Ketogenesis & Diabetic Ketoacidosis (DKA) — Study Notes

1. Fed State (After Eating)

What enters the blood:

• Meal → glucose enters bloodstream

• Blood glucose rises

Pancreas response:

• Beta cells sense high glucose → release insulin

• Insulin:

  • Inhibits alpha cells → ↓ glucagon

  • Acts on:

    • Skeletal muscle

    • Adipose tissue
      → Brings glucose transporters to surface → glucose enters cells

Liver:

• Glucose enters liver without insulin

• Insulin stimulates:

  • Glycolysis: glucose → pyruvate

  • Pyruvate enters mitochondria → becomes Acetyl-CoA

  • Acetyl-CoA + Oxaloacetate → Krebs cycle

Krebs Cycle:

• Produces:

  • NADH

  • FADH₂
    → These donate electrons to ETC → ATP production

Summary of Fed State:

• High glucose

• High insulin

• Low glucagon

• Glycolysis + Krebs active

• High ATP production

2. Fasting / Low Glucose State

Blood glucose drops:

• Alpha cells release glucagon

• Beta cells do not release insulin

Effects of glucagon:

• Inhibits glycolysis & Krebs

• Goal: restore blood glucose (~5 mmol/L)

How glucose is restored:

1. Glycogenolysis:

• Glycogen → glucose → blood

2. Gluconeogenesis:

Making glucose from non-carbs:

• Glycerol (from fat)

• Amino acids

• Lactate

• Oxaloacetate

Lipolysis:

• Triglycerides → glycerol + fatty acids

• Glycerol → glucose (gluconeogenesis)

• Fatty acids → Acetyl-CoA

3. Why Ketones Form

Problem:

• Oxaloacetate leaves Krebs to make glucose

• But Acetyl-CoA needs oxaloacetate to enter Krebs

• So Acetyl-CoA accumulates

Solution:

• Excess Acetyl-CoA snaps together → ketone bodies:

  • Acetoacetate

  • Beta-hydroxybutyrate

  • Acetone

This process = Ketogenesis (in liver)

What ketones do:

• Leave liver

• Cross blood-brain barrier

• In brain:

  • Turn back into Acetyl-CoA

  • Enter Krebs

  • Produce ATP

Important:

• Liver does gluconeogenesis → low oxaloacetate

• Brain does NOT do gluconeogenesis → oxaloacetate available → can use ketones

4. When Ketogenesis Happens Normally

Occurs when:

• Low blood glucose

• Low insulin

• High glucagon
  Example:

• Fasting

• Low-carb diet

This is physiological ketosis, not dangerous.

5. Diabetes Mellitus and Ketogenesis

Type 1 Diabetes:

• Autoimmune destruction of beta cells

• No insulin at all

Consequences:

• No insulin → no inhibition of glucagon

• So:

  • High glucagon

  • High blood glucose (can’t enter muscle/fat)

  • Ongoing gluconeogenesis

  • Ongoing lipolysis → fatty acids → ketones

So patient has:

• High glucose

• High ketones

• Low insulin

• High glucagon

6. Diabetic Ketoacidosis (DKA)

Diagnosis requires 3 things:

1. Diabetes:

• High blood glucose

2. Ketones:

• High blood ketones or urine ketones

3. Acidosis:

• High anion gap metabolic acidosis

7. Why Acidosis Happens

Ketones are acids:

• Acetoacetate → beta-hydroxybutyric acid

• Acid splits → H⁺ + conjugate base

Hydrogen ions accumulate → acidosis

Bicarbonate tries to buffer:

• H⁺ + HCO₃⁻ → H₂CO₃ → CO₂ + H₂O

• So bicarbonate level drops

8. Anion Gap

Formula:

Anion Gap = Na⁺ − (Cl⁻ + HCO₃⁻)

Normal:

• Na ≈ 140

• Cl ≈ 104

• HCO₃ ≈ 24
  → Gap ≈ 12

In DKA:

• HCO₃ drops (used to buffer acid)

• Example:

  • Na = 140

  • Cl = 104

  • HCO₃ = 20
    → Gap = 140 − 124 = 16 → High anion gap

Thus: High anion gap metabolic acidosis

9. Clinical Effects of DKA

Brain effects:

• Ketones & H⁺ stimulate chemoreceptor trigger zone

• Causes:

  • Nausea

  • Vomiting

Breath:

• Acetone is exhaled

• Smells sweet/fruity

Breathing:

• Body tries to remove acid:

  • Carbonic acid → CO₂ → breathed out

• Leads to deep, fast breathing:

  • Kussmaul respiration

Fluids:

• High glucose in urine → glucosuria

• Water follows glucose → polyuria

• Vomiting + urination → dehydration

10. Potassium Shifts

• H⁺ enters cells to reduce blood acidity

• K⁺ leaves cells in exchange

• Blood potassium may appear high initially

• Then lost in urine → hypokalemia risk

11. Treatment of DKA

Main goals:

1. Insulin:

   • Stops ketone production

   • Lowers glucose

   • Suppresses glucagon

2. Fluids:

   • Correct dehydration

3. Electrolytes:

   • Especially potassium replacement

Big Picture Summary

Ketogenesis:

• Normal response to low glucose

• Provides brain with backup fuel

DKA:

• Occurs mainly in Type 1 diabetes

• Due to:

  • No insulin

  • High glucagon

  • Uncontrolled ketone production

• Leads to:

  • High glucose

  • High ketones

  • Metabolic acidosis

  • Dehydration

  • Electrolyte loss

  • Risk of coma and death without treatment