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!

Diabetic Neuropathy Differs in Type 1 and Type 2 Diabetes  (link to full text, request doc share)

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).