(PCSK9 and diabetes)
I look into my crystal ball and I see…. I see another wave of diabetes. Yes, the great Nostrokendrickos has spoken. Why do I predict this? Well, I see those given PCSK 9 inhibitors developing diabetes. I see the pharmaceutical companies telling us that this was completely unexpected, a paradox, and not clinically relevant anyway. Hold on…. no the vision is fading….it is gone.
Being an old fashioned type of person I have this strange belief that the body does not produce complex enzymes for a laugh. It takes a lot of energy and resources to make enzymes, or any another form of highly structured protein. If there is no need for them, and what they do, the body sighs with relief and stops making them. Then, over the years, evolution gets rid of the enzyme altogether. It’s kind of how evolution works.
So when we do have an enzyme Proprotein convertase subtilisin/kexin type 9 (PCSK9) I think: What is its purpose? Can it simply be there by mistake? To be frank, I am not entirely sure what the purpose of this enzyme is, but I now know that if you do not have it, bad things can happen. Here is a study which looked at what happens to mice with no PCSK9:
‘Proprotein convertase subtilisin/kexin type 9 (PCSK9), a liver-secreted plasma enzyme, restricts hepatic uptake of low-density lipoprotein (LDL) cholesterol by promoting the degradation of LDL receptors (LDLR). PCSK9 and LDLR are also expressed in insulin-producing pancreatic islet b-cells, possibly affecting the function of these cells. Here we show that, compared to control mice, PCSK9-null male mice over 4 months of age carried more LDLR and less insulin in their pancreas; they were hypoinsulinemic, hyperglycemic and glucose-intolerant; their islets exhibited signs of malformation, apoptosis and inflammation. Collectively, these observations suggest that PCSK9 may be necessary for the normal function of pancreatic islets1.’
Sorry, I realise that the language is a bit technical, so here is a quick interpretation.
- PCSK9 is an enzyme that degrades/destroys LDL receptors, so cells cannot absorb so much LDL (a.k.a. ‘bad’ cholesterol)
- Without PCSK9, beta-cells in the pancreas (where insulin is made) absorb too much LDL
- These LDL ‘overfilled’ beta cells were found to be malformed, dying (apoptosis) and inflamed
- Mice without PCSK9 which had these ‘overfilled’ beta-cells were also glucose intolerant, did not produce enough insulin and were hyperglycaemic a.k.a. there were diabetic
That was mice, what of men? (And, of course women). Well, if we look at people with familial hypercholesterolemia (FH), they have a lack of LDL receptors, or the receptors don’t work so well due to malformations, or both. Therefore, you get less LDL inside cells, including beta-cells. Therefore:
‘In the cross-sectional analysis from the Netherlands, patients with familial hypercholesterolemia were found to have a 51% lower odds of having type 2 diabetes compared with relatives without the cholesterol disorder, and diabetes prevalence varied by gene mutation type…. Hovingh and colleagues hypothesized that this reduced risk occurs because pancreatic beta cells in people with the condition have decreased cholesterol uptake and improved function and survival2.’
Hovingh was almost certainly right.
Now some people will, no doubt, grab hold of this research to tell us that ‘As we told you all along LDL is dangerous and damaging, it even causes diabetes by harming beta-cells.’ I am sort of waiting for an ‘expert’ to tell us this. Maybe they already have. At which point I shall approach them from behind, then hit them repeatedly with a large wet kipper. I shall then announce, with great satisfaction…
‘No, you idiot, what this shows us is that excess LDL inside cells is damaging and dangerous, but that has absolutely nothing whatsoever to do with having a high LDL level in the bloodstream…..you idiot.’
Anyway, adding this information together with the study on mice, it seems that the basic function of PCSK9 may simply be to ensure that cells do not absorb too much LDL from the bloodstream, thus protecting them from: malformation, inflammation and death. It certainly seems to be true of beta-cells in the pancreas. Is it true for all other cells – who knows, but it is a bit worrying is it not?
What is certainly true is that PCSK9 inhibitors will almost certainly increase the risk of diabetes, to an even greater extent than statins. This seems entirely predictable; in fact I predict it now. I also predict that the increased risk of diabetes will take years to emerge. This will be for various reasons that I would like to go into, but fear libel suits.
However, when this adverse effect does eventually emerge I know that it will greeted with astonishment and surprise by the ‘experts’ and, at least in public, by the pharmaceutical companies marketing these drugs. Although I am perfectly certain that they know all about this research… they always do. They ain’t stupid.
The great Nostrokendrickos has spoken. Put this article in a time capsule, to be opened when PCSK9 inhibitors are found to cause diabetes.
1: Majambu Mbikay, Francine Sirois, Janice Mayne, Gen-Sheng Wang, Andrew Chen, Thilina Dewpur, Annik Prat, Nabil G. Seidah, Michel Chretien Fraser W. Scott: ‘PCSK9-deficient mice exhibit impaired glucose tolerance and pancreatic islet abnormalities.’ FEBS Letters 584 (2010) 701–706
P.S. I wonder what other research they are aware of? I think I might go and find out.