Diabetes - lecture 2

• Metabolic situations II


  Integrated metabolism
• Lecture plan


  • To integrate the basic carbohydrate, protein and fat metabolic pathways of muscle, adipose and liver under various conditions:
  • Fed, fasting and starved
  • Diabetes
  • Exercise
  • Pregnancy & lactation
  • Alcohol ingestion
• Fed state


  1. Insulin

  2. Glucose

  3. Forkhead transcription factor

  4. IRE

  5. Gluconeogenic and fatty acid oxidation genes

  6. SRE

  7. Lipogenic genes

  8. SREBP-1c

  9. ChoRE

  10. ChREBP

  11. Lipogenic genes
• Fasted state


  1. Glucagon has largely the opposite effects

  2. Glucagon

  3. CRE

  4. Gluconeogenic genes

  5. CRE

  6. Lipogenic genes

  7. CREB

  8. via adenylate cyclase,cAMP, protein kinase A
• Fatty acid long-term regulation


  1. CRE

  2. Fatty oxidation genes

  3. CRE

  4. Ketogenesis genes

  5. PPAR a

  6. CRE

  7. Mitochondrial

  8. Peroxisome

  9. Fatty acids
• Type I diabetes


  Unlike in Type I there is still some insulin so avoid lipolysis and ketone body formation
• Exercise & stress


  • Extra signal for glycogen breakdown in exercising muscle
  • δ-subunit of glycogen phosphorylase kinase is calmodulin
  • Ca2+
• Short duration but intense exercise

  1. Anaerobic (glycolysis)

  2. Muscle energy comes from intracellular phosphocreatine and glycogen stores

  3. Little inter-organ interaction

  4. End produce of glycolysis? Lactate

  5. Will drop pHi, inhibits PFK
• Medium term exercise


  1. Muscle glycogen still the main energy source

  2. There is also non-insulin GLUT4 insertion

  3. 'Carb loading' in training

  4. Muscle also increases amino acid oxidation

  5. Increased ammonium

  6. Alanine release
• Cori cycle


  Glucose / alanine (Cahill) cycle
• Advantage of the alanine cycle over the Cori cycle for the muscle cell

  What is the advantage of the alanine cycle over the Cori cycle for the muscle cell?
• Long-term exercise


  1. Glycogen stores / uptake not large enough to sustain long-term exercise

  2. Metabolic response similar to starvation

  3. Increased lipolysis (glucagon)

  4. Fatty acids for muscle fuel (ketogenesis)

  5. Little change in plasma [ketone bodies]

  6. Muscle switches over to β-oxidation
• Switch to fatty acid oxidation in muscle

  • Decreased lipogenesis
• Why muscle cells do not use much glucose during sustained exercise


  • PDH inhibited via PDH kinase
  • Acetyl-CoA
  • NADH / ATP
  • PFK inhibited by citrate
  • Hexokinase inhibited by G-6-P
• Long term stress


  1. Adrenaline is the short term stress response

  2. Raising blood glucose (hyperglycaemia) to prepare body for 'fight or flight'

  3. However, modern stress is often chronic and psychological…
• Longer term stress: the role of cortisol

  1. Steroid hormone, released from the adrenal gland

  2. Raises blood glucose via

  3. Increased gluconeogenesis

  4. Muscle wasting

  5. Glycerol from lipids

  6. Increased glycogen breakdown

  7. Inhibition of insulin

  8. Increases lipolysis – freeing up of energy stores to minimise glucose usage
• Stress


  Diabetes
• Pregnancy & lactation


  1. Foetus (& placenta) are extra metabolically active tissues

  2. Uses glucose for energy

  3. Lactate, fatty acids, ketone bodies, amino acids
• The placenta plays an important role

  • Placenta plays major metabolic role
  • Glucose → lactate
  • Either used by foetus or placenta-liver Cori cycle
  • Produces placental steroids and lactogen
  • Steroids produce insulin resistance
  • Lactogen promotes lipolysis
  • Net result to maintain high plasma nutrients
• Pregnancy fed-starved cycle perturbed

  1. In fed state, plasma glucose / insulin higher than normal (insulin resistance)

  2. After eating, foetal consumption means quicker return to starved state

  3. Plasma glucose, amino acid & insulin levels fall rapidly

  4. Glucagon and lactogen rise → lipolysis, ketogenesis, gluconeogenesis

  5. Foetal glucose consumption can cause maternal hypoglycaemia

  6. Dramatic swings in nutrient / hormone levels make diabetes difficult to control

  7. Maternal hyperglycaemia affect foetal development
• Lactation


  1. Mammary gland needs to take up nutrients for milk

  2. Glucose (lactose & triacylglycerides)

  3. Amino acids (protein)

  4. Fatty acids (triacylglycerides)

  5. If not sufficient in diet, will be sourced from gluconeogenesis, proteolysis, lipolysis

  6. Long term maternal malnutrition

  7. Poor quality milk → infant malnutrition
• Ethanol catabolism


  1. Ethanol + NAD+ → acetaldehyde + NADH + H+ (cytoplasm)

  2. Acetaldehyde + NAD+ + H2O → acetate + NADH + 2H+ (mitochondrial matrix)

  3. Catabolism takes place in the liver

  4. Result: high NADH levels
• Result of high liver NADH levels

  • Lactate cannot be converted to pyruvate
  • Hypoglycaemia
  • Lipogenesis and ketogenesis stimulated
  • ATP high via ETC
  • Inhibits TCA
  • acetate → blood, used by other tissues
• Alcohol – what's your poison?


  • Short term
  • Hypoglycaemia (rarely acidosis)
  • Hypothermia
  • Vasodilation
  • Central temperature regulation
  • Dehydration
  • Long term
  • Acetaldehyde – fixative
  • Cross-links molecules
  • Fatty liver
  • Cirrhosis
• • Metabolism is complex and inter-related at the level of
  • Intracellular pathways
  • Inter-organ co-ordination (hormones)
  • It allows us to maintain appropriate energy metabolism under many conditions, including
  • Fed
  • Fasted / starved
  • Exercise
  • Pregnancy
  • Understanding integrated metabolism helps us to understand diseases such as diabetes.