Diabetes Type I and Type II

Question 1

Why is a supply of glucose important?

Answer 1

A continuous and steady supply of glucose is essential for normal brain function, and importance for many other tissues.

Question 2

What are the limits of blood glucose regulation?

Answer 2

4.0-7.0mmol/L in health

Question 3

Why is glucose regulation important?

Answer 3

Cells get energy, typically from sugars, and break them down ultimately to CO2 and H2O - and on the way, cells harvest the energy of those reactions.

Question 4

Where does glycolysis occur?

Answer 4

Glycolysis occurs in the cytosol

Question 5

Describe the stages of glycolysis

Answer 5

Stage 1: Trap glucose in the cell (Glucose-6-phosphate cannot leave the cell).
Stage 2: Cleave fructose 1,6- biphosphate into two three carbon fragments. These resulting three carbon-units are readily convertible.
Stage 3: Generates ATP from the phosphorylated three-carbon metabolites of glycose.

Question 6

What happens to pyruvate after glycolysis?

Answer 6

Pyruvate (in aerobic conditions) is transported into the mitochondria, oxidatively decarboxylated by the pyruvate dehydrogenase complex to form acetyl-CoA which is the fuel for the citric acid cycle.

Question 7

What is the citric acid cycle?

Answer 7

The citric acid cycle is a series of chemical reactions used by all aerobic organisms to generate energy through the oxidation of acetate derived from carbohydrates, fats and proteins into carbon dioxide and chemical energy in the form of adenosine triphosphate (ATP).

Question 8

What happens in the citric acid cycle?

Answer 8

Oxidises organic fuel derived from pyruvate generating 1 ATP, 3 NADH and 1 FADH2 per turn.

Question 9

Describe the process that occurs in the electron transport chain

Answer 9

In the cristae of the mitochondrion:
Most of the chain’s components are proteins, which exist in multiprotein complexes
The carriers alternate reduced and oxidised states as they accept or donate electrons
Electrons drop in free energy as they go down the chain and are finally passed to O2, forming H2O
Each of the reactions is exergonic and thus releases free energy This free energy is used to translocate protons across the inner mitochondrial membrane, this will generate ATP.
The electrons that finally end up in water are of low energy
During the coupled oxidation reduction reactions, iron ions that are complexed within the proteins become oxidized and reduced. That is, the Fe ions participate in catalysis.

Question 10

How does glucose enter our cells?

Answer 10

There are > 10 different glucose transporters; GLUT 1-4 are the best studied.

Question 11

Describe GLUT 1

Answer 11

GLUT 1 is found in the brain, erythrocytes, placenta and fetal tissue. It has a low Km (approx 1mM). High affinity for glucose and uptake from the bloodstream by GLUT 1 is constant.

Question 12

Describe GLUT 2

Answer 12

GLUT 2 is found in the liver, kidney, intestine and pancreatic B-cell. It has a high Km (15-20 mM). Lower affinity receptor (yet still high affinity); allows intracellular and extracellular glucose to equilibrate across membrane (i.e. glucose entry is proportional to blood glucose levels)

Question 13

Describe GLUT 3

Answer 13

GLUT 3 is found in the brain and has low Km (less than 1 mM(, higher affinity compared with GLUT 2. Allows preferential uptake in hypoglycaemia.

Question 14

Describe GLUT 4

Answer 14

GLUT 4 is found in muscle and adipose tissue. Mostly found within the plasma membranes of cytoplasmic vesicles within the cell. After a meal and at the binding of insulin to receptors on the cell surface, a signalling cascade begins which culminates in the movement of the cytoplasmic vesicle towards the cell surface membrane. It is insulin sensitive, regulate uptake of glucose after food intake. Medium Km (2.5-5 mM). Insulin recruits transporters from intracellular stores increasing glucose uptake.

Question 15

Glucose uptake from the gut

Answer 15

Is almost completely achieved by Na dependent glucose transporters (SGLT 1 and 2), not the GLUT family transporters that other cells use to take up glucose from the bloodstream.
As the name suggests a sodium gradient from the lumen to the cell is needed for glucose uptake. This is why you need Na to promote glucose uptake in oral rehydration solutions.
The transport is saturable, if the glucose in the lumen rises above a certain level not all glucose is absorbed (this is the cause of glycosuria in diabetes).

Question 16

Anatomy of pancreas

Answer 16

Elliptical organ which is retroperitoneal
Size is 12-15 cm in length, weight is 70-100 grams
3 parts - head, body and tail.

Question 17

Function of pancreas

Answer 17

Exocrine: Pertaining to the secretion of a substance through a duct.
Endocrine: pertaining to hormones and the glands that make them and secrete them into the bloodstream through which they travel to affect distant organs.

Question 18

Endocrine function of pancreas

Answer 18

Secretion of the hormones into the blood stream.
There are two major hormones , insulin and glucagon.
Minor ones include somatostatin and pancreatic polypeptide.

Question 19

Define somatostatin

Answer 19

Somatostatin: a hormone that many different tissues produce, but it is found primarily in the nervous and digestive systems affects several areas of the body. In the pancreas, somatostatin inhibits secretion of pancreatic hormones, including glucagon and insulin.

Question 20

Define pancreatic polypeptide

Answer 20

Pancreatic polypeptide: produced and secreted by PP cells (originally termed F cells) of the pancreas, decreases food intake and increases energy expenditure.

Question 21

Which hormones regulate glucose?

Answer 21

Insulin and glucagon

Question 22

What is insulin?

Answer 22

Insulin: first protein whose sequence was identified (1955)
51 amino acids; synthesized as pro-insulin.
Insulin is produced by Beta cells:
Release is stimulated by high blood glucose levels and the parasympathetic nervous system
Increases the uptake and storage of glucose, fatty acids and amino acids in cells and tissues
Gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP - 1) are the two primary incretin hormones secreted from the intestine upon ingestion of glucose or nutrients to stimulate insulin secretion from pancreatic B cells.

Question 23

How beta cells work?

Answer 23

At rest, K+ ions diffuse out of the cell via ATP sensitive K+ ion channel; this creates a potential difference across the cell (inside more negative than outside). The voltage-gated calcium channel is normally closed.
When you eat and blood sugars rise, the GLUT 2 transporter will mediate the uptake of glucose into these cells. At this point, glycolysis occurs in the beta cell and ATP is produced.
Now the ATP sensitive potassium ion channel closes. K+ ions are no longer diffusing out of the cell and the potential difference across the cell becomes positive causing the Ca2+ voltage-gated ion channel to open.
So calcium enters the cell and this causes vesicles to store insulin to move to the cell surface and release insulin.
The digestive tract releases incretins and this increases GLP-1 (Glucagon-like peptide 1) which stimulates the release of insulin.

Question 24

Role of Insulin in Glucose Regulation: after a meal: the fed state

Answer 24

Insulins signals the fed state - it stimulates the storage of fuels and the synthesis of proteins in a variety of ways (anabolic).
In many tissues - e.g. muscle - the major transporter used for uptake of glucose, called GLUT 4, is made available in the plasma membrane through the action of insulin.
Insulin binds to receptor and initiates the recruitment of GLUT4 to the cell surface.
GLUT4 proteins are integrated into the cell membrane allowing glucose to be transported.

Question 25

Role of insulin after a meal: the liver

Answer 25

Insulin accelerates the uptake of blood glucose into the liver by GLUT2.
The catalytic sites of glucokinase (a hexokinase) becomes filled with glucose
The level of glucose-6-phosphate in the liver rises
The increase in glucose-6-phosphate coupled with insulin action leads to a build-up of glycogen stores.
The liver helps to limit the amount of glucose in the blood during times of plenty by storing it as glycogen so as to be able to release glucose in times of scarcity.

Question 26

What is Glycogen?

Answer 26

Glycogen is a multi-branched polysaccharide of glucose that serves as a form of energy storage in animals and fungi. The polysaccharide structure represents the main storage form of glucose in the body.

Question 27

What happens if you cannot convert glucose to energy?

Answer 27

If you cannot convert glucose to energy, we use fat as an alternative energy source which leads to production of ketones.

Question 28

What is Glucagon?

Answer 28

Blood-glucose levels begin to drop several hours after a meal, leading to a decrease in insulin secretion and a rise in glucagon secretion.
Glucagon is produced by alpha cells in response to a low blood-sugar level in the fasting state.
It mobilizes glucose, fatty acids and amino acids from stores in the blood. The main target organ of glucagon is the liver.

Question 29

Functions of glucagon

Answer 29

Stimulates glycogen breakdown and inhibits glycogen synthesis
Inhibits fatty acid synthesis by diminishing the production of pyruvate
Stimulates gluconeogenesis in the liver and blocks glycolysis.

Question 30

Incretins and Glucose Homeostasis

Answer 30

The GI tract releases incretin gut hormones and these promote the release of insulin by beta cells and inhibits the release of glucagon from alpha cells.

Question 31

What is diabetes?

Answer 31

Defined by raised blood glucose
Increased blood glucose is due to either deficiency of the hormone insulin (produced by the pancreas) and/or resistance to insulin.
Uncontrolled diabetes (especially in type 1) is a medical emergency and can be fatal.
Chronically raised blood glucose leads to long term diabetes complications
Diabetes treatment can lead to hypoglycaemia.

Question 32

What types of diabetes are there?

Answer 32

Type 1 diabetes
Type 2 diabetes
Type 3c (diabetes secondary to pancreatic disease)
LADA (Late Onset Autoimmune Diabetes)
MODY (Maturity Onset Diabetes of the Young - rare inherited form of type 2)

Question 33

What is type 1 diabetes?

Answer 33

Islets of Langerhans in pancreas make insulin
Destroyed in type 1 diabetes by autoimmune response.
1:300 of UK population
Doubled in last 25 years
Common in Europe, rare in Japan

Question 34

What are the consequences of type 1 diabetes?

Answer 34

Uncontrolled gluconeogenesis
Failure of glucose uptake into muscle and fat
Use of alternative fuels (fatty acids)
Development of hyperglycaemia, ketoacidosis eventual coma and death if untreated.

Question 35

How many genes are involved in type 1 diabetes?

Answer 35

At least 18 genes involved:
‘HLA’ - three genes
Insulin
Others
Complex environmental interactions

Question 36

Insulin Excess: Hypoglycaemia

Answer 36

Excess of insulin - usually in treatment of diabetes (insulin, Sus)
Can occur with rare insulin secreting pancreatic tumour
Blood glucose falls (less than 2mmol/L)
Sympathetic response (sweating, tachycardia, hunger)
Confusion and coma as brain starved of glucose.

Question 37

What are the two obesity related problems in type 2 diabetes?

Answer 37

There are two obesity related problems in type 2 diabetes: insulin resistance and progressive insulin deficiency

Question 38

Describe insulin resistance

Answer 38

Insulin resistance:
Peripheral tissue are not responsive to insulin; higher levels of insulin are required in order to keep blood glucose within the normal range - genetic component and exacerbated by obesity and physical inactivity.

Question 39

Describe progressive insulin deficiency

Answer 39

Progressive Insulin Deficiency:
Pancreas does not make enough insulin
Amyloid and fat deposits in pancreas
Defective incretin response

Question 40

How does being overweight lead to diabetes and heart disease?

Answer 40

Fat cells lead to:
Reduced response to insulin
High cholesterol and blood fats
High blood pressure
Inflamed arteries
Increase blood clotting