glucose production and release. This returns blood glucose toward normal within minutes to hours
3. Sympathetic nervous system/epinephrine - activated by severe hypoglycemia via the hypothalamus; provides rapid, emergency glucose release from the liver
4. Cortisol and growth hormone - slower-acting (hours to days); decrease peripheral glucose utilization and increase gluconeogenesis during prolonged hypoglycemia

Clinical Relevance

• Adrenergic symptoms (glucose ~50 mg/dL): anxiety, palpitation, tremor, sweating (mediated by epinephrine)
• Neuroglycopenic symptoms (glucose falling further): headache, confusion, slurred speech, seizures, coma, death (from failure of glucose delivery to brain)

Summary Points for Exam

1. Normal fasting blood glucose: 70-100 mg/dL
2. Insulin: only hormone that lowers blood glucose; secreted by beta cells in response to hyperglycemia
3. Glucagon: major hyperglycemic hormone; secreted by alpha cells in response to hypoglycemia; acts on liver
4. Counterregulatory hormones: glucagon, epinephrine, cortisol, growth hormone - all raise blood glucose
5. Liver is the central organ - glucose buffer, glycogenolysis, gluconeogenesis
6. Glucagon/epinephrine act via cAMP-PKA pathway; insulin acts via tyrosine kinase-PI3K-AKT pathway
7. During fasting: glycogenolysis (short-term) → gluconeogenesis (long-term)
8. After meal: glycogenesis and glycolysis dominate under insulin control
9. Hypothalamic glucoreceptors are the neural component of regulation - activate the full hormonal cascade during severe hypoglycemia
10. Somatostatin from delta cells inhibits BOTH insulin and glucagon - fine-tunes the system