What Causes Diabetic Complications?

Type 1 and LADA
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The answer to the questions of what causes complications seems obvious, and anyone would answer that it is hyperglycemia. But there is also some evidence, published in peer review medical journals, suggesting that there are other factors as well. One is genetics, the theory being that along with the whole cluster of genetic factors which predispose a person to develop diabetes in the first place, there are a few which predetermine complications gradually to develop. Another factor is the continuing autoimmunity of diabetes, with this theory holding that since the autoimmune response which first caused the pancreatic beta cells of the patient to be destroyed continues and contributes to the development of the characteristic complications of diabetes. Another is the insulin treatment itself, which often involves patients taking much more insulin than a normal person requires, with this theory stating that the excess amounts of insulin used by diabetics themselves contribute to the complications. Finally, hyperglycemia itself causes the release of stress hormones, and these can also cause vascular damage.

But all this seems counterintuitive, since by Occam’s Razor we should not needlessly multiply scientific hypothesis, and if we have one which already explains the phenomena (hyperglycemia accounting for complications), how can it be that there is another, completely different cause operating in the patient which produces exactly the same complications? However you account for it, it would be good to know the relative magnitude of each of these contributing factors, since they all implicitly diminish the importance of strict blood sugar control, since fixing it would not solve the complications problem.

Here are a few of the many sources which could be cited:

Craig Currie, et al., “Mortality and Other Important Diabetes-Related Outcomes with Insulin vs. Other Antihyperglycemic Therapies in Type 2 Diabetes,” Journal of Endocrinology and Metabolism, 98 (2) 668-677 (2013)

This study found that type 2 diabetics put on insulin to control their blood sugar rather than kept on various oral medications had double the level of diabetic complications though about the same level of blood sugar control.

A. Doria, “Genetics of Diabetes Complications,” Current Diabetes Reports, 10 (6) 467-475 (2010)

V. Granberg, et al., “Autoantibodies to Autoimmune Nerves Associated with Cardiac and Peripheral Neuropathy,” Diabetes Care, 22 (8) 1959-1964 (2005).

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There might be (and likely are) many factors. In my case, my mom was blind, had awful neuropathy and lost kidney function. Mom passed after 23 years as a type 1. I have had type 1 for 43 years and have minor complications. So one might assume I would have similar complications to my mom, but more likely moms complications were because of her understanding of glucose control in the 60’s. My lack of complications is probably the result of the tools I use today.

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It hasn’t always been so obvious! It was not until the early DCCT results came out in the 1990’s that it was obvious, in any formal scientifically proven way, there was any causal link between hyperglycemia and the microvascular complications.

The DCCT was hugely hugely important in establishing this link for many complications, ESPECIALLY the microvascular ones (retinopathy, kidney disease, etc.)

I will agree that lots of doctors thought there was a relation before the DCCT results but they admitted to me at the time that this was just their hunch based on anecdotes and not any actual proven result. Well, that was the more progressive doctors in the 1980’s. The older doctors I had back in the 1980’s? Many of them thought that insulin, or impurities in the insulin, was responsible for complications. Today we would laugh at that but look at how little knowledge was known about average bg’s before A1C measurements and home bg meters became widespread.

(Actually that’s a little circular, A1C and home bg meters themselves weren’t widespread until the time of the DCCT. The DCCT certainly made them more accessible for most diabetics but actually the technology was evolving and their usage was becoming wider even before the first DCCT results. Oh man, it was like stone knives and bearskins before home bg meters.)

My doctors were some of the folks setting up the DCCT and none of them expected to see such a powerful obvious relation between hyperglycemia and any of the complications.

There are many conditions (not quite willing to say “complications”) that commonly occur in diabetics that are often blamed on hyperglycemia, but in fact there seems to be no correlation (or even an anti-correlation) between A1C and their occurence. Frozen Shoulder is an example that seems to be anti-correlated in published results (but there has not been extensive studies).

Another related condition that today nobody thinks is related to hyperglycemia, is hypothyroidism. I think I started a thread few years ago, “how do I know my hypothyroidism wasn’t caused by hyperglycemia?”. Everyone just said it was obviously autoimmune related and not a complication through hyperglycemia, but I didn’t find any published results at all that say this. (Although, in fact I did find some results that say that hypothyroidism falsely raises A1C’s which is kind of the opposite causality than I was asking about!)

Today we often think about these “Related conditions that are not complications of hyperglycemia” in terms of autoimmune attacks, but this often limits our thinking to T1. Other times maybe a more relevant word is inflammation and this would include many of the qualities of T2. Maybe autoimmune vs inflammatory is a largely irrelevant distinction when both T1’s and T2’s are affected but hyperglycemia seems to not be the link.

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Too much insulin --> Bad for your heart.
Some people argue that its the ‘variability’ in the numbers that’s bad (rollercoastering).

I was meaning to mention to you, that since we had a discussion about meal bolus and postpranials, and you mentioned that it was a pain for you - Someone is doing a study for predicting BG numbers for type II’s. But, they said that they would take some type ones to do UI testing and report back. I think it could be helpful (if for no other reason, than I’ll end up looking more closely at the data). If interested, email.

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It has been widely discussed in the diabetes research literature whether the instability of blood glucose values might itself be a cause of complications, and it is certainly well-established that rapid tightening of blood sugar levels temporarily worsens retinopathy, though it is said that if this lower blood sugar is maintained for a long time there is an overall improvement of retinopathy. But what if the patient can only achieve repeated short-term improvements but can’t sustain them because of the intrinsic instability of the blood sugar levels? Wouldn’t this mean that the many brief improvements in blood sugar would cause a net damage?

The diabetic patient is really walking a tight-rope, since both hyperglycemia and hypoglycemia cause complications. A few examples of articles showing that hypoglycemia also causes some of the distinctive complications of diabetes are:

J. Snell-Bergeon and R. Wadwa, “Hypoglycemia, Diabetes, and Cardiovascular Disease,” Diabetes, Technology, and Therapeutics, 14 (Supplement 1) S-51-S58 (June, 2002).

A. Pena, et al., “Hypoglycemia, but Not Glucose Variability, Relates to Vascular Functions in Children with Type 1 Diabetes,” Diabetes, Technology, and Therapeutics, 14 (6) 457-462 (2012).

I. Weiss, et al., “Impact of Glucose Treatment Choices on Cardiovascular Complications in Type 2 Diabetes,” Cardiology in Review, 17(4) 165-175 (2009).