Blood Sugar 140: Diabetic Neuropathy, Is it All About Hyperglycemia?

Continuing on in this series dealing with the neuropathy study from which the following statement has been repeated regarding blood glucose levels:  
Nerve Damage Occurs when Blood Sugars Rise Over 140 mg/dl After Meals  (as stated by Ruhl , Jaminet (Kindle Locations 712-716), and Kresser.)
At the risk of repetition, this does seem to have originated with Jenny Ruhl's interpretations of this study wherein 50% of 72 individuals with neuropathy were diagnosed as IGT having a BG level over 140 mg/dL at the 2-hour mark of an OGTT.   The IGT group was also more likely to have painful sensory symptoms than the roughly one-third who were normoglycemic (the remaining group were frank diabetic).

Now even if we extend a little leeway on extrapolating the 140 mg/dL level out of context, there was another finding in this study that got me thinking, is it the glucose?  This was the finding that both FBG and HbA1c's were normal in most of the IGT and diabetics in this study as I discussed in the last installment.    The hands-down most prominent mechanism by which glucose is considered to be toxic is via the process of glycation.  Whether it's Dr. Cate and her sticky schtick, or L.Ron's description of glycation as basically running amok to some degree in all of us doing damage, or any number of folks RAGEing on about AGEs and aging, the collective finger is pointed at the blood glucose level leading to glycation.  The point in my last post was that if this was the major mechanism in the development of  neuropathy for the subjects in this study, the HbA1c would have followed suit.  This is what led me down the MODY research path as well ... as they don't always present with diabetic HbA1c's.  

In the comments on one of my earlier posts in this series (with apologies for no specific shout-out as I'm time constrained to look it up), one reader wondered out loud why it is that some diabetics seem to develop severe complications and others do not, and/or why some suffer kidney problems while the eyes are spared, and/or why some suffer painful neuropathy etc.etc.  Thinking on this, and the HbA1c discontinuity got me to thinking, is there a difference between neuropathies in T1 and T2 diabetes?  In short order I came across the following study, with a title that answered my question!

ABSTRACT: {bullet pointed for clarity}
  • In this article we describe differences in early metabolic abnormalities between type 1 and type 2 diabetic polyneuropathy (DPN), and how these differences lead to milder initial functional defects in type 2 diabetes, despite the same hyperglycemic exposures. 
  • This early reversible metabolic phase is progressively overshadowed by structural degenerative changes eventually resulting in nerve fiber loss. 
  • In comparison, the late structural phase of DPN affects type 1 diabetes more severely. 
    • Progressive axonal atrophy and loss is hence expressed to a larger extent in type 1 diabetes. 
    • In addition, type 1 DPN is characterized by paranodal degenerative changes not seen in type 2 DPN. 
  • These differences can be related to the differences in insulin action and signal transduction affecting the expression of neurotrophic factors and their receptors in type 1 diabetes. 
  • Downstream effects on neuroskeletal and adhesive proteins, their posttranslational modifications, and nociceptive peptides underlie the more severe resultant pathology in type 1 DPN. 
  •  These differences in underlying mechanisms should be seriously considered in the future design of interventional paradigms to combat these common conditions.
Before I go on, I'm going to repeat the impetus for this series.  It is not to bash carbohydrate restriction or at least management in the treatment of diabetes.  It is not to downplay the very real and serious complications that befall, especially, diabetics with poor or sub-optimal blood glucose control.  It is not to promote healthful glucose spikes.  It IS intended to dispel some of the myths surrounding blood glucose levels, controlling them, and the underlying mechanisms.  While this is primarily directed towards the non-diabetic in the hopes of stemming the tide of rampant glucophobia, hopefully it helps some who are at-risk or diagnosed diabetic make better decisions in conjunction with their doctors to best treat their condition.  

My opinion, and this is only my opinion to be taken for what you find that worth, is that tight glycemic control does improve risks of complications -- it is almost always achieved with a more aggressive insulin therapy regime.  I've also found a number of references indicating that c-peptide therapy (c-peptide levels are used to gauge endogenous insulin production) can be helpful in preventing DPN.

This review is rather long and includes a lot of information worthy of several posts.  If and when I get the time, I'll go into greater detail on it in a separate series.  But here is a general synopsis:
  • These researchers used different diabetic animal models that allow distinguishing the role of hyperglycemia from the role of insulin production.
  • They identify two phases of DPN - 1. A (encouragingly!) reversible metabolic phase, and 2. A degenerative phase.
Here are the money paragraphs:
To summarize, the metabolic abnormalities underlying early functional abnormalities in DPN show obvious differences between the two types of diabetes. No doubt, hyperglycemia plays an important role in the development of DPN, we would argue though, that impaired insulin availability, a potent neurotrophic agent in itself, and consequent aberrant signal transduction may play an equally important role in the pathophysiology of these changes.
In summary, this review has demonstrated marked differences in metabolic factors and their magnitudes in type 1 and type 2 experimental diabetes models, which closely mimic the human conditions. The subsequent development of structural changes relates to different sets of underlying molecular changes and differences in the severities of neurotrophic support, which can be directly related to differences in insulin action.  Therefore, despite exposure to the same magnitude of hyperglycemia over prolonged periods of time the resultant outcome is markedly different. This means that apart from hyperglycemia, perturbations of insulin action and signaling play equally important roles in the development of type 1 DPN.   Such differences have to be taken into account in future approaches to treating and/or preventing this common complication of diabetes.
Some last opinions here, again for what they are worth.  If you are one of those people who cannot tolerate normal amounts of carbohydrate, for whom BG either spikes high and/or stays elevated, eating low carb may simply mask insulin insufficiency.  Iff (an acronym common in my academic circles meaning "if and only if") hyperglycemia is prerequisite for insulin insufficiency to have an effect, then so long as low carb manages your glucose levels, you're safe.  But this hasn't been studied that I've seen (as always if you're aware of something I haven't come across, please pass it along).  


Gabriella Kadar said…
A few years ago I read somewhere (can't remember name or whatnot) that there is a hypothesis that diabetes is first a neurological disease. I was reminded of this reading your post today.
Sly said…
I have developed first symptoms of neuropathy, after several months of low carbing. It was strange.
How that happened? I was diagnosed with LADA. After intensive self-education I started to change my diet and lifestyle. After 3-4 months after diagnosis I was without insulin injections. Good BS, HbA1c around 4.6 - 5. Very good diet, exercise etc. Several months passed and my neuropathy started to show. I was drinking alcohol at that time, not much until I realised, it made my neuropathy worse.
Several months later I visited good diabetologist, she was confused with my neuropathy but she gave me ALA, 600mg daily and large doses of B vitamins. She also encouraged me to use insulin and I agreed, knowing from other sources it could prolong good pancreas functioning. Several months later my neuropathy was gone, though as a rule I use small amounts of insulin.

I'm quite good observer of my own body, and I suspected for some time, that insulin is playing bigger role than just pushing glucose to the cells.
I feel better having shots of insulin even though I could almost always replace them with more exercise, less eating and more drinking to achieve normal BG. I still try to be on the lower side with insulin most of the time (it helps with avoiding hypos), but sometimes I just eat carbs and use more insulin, which allows me to be psychologically satisfied. HbA1C has worsened a bit, but still is less than 6.
CarbSane said…
I've read that too -- and it is interesting that Alzheimer's is sometimes being referred to as Type 3 diabetes (
Anonymous said…
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Anonymous said…
It's possible that it could be both glucose and lack of insulin, but this post certainly casts doubt on the idea that it's definitely all the glucose.

Your old posts about lipotoxicity raises more questions about what people should actually do about diabetes. It's always "insulin insulin insulin glucose glucose glucose" with low-carbers but fatty acids can be toxic if poorly metabolized too. And I think that low carb can reduce lipotoxicity by lowering extremely high insulin levels, but just the sheer fat load of a low carbohydrate diet may exacerbate the problem in diabetics, insulin notwithstanding. There is tragically little research on low carb diets and lipotoxicity for diabetics (that I know of, I have looked), some that suggests that it reduces postprandial lipemia, but that doesn't tell us what's happening inside the cells, just in the blood. From what I have seen of many long-term low carbers is that low carb hasn't really fixed their glucose metabolism, in fact it has made it worse in some.

I think that we should sort that one out before anybody says that because glucose and insulin do this or that on low carb then low carb is da best evar for diabetes.
Anonymous said…
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Anonymous said…
And that was triglycerides, not free fatty acids*

Has low carb ever been shown to improve all-cause mortality in diabetics?
CarbSane said…
Thank you for sharing your story here Sly. Your mental wellbeing is as important as anything else. BTW, there appears to be a paradox with insulin as those who are healthier tend to have low insulin levels. This is simply because they are insulin sensitive.
Mario Iwakura said…
Some food for your toughts...

H. Pylori and IR:

H. Pylori erradication on IR, serum lipids and low-grade inflammation:

H. Pylori and diabetic neuropathy:

CarbSane said…
Yeah, Stabby, I think it's more rapid clearance of pp triglyceride, my hunch would be via ASP stimulation. I'm going to be blogging on a recent study that brings things full circle to those fatty acids. To me, the evidence is overwhelming that lipotoxicity precedes glucotoxicity in the progression of diabetes. I've always got this study/post in the back of my mind when thinking about these things: Yes, one will burn more fatty acids, but if fatty acids aren't properly stowed in the fat cells, I don't think that can be a good thing. Like I said about insulin here, if one manages glycemia with LC and hyperglycemia is necessary for lipotoxicity, then you're safe. As to: "Has low carb ever been shown to improve all-cause mortality in diabetics?" I don't think it's ever been studied. This is why I started looking into this stuff. What I don't get is people like Dana Carpender whose health has declined substantially in ways directly related to insulin sensitivity (PCOS and IFG), worsened hypothyroid, etc. who are still convinced they are eating a diet that is healthy for them. More testament to the religiosity of all of this!

Anonymous said…
Great answer, thanks. Oh geez, that graph! O_O I'd be concerned about that too.

Low carb improves hyperglycemia and hyperinsulinemia and that will reduce lipotoxicity, but those are but two factors, so I can't see that making it all better. It might be, but it needs to be studied more. I'm especially worried about the low-carb-exericise-is-useless camp. Maybe less worried about the Mark Sisson holistic approach low carbers.
Jason Sandeman said…
I find it funny that when you talk to LC diabetics (Which is about EVERY diabetic forum out there!) it seems that the focus is always JUST on glucose control and the avoidance of insulin.
I blame Taubes for a lot of it, but there is another culprit in my books - Dr Bernstein.
At the surface, LC works. Sure, the BG numbers are kept down.
If it were only that simple.
I'm sure that there is plenty more going on with insulin. It's a catalyst hormone in my books.
To remove insulin completely is to diminish what Dr. Banting discovered, and saved millions of people with.
On another note - and this is interesting - 99% of insulin today is synthetic. I know a diabetic of 70ish years (that's over 65 years as a T1D) who developed neuropathies and gained weight when he switched to synthetic after pork insulin became unavailable.
I would tender that there are more subtle hormones we don't understand that bind with natural insulin to regulate function in our bodies. The absence of insulin and regulation by diet&exercise alone may actually be what's causing neuropathies in the first place.
Perhaps this is why studies have not been done. If you listen to Taubes, LC is the way to go. If you ask my Endo, he laughs. All he has to do is pull out some pictures of children and adults in the glorious times before the discovery of insulin.
Sobering pictures.
CarbSane said…
Hey Jason, I was hoping to hear from you here! We've discussed Bernstein here before. My impression of him was that he was anti insulin and other meds and very low carb. Then people tell me that's not so. Some of his book is available online, and I've read parts. Regardless of what he writes, something in the manner he writes it has been taken by the low carb community to believe that extreme carb restriction is the best and should be the only way to deal with diabetes. His diet of 12 12 7 or is it 12 7 7 or whatever, even 12 12 12 makes for 36g = VLC as far as most people are concerned.

There's often one position, etc. of a person that can bring all other things into question, and for me that is Bernstein's source for his contention that normal BG's should be in the 80's all day long. This was apparently derived from testing random pharma salesmen to his practice, and they had BG's in the 80's. I don't think we should aim for high BG spikes, but on the otherhand -- especially for the non-diabetics -- this notion that BG should only rise like 10-20 points and be back down in an hour has no basis and it's not how normal insulin action works.

Interesting about that synthetic v. porcine insulin. I wonder if the difference is the animal derived includes more proinsulin (w/c-peptide). I'm coming across a lot of stuff on c-peptide and neuropathy. It's tangential so I probably won't be blogging on it, but something I'd file away for future reference were I a diabetic.
Jason Sandeman said…
I've read Bernstein's book. It is chock full of scientific facts and tests. (Laf)
His diet advocates a restriction of 6-12-12 for carbs. 30 grand for the whole day. Then, he gives lists of what is out and in for food - based on his self observation.
Worse, he even goes as far to "test" the sugar of an item by chewing it, then spitting it onto a litmus paper. (I think that's what it's called.) There is a YouTube video floating around where he was debating a nutritionist about the carbs in bread.

I was "introduced" to this doctor by people in the LC community. I read his book, and truth be told, it seriously messed me up. It scared me in other ways too - but the main thing was that I was avoiding my insulin.
I developed anxiety and health disorder from the symptoms I was getting. The irony is that it was the blood sugar swings that were causing it.
Once I got onto an insulin regiment, then things improved. My weight stabilized, I am way calmer, and I can *gasp* eat how I like, with sense.
I truly believe that VLC restriction puts you into a no-win situation. If your body is not acclimated to carbs as a fuel source, then you see all kinds of spikes from weird stuff. Any T1D can tell you about how their blood sugar spiked
Jason Sandeman said…
Dang iphone!!!!
I was saying a T1D VLC can have a huge spike of 100+ from eating green beans, or too much protein.
Bernstein functions on what he calls "the law of small numbers." Meaning, the VLC protocol requires very little insulin for correction factors, so there is less a chance of hypoglycemia. His premise is that the corrective factor is -/+ 20%, so the smaller the number of units, the smaller the chance of mistake in injection.
It works, in a crude fashion - as if glucose is the only worry a diabetic has. He'll, even using Gedguadis's own analogy - Insulin is a master hormone. There's more to it than just glucose. I'm not sure if you followed the whole Steven Cooksey fiasco - but 95% of that guy's shtick is based off of the back of Bernstein.
Jason Sandeman said…
Here is that lovely clip:
CarbSane said…
OMG -- just watched that! Humans evolved eating flesh, that's why we have canine teeth? LOL. Don't suppose he's noticed we share far more tooth similarities to herbivores. Wowza!

Yeah, I'd read his test your food with glucose sticks. Funny how he should mention evolution and then demonstrate mixing with saliva and putting it on the test strip. The enzymatic breakdown begins in our mouths!!

blogblog said…
Baboons must eat elephants judging by the size of their canines. (sarc)
CarbSane said…
I followed the Cooksey thing a bit. BTW, read your blog post on that but can't seem to find it now. Cooksey got his own self into hot water handing out business cards at a conference. I'm surprised by the number of degreed and licensed folks in this community who see nothing wrong with someone lacking that investment in their "business" operating without a license. Heck, even promoting their work. There are a number of alternative medicine/nutrition paths to go.
Unknown said…
Hi Evelyn, I've just started reading back posts on your blog. I've been thinking that I am a prediabetic based on a couple years of home blood glucose testing and the info on Jenny Ruhl's website. This comment of yours caught my attention. Can you elaborate a bit on how "normal insulin action works"? My BG takes 3-4 hours to come down to preprandial readings and then I generally eat again and send it back up so that it ends up being 100-120 most of the time. I've been gradually cutting my carbs more and more (15 g per meal now) and I am very unhappy at that level and my BG is still not going up and back down like it "should". Now I am wondering: Is this unhealthy or not?

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