Lecture 2: Glucose Homeostasis

Question 1

What is glucose?

Answer 1

A monosaccharide, and the most important simple sugar in the body. Used for aerobic and anaerobic respiration.

Question 2

Name 4 monosaccharides.

Answer 2

Ribose
Glucose
Fructose
Galactose

Question 3

Name 3 disaccharides and their constituents.

Answer 3

Maltose (Glucose - Glucose)
Sucrose (Fructose - Glucose)
Lactose (Glucose - Galactose)

Question 4

Name 3 polysaccharides and describe their structure.

Answer 4

Cellulose (B-Glucose 1,4 bonded, H bonds between chains)
Glycogen (a-Glucose 1,4 bonded, with 1,6 bonds giving it a branched structure)
Starch (Mixture of amylose and amylopectin)

(amylose - a-glucose, 1,4 bonding, consisting of long straight chains)
(amylopectin - a-glucose, 1,4 and 1,6 bonding, branched)

Question 5

What is the difference between amylopectin and glycogen?

Answer 5

Amylopectin has less 1,6 bonds and therefore less branching, leading to a more linear structure.
Glycogen has 1,6 bonds twice as frequently, leading to branching until it is impossible anymore, giving it a more globular structure.

Amylopectin is less soluble than glycogen.

Question 6

What forms of glucose can humans use and which can they not?

Answer 6

beta-Glucose, can’t be processed.
alpha-Glucose, can be processed.
L-Glucose, can’t be processed.
D-Glucose, can be processed.

L-Glucose, unlike D-Glucose, does not occur in nature, but can be made in laboratories.

Question 7

What happens when glucose use becomes higher than the intake?

Answer 7

Triglycerides and proteins will get broken down and used. (fatty acids, and amino acids)

Question 8

How many grams of glucose is roughly present in plasma/extracellular fluid at one time?

Answer 8

Around 10 grams.

Question 9

What concentration of plasma glucose typically indicates hypoglycaemia?

Answer 9

Less than 2.2 mmol/L

Question 10

What is the difference between the function of the liver and muscles in glucose use?

Answer 10

Glycogen stored in muscles is only used by the muscles, whereas the liver can release glucose into the rest of the body.

Question 11

What are all the processes involved in glucose storage and production?

Answer 11

Glycogenesis - The conversion of glucose into the polysaccharide glycogen

Glycogenolysis - The breakdown of glycogen into glucose.

Gluconeogenesis - The production of glucose from other precursors

Question 12

Describe how levels of glucose homeostasis reactions shift when eating and fasting.

Answer 12

Glucose from a meal will be circulated in the blood, resulting in a spike as Glycogenesis will convert excess glucose. Glycogenolysis will maintain glucose levels, with the ratio of glycogenolysis : gluconeogenesis decreasing the longer you wait before eating again. After extreme fasting gluconeogenesis is the principle source of glucose.

Question 13

Describe the process of glycogenolysis.

Answer 13

Glycogen phosphorylase removes glucose-1-phosphate from branches of glycogen, adding an inorganic phosphate to the first carbon.
When the glycogen chain reaches 4 glucose residues in length, a debranching enzyme will remove 3, leaving a single 1,6 bonded glucose residue that will be hydrolysed by the secondary function of this enzyme.

Due to the frequency of chains in glycogen, the ratio of glucose-1-phosphate to glucose in glycogenolysis is 10:1.

Question 14

What happens to glucose-1-phosphate after glycogenolysis?

Answer 14

Can be used in glycolysis to produce pyruvate, after being converted to glucose-6-phosphate by phosphoglucomutase.

Can be converted back into glucose by glucose-6-phosphatase in the liver and kidney.

Question 15

What becomes the main energy source when fasting?

Answer 15

Ketones derived from fat become the major energy substrate.

Question 16

What are the usual blood glucose levels when fasting and postprandial (after meal).

Answer 16

Fasting blood glucose - 4 - 5.4 mM
Postprandial can be up to 7.8 mM

Question 17

What ways can glucose be formed in gluconeogenesis?

Answer 17

Glycogenolysis.

Glycerol can be converted to glucose by conversion to dihydroxyacetone phosphate, then to glyceraldehyde-3-phosphate.

Glucogenic amino acids can be converted to glucose by first being converted into pyruvate. Can also enter the TCA at several steps.

Lactate can be used to make glucose through conversion to pyruvate.

Acetone can be converted to pyruvate to make glucose.

Question 18

What do triglycerides ultimately end up as?

Answer 18

The glycerol can be used to make glucose. The fatty acids can be used to produce acetyl-CoA in beta-oxidation, and in abundance, acetyl-CoA is converted by thiolase to ketone bodies.

Question 19

Describe the process of glycogenesis.

Answer 19

1. Glucose is converted to glucose 6-phosphate by hexokinase.
2. Glucose 6-phosphate is converted to glucose 1-phosphate by phosphoglucomutase.
3. Glucose is bonded with a UMP molecule by UDP Glucose pyrophosphorylase to make uridine diphosphate glucose. (The UMP comes from a nearby UTP molecule that loses a pyrophosphate)
4. Pyrophosphate is cleaved by pyrophosphatase into 2 AMP and release energy to couple it to further steps.
5. An enzyme, glycogenin, which has tyrosine residues can autoglycosylate glucose onto itself, forming primer chain of 8-12 residues with a-1,4 glycosidic bonds.
6. The enzyme glycogen synthase can add further glucosyl residues with a-1,4 glycosidic bonds.
7. Branching enzyme takes 5 - 8 of the 1,4 glucosyl residues and transfers them to a different part of the earlier chain, forming an a-1,6 glycosidic bond. This new chain can be added to by glycogen synthase.

Question 20

How is blood glucose controlled by the body?

Answer 20

Through the use of hormones.

Insulin is the regulatory hormones (decreases levels of glucose by stimulating glycogenesis, promoting uptake of glucose into peripheral tissues, and suppressing hepatic production of glucose).

Counter-regulatory hormones promote an increase in blood glucose by stimulating glycogenolysis, reducing muscle cell glucose uptake, and making cells resistant to insulin.
These counter-regulatory hormones are glucagon, epinephrine, cortisol and growth hormone.

Question 21

How is glucose transported?

Answer 21

In the small bowel and kidney, sodium/glucose co-transporters promote uptake of glucose and galactose. ATP-sodium dependent

Facilitative glucose transporters (GLUT) located on the surface of all cells, with multiple variations. 14 exist but most well studied are labelled GLUT 1 - 7. And 5 are the most important.

Question 22

What are GLUT-1 transporters?

Answer 22

Widely distributed in the body. Highly concentrated in endothelial cells of blood-tissue barriers, important in blood brain barrier. RBCs use GLUT-1 heavily. Therefore one of the specialised roles is transporting glucose from blood to organs that have little access to small solutes via passive diffusion.

Question 23

How do GLUT-1 transporters work?

Answer 23

The glucose will bind to the transporter and cause a conformational change that will push it through on the other side of cell membrane and release it.

GLUT-1 is insulin-independent.

Question 24

What are GLUT-2 transporters?

Answer 24

GLUT-2 is present in plasma membrane of hepatocytes, pancreatic cells, intestinal and kidney cells, as well as the hypothalamus.

Primary tissue is the liver, and to a lesser degree, pancreatic B cells.

High Km therefore low affinity for glucose, and will only uptake when there is a very high concentration, so liver lets the rest of the body use glucose before it. B-cells will uptake glucose (that stimulates insulin release) in high concentrations therefore only releasing insulin at high blood glucose.

Insulin independent.

Question 25

How do GLUT-2 transporters work?

Question 26

What are GLUT-3 transporters?

Answer 26

Highly present in the brain, neurons and sperm cells.

High affinity for glucose, that’s why it is useful in an energy demanding organ like the brain.

Insulin-independent.

Question 27

What are GLUT-4 transporters?

Answer 27

Primarily present in the skeletal muscle, adipose tissue and the heart.

The most important transporter for depositing glucose in muscle and adipose tissue, to either be converted into glycogen in muscle or to assist in lipogenesis in adipose, if not simply used for energy.

Moderate affinity for glucose

Insulin-dependent.

Question 28

How does GLUT-4 work?

Answer 28

When insulin binds to insulin receptors on the surface of muscle or adipose cells, a conformational change occurs where GLUT-4 transporters are moved from cytoplasm to cell membrane to allow glucose transport.

Question 29

What is insulin? Describe the structure.

Answer 29

A peptide hormone produced by beta-cells in islets of Langerhans. Regulates blood glucose levels.

It consists of 51 amino acids in two separate chains (alpha and beta). The two chains are joined by 2 disulphide bridges, with a third being present within the alpha chain.

Question 30

Describe the process of insulin secretion.

Answer 30

Beta-cells in the pancreas detect high levels of metabolites of glucose and will result in insulin exocytosis.

There are two phases of insulin secretion.
Phase 1 is the secretion of preformed insulin and will last roughly 15 minutes.
Phase 2 relies on newly synthesised insulin that lasts up to 2 hours.

Question 31

What are the metabolic effects of insulin on the liver?

Answer 31

• Stimulates conversion of glucose to glycogen (glycogenesis)
• Stimulates synthesis of long chain fatty acids (lipogenesis), as energy is required for this, glycolysis is stimulated.
• Inhibits gluconeogenesis and glycogenolysis.

All effects are to reduce use of alternative energy sources and use readily available glucose.

Question 32

What are the metabolic effects of insulin in the muscle?

Answer 32

• Stimulates glucose uptake and metabolism
• Stimulates glycogen synthesis (only if muscle have received enough glucose)
• Stimulates cellular uptake of amino acids and protein synthesis.

The effects are to stop muscles from using alternate energy sources, build up glycogen reserves, and reverse any breakdown of proteins into amino acids for gluconeogenesis.

Question 33

What are the metabolic effects of insulin in adipose?

Answer 33

• Stimulates uptake of glucose.
• Stimulates triglyceride synthesis from glycerol and fatty acids.

This is to use readily available glucose to produce reserves of fat for fasting use.

Question 34

What is glucagon and its function?

Answer 34

A peptide hormone produced by alpha-cells in the pancreas.
Released when blood glucose is low, or when exercising or stressed.
Effects are exerted by stimulating glycogen phosphorylase, breaking down glycogen into glucose, and stimulating gluconeogenesis. Will inhibit glycogen synthase. Also stimulates the body to use fat stores, and inhibits glucose breakdown to reduce the use of glucose.

Causes increased ketogenesis through stimulation of beta-oxidation of fatty acids.

Question 35

What is epinephrine and its function in glucose regulation?

Answer 35

Epinephrine is a catecholamine produced in the adrenal glands.
It is released into the blood to prepare tissues such as muscles, lungs, and heart for bursts of activity.

It raises blood glucose by stimulating the production of glucose in the liver and reducing the disposal of glucose in insulin dependent tissues.

It stimulates glycogen phosphorylase, and inhibits glycogen synthase.

Promotes anaerobic breakdown of glycogen into lactate for ATP.

Stimulates triacylglycerol lipase in adipose, promoting fat use for energy.

Insulin will stimulate glucagon, while inhibiting insulin.

Question 36

What fuel source is primarily used by the brain (only the most important organ)

Answer 36

Glucose. Using 20% of glucose derived energy.

Question 37

What effects does insulin have on glucagon?

Answer 37

It inhibits the release of glucagon from the pancreas, as well as decreasing glucagon gene expression.

Question 38

What is somatostatin?

Answer 38

A 14-amino acid long peptide hormone. Expressed in central and peripheral nervous system, the gut and other organs. It has a counter-regulatory function on thyroid-stimulating hormone, growth hormones, prolactin, insulin, and glucagon

Question 39

What is the effect of somatostatin on glucose metabolism?

Answer 39

It inhibits both glucagon and insulin, useful to keep insulin low and glucose levels high.

Also inhibits gut hormones that aid in digestion.

Question 40

What are incretin hormones?

Answer 40

Peptide hormones found in the gut that increase levels of insulin, and therefore decreases glucose levels.

An example is glucagon-like peptide1 (GLP-1). Produced by the cells of the ileum and colon. It stimulates insulin and inhibits glucagon, also delays stomach emptying.

It was noticed that insulin levels would spike more when eating than when receiving intravenous glucose. Therefore glucose in the digestive tract stimulates insulin secretion in anticipation of following glucose rise.

Question 41

What are the two main incretin hormones?

Answer 41

Glucose-dependent insulinotropic peptide, or gastric inhibitory peptide (GIP). GIP is produced by cells in duodenum, and stimulates insulin secretion.

GLP-1 (glucagon-like peptide-1). GLP-1 stimulates insulin and inhibits glucagon secretion.
Infusion of GLP-1 can improve insulin sensitivity and secretion in diabetes.