13. Signal transduction

Question 1

What are the 5 main steps of signal transduction?

Answer 1

1.Release of a primary messenger by ligands

2. Reception of primary messengers by receptors
3. Delivery of message inside the cell by a second messenger
4. Activation of effectors that directly alter physiological respose
5. termination of signal

Question 2

What is insulin and its structure?

Answer 2

It is a peptide hormone consisting of 2 chains linked by 3 sulfide bonds.

Question 3

What is the structure of the insulin receptor?

How is the receptor embedded into the cell membrane?

Answer 3

It is a tetramer formed by 2 dimers, where each dimer consist of α and β subunit.

both α subunits form a binding extracellularly for a single insulin to bind to it, and both β subunits are located inside the membrane (intracellular). Both β subunits have a protein kinase domain.

Question 4

When insulin binds to the insulin receptor, list down briefly the sequence of events in which signals can be transmitted to allow glucose uptake. [8]

Answer 4

• Insulin binds to receptor, both α subunits close in and surround insulin molecule
• Inside the cell, the protein kinase domains on β subunits come together. The flexible activation loop of one kinase subunit fits into the active site of the other kinase subunit within the dimer.
• Kinase domains catalyse reaction of phosphoryl group from ATP to tyrosine residues inside the activation loop. This i s known as autophosphorylation
• Activation of insulin Receptor Tyrosine Kinase (RTKs) upon phosphorylation, and signal amplified in certain stages.
• kinase binds to phosphorylated receptor and gets phosphorylated.
• kinase phosphorylate other proteins, and proteins in turn phosphorylate other proteins, forming a cascade.
• eventually, RAB protein gets phosphorylated and fall off the motor proteins Glut 4 storage vesicles
• After motor vehicles are free, vesicles merge with membrane and glucose move into cell through the glut 4 protein, a channel protein

Question 5

What are the 2 main functions of insulin?

Answer 5

1. Encourages uptake of glucose into cells for storage of glucose as glycogen when blood glucose is high
2. Inhibits gluconeogenesis (breaking down of non-carbohydrate molecules like proteins and lipids into glucose)and glycogenesis (glycogen –> glucose) in the liver since blood glucose is already high

Question 6

Insulin is secreted by what cells?

Answer 6

Pancreatic β cells

Question 7

After insulin is secreted from β cells into blood stream, which 3 types of cells does insulin mainly travel to?

Answer 7

1. Liver cells
2. Muscle cells
   3. Fat (adipose) cells

Question 8

What are 3 hormones produced by the gastrointestinal tract and what do they do?

Answer 8

1. Glucagon-Like Peptide 1 (GLP-1) : secreted by intestinal L cells and induces feelings of satiety

• inhibits glucagon secretion by pancreatic α cells , potentiates (increases) glucose-stimulated insulin secretion (GSIS) by pancreatic β cells

2. Ghrelin : (hormone that makes you hungry) : secreted by stomach, acts on regions of hypothalamus (brain) to stimulate appetite
3. CCK: Cholecystokinin (hormone)
   - Secreted by upper small intestine
   - Helps in digestion – stimulates gallbladder to contract and release stored bile into the intestine

Question 9

Carbohydrates are stored as glycogen per day. What happens to excessive carbohydrates?

Answer 9

They get converted into fats and stored as triglycerides

Question 10

excess amino acids are stored in the body. True or False?

Answer 10

False, they are not stored as amino acids, but also converted into fat

Question 11

[DIABETES : TYPE 2]

What is type 2 diabetes characterized by? [2]

Answer 11

1. High levels of circulating blood glucose
2. Insulin resistance – insulin may bind to receptor, but cells are not responsive to the signaling.

Question 12

How does type 2 diabetes develop? [2]

Answer 12

1. Under-utilization of glucose by cells.
2. Excessive breakdown of glycogen into glucose in the liver (over-production of glucose by liver : glycogenesis)

*glycogenesis : glycogen –> glucose

Question 13

How is obesity linked to insulin resistance?

Answer 13

• In obesity, there is excess triglyceride consumed
• Thus exceeding the fat-storage capacity of adipose cells (fat cells)
• fat accumulation in muscle / liver tissues
• fat interferes with the signaling of insulin, thus signal not as well-received by proteins within cells, leading to insulin resistance

Question 14

In an attempt to overcome cells not responding well to insulin, how do the pancreatic β cells react and what effects does this have?

Answer 14

• Pancreatic β cells respond by producing more insulin to drive insulin action
• Endoplasmic Reticulum stress builds up, unfolded/misfolded proteins accumulate
• Unfolded protein response (UPR) is initiated, causing β cells to be inflamed and die.

Question 15

What happens in Type 1 diabetes?

Answer 15

Autoimmune destruction of β cells, thus body produces insufficient insulin.

Question 16

In type 1 diabetes, there is a lack of insulin. What are some effects due to the lack of insulin?

Answer 16

1. impaired entry of glucose into adipose and muscle cells (due to high glucagon:insulin ratio)
2. Liver stuck in glucogenic and ketogenic state

• insulin inhibits gluconeogenesis since there is already high blood glucose. However, since there is lack of glucose, liver still breaks down non-carb molecules like lipids and proteins into glucose
• Ketogenic : conversion of amino acids into ketone bodies, and ketone bodies are to be utilized for energy (since glucose cant enter cells , cells cant breakdown glucose for energy, so break down ketone bodies for energy instead)

3. Excessive level of glucagon leads to a decrease in Fructose 2,6-biphosphate (intermediate product of glycolysis), thus increasing gluconeogenesis in liver. F-2,6-BP usually stimulates glycolysis (break down of glucose) and inhibits gluconeogenesis in the liver
4. excessive amount of glucose produced by liver

Question 17

Why is diabetic ketosis rarely a problem in Type 2 diabetes?

Answer 17

In type 2 diabetes : insulin resistant, but sufficient insulin is produced.

This means that insulin can still cause glucose uptake for cells to utilise glucose as a source of energy, just that uptake of glucose is not as efficient as in a normal person.

However, in type 1 diabetes, there is insufficient insulin, so glucose cannot even enter cell and cells have to rely on converting amino acids into ketone bodies, and break down ketone bodies in a process called ketosis for energy

Question 18

What is hyperglycemia? Is it present in type 1 or type 2 diabetes

Answer 18

High blood glucose. It is present in both type 1 and 2 diabetes.

Question 19

Why is regulation of glucose (glucose homeostasis) important?

Answer 19

Glucose is the only source of fuel for the brain, and brain cannot rely on amino acids/lipids fo energy.

Question 20

What are the 2 main hormones regulating the starve fed cycle and what are their functions?

Answer 20

1. Insulin : encourage uptake of glucose by cells and inhibiting gluconeogenesis (break down of non-carbs into glucose, e.g. lipids and proteins, carbon backbone) + glycogenesis
2. Glucagon : encouraging breakdown of glycogen into glucose (glycogenesis) + encouraging gluconeogenesis

Question 21

In the fed state, what happens?

Answer 21

1. Blood glucose levels rise as food is digested
2. Insulin is secreted

Question 22

In the fed state, insulin is secreted. What does insulin do? [6]

Answer 22

1. allow uptake of glucose by fat/liver/muscle cells and storage as glycogen in liver and muscle cells
2. Suppress gluconeogenesis + glycogenesis by liver
3. Accelerates glycolysis in liver to break down glucose into energy (since there is excess glucose)
4. Stimulate storage of fuels and synthesis of proteins
5. Promotes uptake of branches chain amino acids by muscle (Leucine, Isoleucine, Valine)
6. Inhibits protein degradation and maintaining protein levels in cells and tissues
   - since glucose is high, glucose broken down for energy and proteins are less likely to be degraded

Question 23

What happens during early fasting during the night?

Answer 23

• blood glucose levels decreases
• glucagon is secreted by pancreatic α cells

Question 24

During early fasting in the night, what does glucagon do? [4]

Answer 24

1. Glucagon primarily acts on liver to break down glycogen into glucose (glycogenesis)
2. Stimulates gluconeogenesis (break down of non-carbohydrates, such as lipid and proteins) in the liver
3. Inhibits fatty acid synthesis – diminishing production of pyruvate and lowering activity of acetyl CoA carboxylase
4. Blocks glycolysis by decreasing level of Fructose - 2,6- Biphosphate (intermediate needed in glycolysis)
   - Since low [glucose], decrease breakdown of glucose into energy, helping to conserve glucose for release into bloodstream via glycogenolysis (glycogen → glucose) and gluconeogenesis (lipid/protein → glucose)

Question 25

What happens in the refed state after waking up and eating breakfast?

Answer 25

• Glucose converted to glycogen in liver
• Excess glucose is used to synthesize fatty acids