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What predicts diabetic peripheral neuropathy?

A new study published in Diabetes Care has found that that the main predictors for developing diabetic peripheral neuropathy (DPN) may actual be obesity factors. But, as we always say is this the full story?

What do we know about diabetic peripheral neuropathy (DPN)?

We know around half of all people with diabetes will develop DPN. We also know that DPN is the critical factor in developing diabetic foot ulcers (DFU), as motor DPN causes high plantar pressures and sensory DPN causes a loss of sensation which provides the ‘perfect storm’ for a DFU. So developing DPN starts the stairway to amputation. But, even though DPN is critical, we don’t know exactly what causes it.

A Cochrane review summarized the hypothesized causes to be the hyperglycemia from diabetes activating various biochemical pathways: polyol, advanced glycation end product, diacylglycerol-protein kinase C or hexosamine pathways. A recent Diabetes Care review suggested the activation of these pathways then results in DNA damage, mitochondrial dysfunction, cellular injury and irreversible nerve damage. We know what you are thinking, “well that’s all just lovely, but what clinical things cause DPN?”

Well the same Diabetes Care review suggested the common risk factors identified so far were: hyperglycaemia, hypertension, hyperlipidaemia, smoking, increased age, weight and height. But, also that so far only cross-sectional studies of various quality have studied DPN. And that’s where this new large longitudinal study from Denmark just might help.

What did this new study do then?

Well this new longitudinal cohort study was part of a much larger RCT into the intensive treatment of people with diabetes in primary care in Europe, the ADDITION study. This study used the data from patients recruited from 190 GP practices in Denmark in 2001-2006. And only patients with a new diagnosis of type 2 diabetes and no diagnosis of DPN on testing at baseline had their data included.

The included patients had a whole range of characteristics tested and collected, including demographics, comorbidities, medications, blood samples, smoking, alcohol and hospitalisation history. They were then followed-up after 6, 12 and 13 years and retested for DPN. The test the study used to diagnose DPN was the validated Michigan Neuropathy Screening Instrument Questionnaire (MNSIQ). The MNSIQ is essentially a self-reported survey of 15 questions on various signs and symptoms of DPN.  Patients reporting >4 of these signs and symptoms were defined as having DPN. Last, they used some complex statistical models to see what factors independently predicted developing DPN.

So what did they find?

First, they included 1,256 eligible patients. Unfortunately, at the 6 year follow-up only 917 patients were tested for DPN; as 234 patients had either died or been lost to follow-up. And by the 13 year follow-up 720 patients were tested for DPN; as 224 more patients had died or been last to follow-up. But, after 13 years they found that 78 patients (10%) had developed DPN for an annual incidence of 0.7%.

Second, they found that increased weight, waist circumference, BMI and low HDL cholesterol levels were independent predictors for developing DPN; in those patients completing at least one follow-up DPN test and after controlling for age and sex. Interestingly, they also identified from the blood samples that methylglyoxal, a highly reactive glucose-derived metabolite biomarker, was also a predictor of DPN.

What was good or bad about this study?

This study had many strengths, including: i) large number of newly diagnosed patients with diabetes from multiple sites across a nation were recruited, ii) a large number of baseline characteristics were robustly collected, iii) used a validated screening tool to diagnose DPN, iv) patients were followed up for a long period, and v) they used complex statistics that adjusted for a range of factors. But, some of the strengths of the overarching ADDITION study proved to be some of the limitations for this specific study.

These limitations included: i) patients had very well controlled blood glucose levels due to the ADDITION interventions, so there were very low numbers with hyperglycaemia and this was probably why they did not find hyperglycaemia was a predictor; ii) DPN was not the primary aim of this study so more patients than usual may have been lost to follow-up testing for DPN; iii) the MNSIQ is a screening tool and doesn’t confirm DPN, but in saying that a score of >4 is a relatively high threshold, so they may have underestimated the incidence of DPN; iv) they tested for predictors in those attending at least had one follow-up but not both; and v) this study only included those with type 2 diabetes, so we can’t necessarily translate these findings to those with type 1 diabetes

So what does that all mean?

Well, the authors summed it up nicely stating, “This study provides further epidemiological evidence for obesity as a risk factor for DPN. Moreover, low HDL cholesterol levels and higher levels of methylglyoxal, a marker of dicarbonyl stress, are identified as risk factors for the development of DPN.”

Why obesity as a risk factor we hear you ask? Well when you look through the individual predictors they found – increased weight, increased waist circumference, increased BMI and decreased HDL cholesterol –all are characteristics of obesity. These same factors have also been found in previous similar cross-sectional studies investigating DPN.

The authors also suggest that hyperglycaemia wasn’t identified as a risk factor because their patients had lower HbA1c than the general population and that hyperglycaemia would likely be a risk factor in more general populations. They also suggest the 0.7% annual incidence of DPN is also probably low because of the lower HbA1c in their patients too. Last, their finding that high levels of methylglyoxal in the blood predict DPN may suggest it could be used as a biomarker for DPN in future.

Overall, these findings highlight the link between obesity and developing DPN. Also they suggest that methylglyoxal may be a biomarker to predict or classify the severity of diabetic foot disease in future, similar to the use of eGFR to classify kidney disease. Regardless, with obesity linked to causing DPN, and DPN critical to starting the stairway to amputation, then tackling obesity early in people with diabetes should also bring us a step closer to our national goal of ending avoidable amputations in a generation.

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