Lecture 8: Diabetes Flashcards
How can we test for type II diabetes?
There are two ways we can test for it.
1) Oral glucose tolerance test. A person fasts and is then given glucose. We check the ability to keep glucose at around a 5 mM glucose concentration. This is used more for diagnosis.
2) Another method is to measure the measure glycated haemoglobin over several months or at regular intervals. This is used more to check how treatment is going.
What are the changes in carbohydrate metabolism?
The failure of β cells to compensate for insulin resistance can explain changes in carbohydrate metabolism.
• Gluconeogenesis isn’t inhibited. This means that the liver overproduces glucose from this pathway.
• The muscle fails to utilise enough glucose (from oxidation or glycogen storage). It doesn’t take up enough glucose either (lack of GLUT4 recruitment). This causes post-prandial hyperglycaemia.
What are the changes in fat metabolism?
The failure of B cells to compensate for insulin resistance can explain some of the changes in fat metabolism.
• Lipolysis isn’t inhibited. There is decreased LPL activity. This can lead to atherosclerosis.
• NEFA concentration increases from 0.2-1 mM to 3-4 mM.
• The increased availability of fatty acid means that glucose metabolism is suppressed in the muscle via the Randle cycle. This means that blood glucose rises from 10-12 mM.
What are the changes in ketone body metabolism?
Ketone body metabolism is upregulated in the liver due to increased availability of fatty acid.
• Ketone body concentration may exceed the capacity of the kidney to break them down.
• We find ketone bodies in the urine.
• Blood pH falls from 7.5 to 7.1. This is known as diabetic acidosis.
• In adapted starvation, liver glutaminase is upregulated. This doesn’t happen in diabetes.
How does lipoprotein lipase change?
LPL normally breaks down TAGs found in chylomicrons and VLDLs.
• Lipoprotein lipase is hydrolysed in the diabetic state. Remove of TAGs from circulation is impaired.
• There is an inverse relationship between TAG and HDL levels.
• CEs and TAGs are exchanged between HDLs and VLDLs by CETP (cholesteryl ester transfer protein). The rate of exchange of HDL CEs for VLDL TAGs increases.
What is the paradox of liver metabolism? How do we explain it?
The paradox of liver metabolism is made up of two parts.
• GNG causes an overproduction of the liver due to insulin resistance. However, glycogen breakdown does not increase as we would expect with IR.
• The liver overproduces VLDL TAGs. This can’t be explained by insulin resistance.
We can explain it in two ways.
Lipid metabolism is controlled by precursor supply
• Rate of liver GNG is controlled by substrate supply.
• Glycerol from adipose and amino acids from the muscle.
• Insulin resistance in these tissues increases supply.
• The liver doesn’t need to be insulin resistant. The effects from other tissues.
• This also applies to fat metabolism. TAGs are overproduced in the adipose tissue.
• So, you are getting excess GNG substrates, excess fats and excess glucose (liver equilibrates to the blood level).
• Liver produces TAGs which are exported to the glucose.
Liver insulin resistance is selective, not global
• Insulin resistant in the carbohydrate, not fat metabolism.
• FOXO1 pathway is affected (GNG) but the SREBP1c (lipogenesis) isn’t affected.
