Saturday, June 26, 2021

Metformin (12) You don't need to be SHORT

Metformin is a drug which blunts the action of insulin.

Metformin is the most widely prescribed insulin sensitising agent in the world.

Discuss.

It is quite core to any logical self consistent view of the world that metformin is an agent which blunts insulin signalling, as per the ROS/Protons hypothesis via inhibition of mitochondrial glycerophosphate dehydrogenase.

The first clinical hint that this might be correct was from this study

discussed in this post.

If you are unlucky enough to be born with with SHORT Syndrome, a genetic defect in the insulin signalling pathway, you need to be hyperinsulinaemic to maintain normoglycaemia, especially during an OGTT. If some joker puts you on to metformin for 4 days then repeats the OGTT the level of insulin needed to maintain normoglycaemia goes from extremely high (690microU/ml, pax the typo on the graph) up to way too high to measure (well over 1000microU/ml for over an hour), like this:










Note, apart from the typo for insulin units, that the colours were switched between the graphs. Oops.

SHORT Syndrome is rare. Finding studies of the effect of acute metformin administration on the results of an OGTT in normal people is quite difficult. The closest I have is looking at the effect of metformin on an OGTT in obese people who still have a normal OGTT result. This is the paper

Effects of short-term metformin treatment on insulin sensitivity of blood glucose and free fatty acids

and here are the results for the obese normal OGTT people. Dashed line is under metformin after a ten day course, solid line before metformin:








The increased level of insulin secreted is not quite enough to effectively control blood glucose. As I might have mentioned, metformin blunts insulin signalling. No surprises there then. 

However, if you give the metformin to someone who is already insulin resistant or has type 2 diabetes, the opposite happens, same study:









This has a lot of bearing on what we mean by diabetes but might be better left for a few posts while I run though the transition form health through obesity to impaired glucose tolerance to frank DMT2.

Peter

2 comments:

salix said...

Peter, have you heard of the new wonder drug for obesity and T2D : Wegovy (semaglutide)

When I saw it works by increasing insulin secretion I got a bad feeling.

What do you think?

Passthecream said...

Intriguing. I am eagerly awaiting the continuation of this thread!

MODY, mature onset diabetes of the young, comes in several varieties. Some are more like T2dm and some more like T1dm. I wonder if there is any good ogtt vs insulin vs sugar data for the various MODY types similar to the ones you've detailed there?


https://www.health.harvard.edu/a_to_z/maturity-onset-diabetes-of-the-young-mody-a-to-z