Fast Feed Cycle

Question 1

How is metabolic homeostasis achieved?

Answer 1

Normal cell functions require a constant source of fuels regardless of food intake or fasting/starvation.

Metabolic homeostasis in tissues results from the balance between: - Storage of energy.
- Mobilization of stored energy.

This is achieved with communication by:

• Blood with hormones or substrates.
• Nervous system.

Question 2

What is the special role of metabolic homeostasis?

Answer 2

Many cells depend on glucose and glycolysis for their energy needs and the blood glucose level is tightly controlled.

1. Insulin and glucagon are the main hormonal regulators of blood glucose levels and the release of insulin or glucagon responds directly to glucose molecules in the blood.
2. Epinephrine, cortisol and growth hormone are insulin counterregulatory hormones and are released to prevent hypoglycemia

Question 3

Insulin and glucagon have a dominant role in homeostasis. Explain this

Answer 3

• They regulate fuel storage and mobilization.
• Their blood levels are continuously fluctuating.
• Their plasma half-lives is in the range of minutes.
• They are both released and stimulated by arginine to
assure that both hormones are present in blood.

It is the ratio of serum insulin-to-glucagon that determines a
metabolic change

Question 4

What is the metabolic function of insulin?

Answer 4

Insulin is the major anabolic hormone and promotes storage of fuel or usage for growth
Glycogenesis in liver and muscle.

Fatty acid and TAG synthesis in liver (release of VLDL). Protein synthesis in muscle and liver (serum proteins).

Question 5

Explain the function of glucagon

Answer 5

Glucagon is the major hormone for fuel mobilization
Hepatic glycogen degradation and gluconeogenesis. Hepatic ketone body synthesis and release.

TAG degradation in fat cells and release of fatty acids and glycerol at low insulin/glucagon ratio.

Glucagon receptors are mainly found in liver and renal cortex

Question 6

Insulin action is counteracted by….

Answer 6

Glucagon and epinephrine

Question 7

Explain the homeostatic changes in homeostasis

Answer 7

Stress situations overrule other regulations
(Insulin counterregulatory hormones)

• Under stress situations: the pituitary gland releases ACTH which stimulates release of cortisol

Cortisol is released from the adrenal cortex and stimulates in the adrenal medulla the methylation of norepinephrine to epinephrine and the release of both catecholamines.

— Epinephrine inhibits insulin release from b-cells and stimulates glucagon release from a-cells of pancreas.

Question 8

Give the general time frame of the feed and fast state

Answer 8

The postprandial (absorptive) phase is the time of the feed state with ongoing digestion and absorption after a meal (prandi) which is approximately 2 hrs after food intake.

The post-absorptive phase is the time of the fasting state where the food is completely digested and absorbed which is approximately 5 hrs after a meal or the time after an overnight fast.

Early phase of starvation starts about 3 days after last food intake. The time after 10 days of fasting/starvation can be seen as
prolonged starvation

Question 9

What role does the liver have a central role in reducing the rise of blood glucose after a meal?

Answer 9

The liver has a central role in reducing the rise of blood glucose after a meal

The liver receives blood from the portal vein containing dietary monosaccharides and insulin.

Insulin assures that the sugars are trapped inside of the hepatocytes to reduce the rise of postprandial blood glucose levels and to support blood glucose homeostasis.

At very high blood glucose levels following extensive glycolysis, insulin stimulates the hepatic synthesis of fatty acids, TAGs and cholesterol. VLDLs are released into the blood.

Question 10

Describe the change to fasting in the fast-feed cycle

Answer 10

In the post-absorptive phase the blood glucose levels are lower than after immediate food intake because in the postprandial phase insulin favored the usage of glucose.

The lower blood glucose level stimulates the release of glucagon and reduces insulin release.

The low insulin-to-glucagon ratio during fasting leads to release of the following into the blood:
• Glucose (from liver).
• Free fatty acids and free glycerol (from fat cells)

Question 11

What does the liver do in a fasting state?

Answer 11

During fasting the liver prevents further drop of post-absorptive blood glucose levels.

Hepatocytes stop the following:
Glycogen synthesis.
Glycolysis.
Synthesis of fatty acids and cholesterol.

Hepatocytes begin the following:
Glycogen degradation (glucagon and epinephrine).
Gluconeogenesis (glucagon and cortisol).
Release of glucose into the blood.

Glycogen degradation and gluconeogenesis are favored by the low insulin/glucagon ratio.

Question 12

Describe how substrates determines the pathways in liver, muscle and fat

Answer 12

Availability of substrates from the blood determines pathways in liver, muscle and fat

1. High levels of blood glucose after a meal:
   Liver: Glycolysis, synthesis of glycogen, fatty acids, TAGs, cholesterol and VLDL.
   Muscle: Glycolysis and glycogen synthesis. Fat cells: Glycolysis and TAG synthesis.
2. High levels of blood free fatty acids during fasting: Liver: b-oxidation of fatty acids and ketone body synthesis.
   Muscle: b-oxidation of fatty acids and ketone body usa

Question 13

How do different substrates flucutate in the blood up to 40 days of starvation ?

Answer 13

Glucose: reduced to 3.8 Mm at fay 3 (no further drop)

Fatty acids: increased to 1.2 Mm at day 3 (no further increase)

Acetoacetate: increased to 1.2 Mm at day 10 (no further increase)

Hydroxybutyrate: increased to 5.8 Mm at day 25 (no further increase)

Question 14

Describe the homeostasis of post prandial liver metabolism

Answer 14

High insulin levels

Glycogenesis is active.
⚫ Glycolysis is active.
⚫ Fatty acid synthesis is active.
Glycogenolysis is inhibited

Gluconeogenesis is inhibited b-oxidation is reduced
⚫ PPP is active.
(NADPH is used in the synthesis of fatty acids and of cholesterol).
⚫ PDH is active and connects glycolysis to the TCA cycle.
⚫ TCA cycle is active.
⚫ Cholesterol synthesis and TAG synthesis are active and VLDLs are released into the blood

Question 15

Describe postprandial adipose tissue metabolism

Answer 15

After a meal insulin activates lipoprotein lipase in capillaries of adipose tissue and GLUT-4 transporters in the fat cell plasma membrane. Inside of fat cells insulin stimulates TAG synthesis.

Lipoprotein lipase generates free fatty acids

Increased/high serum insulin/glucagon ratio

Question 16

Describe high muscle metabolism

Answer 16

Insulin activates glucose uptake from the blood (via GLUT-4)
Glycogen synthesis and glycolysis take place.

Insulin activates amino acid uptake from the blood.
Protein synthesis is stimulated especially by leucine.

Usage of branched-chain amino acids for protein synthesis and for energy metabolism

Question 17

Describe fasting liver metabolism

Answer 17

Glycogen synthesis is inhibited Glycolysis is inhibited
PPP is reduced
PDH is inhibited
TCA cycle is inhibited
Fatty acid synthesis is inhibited
Cholesterol synthesis is inhibited TAG synthesis is inhibited

Glycogen degradation is active

Gluconeogenesis is active

B-oxidation is active

Ketone body synthesis is active

Question 17

Describe fasting liver metabolism

Answer 17

Glycogen synthesis is inhibited Glycolysis is inhibited
PPP is reduced
PDH is inhibited
TCA cycle is inhibited
Fatty acid synthesis is inhibited
Cholesterol synthesis is inhibited TAG synthesis is inhibited

Glycogen degradation is active

Gluconeogenesis is active

B-oxidation is active

Ketone body synthesis is active

Question 18

Describe fasting adipose tissue metabolism

Answer 18

TAGs are degraded in fat cells resulting in the release of free fatty acids and glycerol into the blood

Question 19

Describe the fasting muscle metabolism: low insulin and high cortisol

Answer 19

Free fatty acids and ketone body uptake from the blood for energy metabolism in resting muscle.

Protein degradation is stimulated by cortisol.

Amino acid release into the blood.

Activated alanine-glucose cycle

Question 20

What is the significance of glucose and ketone body?

Answer 20

Glucose is always needed for the synthesis of neurotransmitters. Ketone bodies are available during starvation and are used for energy metabolism.

The brain has no significant glycogen store or TAGs.
Uptake of glucose is mostly insulin-independent and performed mainly by GLUT-1.
(some brain areas have GLUT-4)

Most fatty acids cannot pass the adult blood brain barrier with exception of the dietary essential fatty acids. In the developing brain, also arachidonic acid and DHA can pas

Question 21

Summarize liver functions related to glucose homeostasis in the feed-fast cycle

Answer 21

⚫ The liver “buffers” blood glucose levels:

⚫ After a meal hepatocytes reduce elevated blood glucose levels whereas during fasting hepatocytes release glucose into the blood.

⚫ Glucose flows with the gradient in both directions via GLUT-2.

⚫ Ketone bodies have a “protein sparing effect” in starvation. Less gluconeogenesis from amino acids is needed as ketone
bodies are used instead of glucose in other cells

Question 22

What are the fat tissue functions related to glucose homeostasis in the feed-fast cycle?

Answer 22

⚫ The adipose tissue reduces elevated blood glucose levels after a meal using GLUT-4. Glucose is needed for the synthesis of the glycerol backbone of TAGs.

⚫ During fasting fat cells degrade TAGs releasing free fatty acids and free glycerol into the blood. Glycerol can be used for gluconeogenesis.

⚫ Fatty acids are generally used for energy metabolism. In the liver and kidney cortex, NADH and acetyl CoA are needed as allosteric regulators for gluconeogenesis.

Question 23

Summarize glucose homeostasis in the feed-fast cycle

Answer 23

The muscle contains GLUT-4 and reduces elevated blood glucose
levels after a meal.

⚫ During fasting muscle protein is degraded (cortisol) and amino acids
are released into the blood which are used for hepatic gluconeogenesis.

⚫ The brain always needs glucose uptake.

⚫ Low blood glucose levels mediate the release of insulin counterregulatory hormones through release of ACTH.

Question 24

What glucose transporters are relevant in postprandial state?

Answer 24

⚫SGLT-1 performs uptake of dietary glucose or galactose into the enterocytes (secondary active transport against gradient, sodium-cotransport).
⚫SGLT-2 is found in the kidney for re-uptake of glucose. (SGLT-2 inhibitors used for diabetes treatm.)
⚫GLUT-5 performs mainly the uptake of dietary fructose (passive transport).
⚫GLUT-2 performs the release of all monosaccharides into the portal vein and the uptake into the liver (passive transport).
⚫GLUT-2 is used for uptake of glucose into b-cells of pancreas (This allows “measurement” of high blood glucose which leads to high ATP in b-cells that triggers the release of insulin granules).
⚫GLUT-4 allows reduction of elevated blood glucose via uptake into muscle and adipose tissue (Insulin-dependent passive transport).

Question 25

What glucose transporters are most relevant during fasting?

Answer 25

⚫Glucose is released by the liver into the blood via GLUT-2 (always with the concentration gradient).
Independent of the feed-fast cycle:
⚫GLUT-1 performs uptake of glucose into RBC and also through the blood brain barrier into the brain.

⚫GLUT-3 performs uptake of glucose mainly into the nervous tissue.