C peptide test and Medication

OK there is a graph of insulin response for Ozempic on the Novomedlink site. It is copyright, so I cannot share it here. Basically it shows two stages of comparison between groups, one at baseline, and another after 12 weeks of treat,ment. The baseline comparison is the sample group vs the placebo group, and it can be seen that the two graphs are linear and track each other, so the behaviour of the pancreas is indeed glucose dependant as claimed. Looking at the 12 week graphs, the comparison changes to the intervention group vs "Healthy people", but not the placebo group. so not comparing the same test cohort members. Again the two graphs are linear and track each other.

First observation - although the GLP-1 agonist is present in the blood, the normal GLP-1r route from the alpha cells is still rolling and providing the correct stimulus. There is no evidence that the agonist med is actually contributing anything. To show that the comparison should have been against the placebo group.

Now normally insulin secretion rate used to be expressed as pmol/min. But drug companies prefer to use pmol/kg/min. The effect of this is that the rate is now totally dependant on body weight or BMI. Comparing within a group at the same time is valid, but where the primary intervention is weight loss, then over time, and as the weight decreases, so the insulin secretion rate will rise, which again is shown by these graphs. It is in the mathematics. Again, the 12 week
graphs do not show that the Ozempic has changed the pancreatic response only the magnitude of it which may just be from losing the kg.

GDM06 said:

Changing the approach to type 2 diabetes treatment: A comparison of glucagon-like peptide-1 receptor agonists and sulphonylureas across the continuum of care​

https://doi.org/10.1002/dmrr.3434

I am actually traveling to Belgium this weekend, but when I am back I can provide more. Hopefully will be able to at least relieve some of your skepticism about GLP-1 RA.
Its mechanism of action is actually while it's been used in some type 1 diabetic, without worrying too much about the risk of hypoglycemia.

Click to expand...

Errm. If you look at the author credentials, the main authors are employees of Eli Lilly. It reads like a sales spiel, with lots of bland statements that look like fact, but to me seem more like the Emperor's New Clothes. It is easy to say that the agonist is controlled by glucose, but I still see no mechanism by which an exogenous application of the agonist is limited or controlled. as I said, under normal homeostasis, GLP-1 (nat) only lasts 11 minutes in the blood. these agonists last 11 hours up to 6 days or more. GLP-1(nat) is responsive to glucose levels since it is controlled by glucagon but the drug maker claims that glucagon is significantly reduced, so this safety feedback to prevent hypo is further compromised. there are aspects to this class of meds that I have yet to find a description for a viable control mechanism. The graphs of insulin secretion are also not giving viable evidence of improved insulin function. They are miraculously showing what the manufacturer wants us to see.

This paper seems to agree with me that the agonists do excite the GLP-1 receptors continuiously while the drug remains in the blood

OK I think I have found the mechanism that the Beta Cells require GLP-1 for and how it is glucose dependant. It is described in section 4.3.1 of the following paper. Basically, when the beta cells start producing insulin from proinsulin, there is a cyclic oscillation that pumps the reaction depending on the presence or absence of potassium and calcium It is electrically driven and this is altered in the presence of glucose, and when levels are below 5mmol then the pump effectively shuts down. Not sure why this does not happen when other conditions such as sulfonyl use can go on to cause a hypo.

C-Peptide testing is a bit of a maze. Are you aware that there are two different ways of testing i.e. Blood plasma test and the urine test. I've had both with varying results, In both cases the specimen needs to be handled carefully and I believe quickly refrigerated. My consultant was more interested in the urine test and the ratio with creatinine. The problem with creatinine is that it can vary from person to person and depends on the state of the kidney as my wife who had a kidney transplant knows. It's a bit of a black art.

Daibell said:

C-Peptide testing is a bit of a maze. Are you aware that there are two different ways of testing i.e. Blood plasma test and the urine test. I've had both with varying results, In both cases the specimen needs to be handled carefully and I believe quickly refrigerated. My consultant was more interested in the urine test and the ratio with creatinine. The problem with creatinine is that it can vary from person to person and depends on the state of the kidney as my wife who had a kidney transplant knows. It's a bit of a black art.

Click to expand...

Creatinine also depends very much on whether your diet includes animal products, and how recently you ate. It is also dependant on recent exercise levels.

OK Now that I have digested the info on the GLP-1 RA medication, I feel a need to refine an answer I gave to the OP earlier.

While the medication is still active in the blood then it will override the normal operation of the intrinsic GLP-1 / Glucagon control regime. That will still have some effect but the medication will probably flood the GLP-1 receptors with tha agonist versions. These agonists will remain for at least the half life of the medicaton, and probably longer since they are designed to be impervious to attack by the DPP-4 hormones that usually remove the natural GLP-1R within 11 minutes. so the beta cells will remain primed and ready to go for much longer than we are designed to operate with.

Once primed, then it seems that while glucose levels are above 5 mmol/l then insulin will be generated and released. if the glucose level is 20 mmol/l or above then the pancreas will be running at maximum output and being thrashed. If Insulin resistance is high then this high level of insulin will persist way past the point where glucagon would naturally terminate the glucose / glucagon cycle by reducing and removing the GLP-1 enable.

The effect of the sulphonylurea meds I believe is to shift the voltage scale that controls the pulsing of the pump in the Beta Cells, and so the glucose level 'seen' by the beta cell appears to be higher than it really is, so again, the pancreas will overdrive the insulin output.

I don't know. But I do know in the US they want your blood glucose level to fall within certain perimeters when doing a C-peptide test. Too high of a BG level means your pancreas, if it is still trying to produce insulin, will make more and skew the test. Too low and your body might release glucagen to deal with it and then your liver increases insulin to deal with that spike. Per Joslyn 50% of long term type 1's still try to produce a small amount of insulin off and on. And newer T1's ones don't completely lose the ability for 8 years plus.

So in other words what you do, can influence your test. If a drug helps your pancreas make more insulin at all, that could influence the test. I don't know the guidelines you need to qualify as a T1, but usually you can find out, so if you are pretesting you will want to know. Small influences could potentially be an issue.

Some old timers here have had some issues. Insurance companies more readily supply a pump etc for T1's here and are pretty good about taking a past diagnosis. But Medicare which is what you go on here after the age of 65 wants solid proof of a C-peptide test of being a Type 1 to qualify without need for a pump. A past test will work, but a lot of old timers never had the test because they were diabetic way before it was used. And now they have to get one. An antibody test doesn't always come up positive if you've been a T1 for a long time as the antibodies have pretty much gone down to very small or non existent levels once you aren't producing all those beta cells.

We just had a case of an old timer type 1 since he was a kid that knew he produced small amounts of insulin. His first test didn't qualify. The next test he made sure he fasted, and ate low carb the night before, because eating can cause you to try to produce insulin, and he made sure he was around a BG level of 5.6 for the test. Watch out for high protein too because with a lack of carbs your body will use insulin on protein too. He barely qualified, but he did qualify.