Regulation of Blood Glucose in the Body

Blood Glucose & Metabolic Adaptation in Starvation

Maintaining blood glucose levels within a normal range (70–110 mg/dL) is essential for homeostasis. The body regulates glucose levels through hormonal control, metabolic pathways, and organ-specific functions.

Several hormones control blood glucose by either increasing or decreasing its levels.

A. Hormones that Decrease Blood Glucose (Hypoglycemic Hormone)

🔹 Insulin (Secreted by β-cells of the pancreas)

• Promotes glucose uptake by cells (via GLUT4 in muscle & adipose tissue).

• Stimulates glycogenesis (storage of glucose as glycogen in the liver & muscles).

• Inhibits gluconeogenesis and glycogenolysis.

• Enhances lipogenesis (conversion of glucose to fats).

Effect: Lowers blood glucose levels after a meal (Postprandial state).

B. Hormones that Increase Blood Glucose (Hyperglycemic Hormones)

1️⃣ Glucagon (Secreted by α-cells of the pancreas)

• Stimulates glycogen breakdown (glycogenolysis) in the liver.

• Promotes gluconeogenesis (formation of glucose from non-carbohydrate sources).

2️⃣ Epinephrine (Adrenaline) (From adrenal medulla)

• Increases glycogenolysis in muscles and liver during stress.

• Inhibits insulin secretion.

3️⃣ Cortisol (From adrenal cortex)

• Enhances gluconeogenesis by breaking down proteins into amino acids.

• Reduces glucose uptake by tissues.

4️⃣ Growth Hormone (GH) (From anterior pituitary)

• Decreases glucose uptake by muscles and fat.

• Increases lipolysis and gluconeogenesis.

Effect: Increases blood glucose levels during fasting, stress, or energy demand.

2. Metabolic Pathways Controlling Blood Glucose

3. Organ-Specific Role in Blood Glucose Regulation

4. Clinical Conditions Related to Blood Glucose Regulation & Diabetes Mellitus

Summary

1. Hormonal Regulation of Blood Glucose

🍽️ 1. After Meals (Fed / Postprandial State)

🔹 Goal:

• Utilize and store excess glucose.

• Maintain plasma glucose within 70–110 mg/dL

🔹 Key Hormone: Insulin ↑

🌙 2. During Fasting (Post-absorptive Phase)

🔹 Goal:

• Maintain normal blood glucose (for the brain, RBCs)

• Mobilize stored fuel

🔹 Key Hormone: Glucagon ↑, Insulin ↓

How the body maintains blood glucose homeostasis under three conditions:
A. Fed (post-meal), Fasting, and Starvation.

🕯️ 3. During Starvation (Prolonged Fasting, >2–3 days)

🔹 Goal:

• Spare glucose & protein

• Shift fuel use to fats and ketones

🔹 Hormones: High Glucagon, Cortisol, Epinephrine

Overview:
Maintaining normal blood glucose (~70–110 mg/dL) is a tightly coordinated process involving multiple organs — each with specific enzymes, transporters, and hormonal responses.
🔁Key regulators: Insulin, Glucagon, Cortisol, Epinephrine, and Growth Hormone.

1. Diabetes Mellitus

a. Type 1 Diabetes (T1DM)

• Cause: Autoimmune destruction of pancreatic β-cells → absolute insulin deficiency

• Metabolic Effects:

  • Hyperglycemia due to lack of glucose uptake in muscle & adipose tissue

  • ↑ Hepatic gluconeogenesis & glycogenolysis → further raises blood glucose

  • Lipolysis ↑ → ketone production → risk of Diabetic Ketoacidosis (DKA)

• Organ Involvement: Pancreas (β-cell destruction), liver (excess glucose output), adipose (FFA release), muscle (impaired glucose uptake)

b. Type 2 Diabetes (T2DM)

• Cause: Insulin resistance ± relative insulin deficiency

• Metabolic Effects:

  • Muscle & adipose resist glucose uptake → hyperglycemia

  • Liver continues gluconeogenesis despite high glucose

  • Mild ketone production; rarely DKA unless stressed

• Organ Involvement: Muscle, liver, adipose, pancreas

a. Liver – The Central Glucose Buffer (main Regulator)

Main Role: Maintains blood glucose by storing it after meals and releasing it during fasting/starvation.

Hormonal Regulation:

• Insulin → activates glycogen synthase, inhibits glucose-6-phosphatase.

• Glucagon → activates phosphorylase, PEPCK (for gluconeogenesis).

Outcome: Keeps blood glucose constant between meals.

b. Skeletal Muscle — Major Glucose Consumer

Main Role: Utilizes glucose for energy (ATP) and stores it as glycogen (but cannot release it back into the blood).

Note: the reason being

• No glucose-6-phosphatase, so muscle glycogen cannot contribute to blood glucose directly.

Summary Table — Metabolic Pathways by State

c. Brain — Glucose-Dependent Organ

Main Role: Continuous glucose user; cannot store or synthesize it.

Transport: GLUT3 (high-affinity transporter, insulin-independent)

Critical Point: Brain hypoglycemia → confusion, coma, irreversible damage.

d. Adipose Tissue — Energy Storage & Release

Main Role: Stores energy as triglycerides (fat); releases fatty acids during fasting for energy.

e. Pancreas — The Control Center (Hormonal Regulation)

Main Role: Senses blood glucose and releases hormones accordingly.

Balance:

• Fed → Insulin dominates (Decreases Glucose)

• Fasting → Glucagon dominates (Increases Glucose)

f. Kidneys — Gluconeogenesis & Reabsorption

Main Role: Supports blood glucose during prolonged fasting; prevents urinary glucose loss.

• Filter excess glucose in diabetes/glucose appears in urine

• Perform gluconeogenesis during prolonged fasting.

g. Small Intestine — Absorption Site

Main Role: Absorbs glucose after meals → delivers via portal vein to liver.

• Transporters: SGLT1 (active), GLUT2 (facilitated)

• Incretins (GLP-1, GIP) stimulate insulin release.

Key Integration Summary

1. Fed State:
   Insulin promotes glucose uptake, storage, and utilization.
   → Pathways: Glycolysis, Glycogenesis, Lipogenesis.

2. Fasting:
   Glucagon maintains blood glucose via glycogenolysis and gluconeogenesis.

3. Starvation:
   Fatty acid oxidation & ketogenesis dominate.
   → Brain adapts to ketones, sparing glucose and protein.

Key Takeaways:

1. Liver = main regulator (buffer & glucose supplier)

2. Muscle = glucose consumer, glycogen storage

3. Brain = glucose priority; switches to ketones during starvation

4. Adipose = stores fat; releases FFA for energy & gluconeogenesis

5. Pancreas = hormonal controller (insulin/glucagon)

6. Kidney = secondary glucose production

7. Small intestine = nutrient absorption & incretin signaling

2. Hypoglycemia

• Cause: Excess insulin, insulinoma, adrenal insufficiency, postprandial reactive hypoglycemia

• Metabolic Effects:

  • Brain glucose deprivation → neuroglycopenic symptoms (confusion, seizures)

  • ↑ Counter-regulatory hormones: glucagon, epinephrine → glycogenolysis, gluconeogenesis

• Organ Involvement: Pancreas (insulin/glucagon), liver (glucose output), brain (glucose sensing)

3. Insulin Resistance & Metabolic Syndrome

• Cause: Chronic overnutrition, obesity, sedentary lifestyle

• Metabolic Effects:

  • Muscle/adipose resistant → decreased glucose uptake

  • Liver continues glucose production.

  • Hyperinsulinemia initially, later β-cell dysfunction → T2DM risk

• Organ Involvement: Liver, muscle, adipose, pancreas

5. Hyperglycemia in Stress/Illness

• Cause: Critical illness, surgery, trauma → ↑ cortisol, catecholamines, glucagon

• Metabolic Effects:

  • Liver ↑ gluconeogenesis & glycogenolysis

  • Insulin resistance in muscle/adipose → hyperglycemia

• Organ Involvement: Liver, muscle, pancreas, adrenal glands

4. Glycogen Storage Diseases (GSDs)

• Cause: Genetic defects in glycogen metabolism enzymes

• Examples:

  • Von Gierke Disease (GSD-I): Glucose-6-phosphatase deficiency → fasting hypoglycemia, hepatomegaly

  • McArdle Disease (GSD-V): Muscle glycogen phosphorylase deficiency → exercise intolerance

• Organ Involvement: Liver, muscle

7. Pancreatic Disorders

• Exocrine or endocrine tumors: Insulinoma → hypoglycemia; Glucagonoma → hyperglycemia, diabetes

• Pancreatitis / Resection: Can lead to secondary diabetes (loss of β-cells)

6. Hypopituitarism / Hormonal Deficiencies

• Cause: Deficiency of growth hormone, cortisol, thyroid hormone

• Metabolic Effects:

  • ↓ gluconeogenesis, glycogenolysis → fasting hypoglycemia

• Organ Involvement: Liver, pancreas, adrenal glands

Key Takeaways:

• Hyperglycemia is commonly due to insulin deficiency or resistance.

• Hypoglycemia occurs due to excess insulin, enzyme defects, or hormonal deficiency.

• The liver, muscle, adipose tissue, and pancreas are central organs; the brain is the primary consumer of glucose.

Other pathways:

- Stress Hyperglycemia → ↑ Cortisol, Catecholamines → Liver gluconeogenesis ↑

- Hormonal deficiencies (GH, Cortisol, Thyroid) → ↓ Glucose output → Hypoglycemia

- Brain → Critical glucose consumer in all conditions