Biochemistry- control of blood glucose

Question 1

How does insulin decrease blood glucose and what problem happens when this system breaks down (leading to type 1 and type 2 diabetes)

Answer 1

Insulin stimulates the translocation of GLUT4 transporters (glucose carriers) from intracellular vesicles to the plasma
membrane, causing an increase in glucose uptake. With the exception of the liver, this occurs in all insulin-sensitive tissues.

 Insulin stimulates increased glucose uptake by muscle and adipose tissue in particular.
 Insulin causes tissues to increase the rate at which they use glucose, through glycolysis, fatty acid synthesis and
glycogenesis. Different tissues will make the use of the extra glucose in different ways.
 If insulin is not made, or not responded to, plasma glucose levels will be higher, especially after a meal.

 The higher levels of plasma glucose increase the likelihood of glucose reacting with proteins in the blood, or on the vessel
walls.
 When glucose reacts with proteins, it impairs their function and is the starting point for many diabetes-associated problems
(e.g. CHD).

Question 2

What is a dominant pattern of inheritance

Answer 2

One faulty copy of the gene leads to the condition. In the case of MODY, one faulty hexokinase gene means that too little
glucose is trapped in pancreas β-cells, leading to lower increases in insulin secretion.
 Both heterozygotes and homozygotes are affected.
 Affected individuals have at least a 50% chance of passing the condition onto their children. For homozygotes, it would be
100%.
 The faulty gene is on an autosomal (non-sex) chromosomes, otherwise the inheritance pattern would be affected by
gender.

Question 3

How is hexokinase affected by the change in glucose concentration after a meal

Answer 3

Hexokinase has a Km that is much lower than the normal range of plasma glucose concentrations, and the glucose
concentration in the fed state. The Km gives a rough idea of what substrate concentrations the enzyme activity is responsive
too.

 In the liver, glucose uptake is extremely high during the fed state, so any hexokinase would be effectively saturated. The
enzyme does not get saturated at exactly twice the Km.

 Liver hexokinase activity would not be increased as plasma glucose levels rise. Liver expresses very little hexokinase.

 In tissues expressing GLUT4:
o The increased glucose uptake would allow hexokinase activity to increase. The lack of GLUT4 in the membrane
during fasting limits the amount of glucose that hexokinase can access.
o The increase in hexokinase activity after a carbohydrate rich meal would be limited. As well as the low Km,
hexokinase is inhibited by its product, so the cell only takes up glucose according to its requirements.

Question 4

How is glucokinase affected by the change in plasma glucose after a meal

Answer 4

The Km of glucokinase is very high, so the enzyme is not easily saturated.

 As glucose concentrations increase, glucokinase activity will also increase.
 Due to the high Km, glucokinase activity is also very low when glucose concentration are low, so an increased glucose
concentration has a large effect on its activity. This means that cells are able to sense changes in the plasma glucose
concentration.

Question 5

What is the role of glucokinase in the liver

Answer 5

Glucokinase allows the liver to effectively sense and respond to changing levels of glucose in the blood.

 Glucokinase activity is highly dependent on plasma glucose concentrations, so its activity, and therefore the intracellular
concentration of glucose-6-P is representative of plasma glucose levels.

 Glucokinase allows liver cells to begin responding to increased plasma glucose without the need for insulin.

This is especially
important as glucose absorbed by the small intestine reaches the liver first.
 High expression of glucokinase also allows the liver to trap large amounts of glucose during the fed state. In contrast to the
lower amounts expressed by the pancreatic β-cells, which are only used for glucose-sensing.
 Glucokinase works in concert with GLUT2, a transporter with a high Km for glucose, so that glucokinase activity is not
limited by low rates of glucose uptake into the cell. This applies to the liver and the pancreas β-cell.

Question 6

What is the role of glucokinase in the pancreas

Answer 6

Glucokinase allows the pancreas to secrete more insulin in response to increased plasma glucose.
 Glucokinase is not required for basal insulin secretion. An insulin secretion in MODY patients during fasting was near normal.
 One functioning copy of glucokinase allows some increase in insulin secretion when plasma glucose is elevated. Two faulty
copies of glucokinase leads to an earlier-onset, more severe form of diabetes.