Can Whole Food Plant Based Diet Reverse Neuropathy

Abstract

Introduction

Diabetic polyneuropathy (DPN) is a debilitating condition and associated with significant morbidity, including gait disturbances, reduced quality of life, and pain, that is often resistant to conventional treatments. Treatment of DPN is based on several major approaches, including risk factor management, intensive glycemic control, and symptomatic pain management. Although some authors argue that none of the existing treatment options are satisfactory, an alternative strategy is frequently overlooked: the use of a whole-food, plant-based diet. The aim of this review was to systematically investigate whether a whole-food, plant-based diet could beneficially affect patients suffering from type 2 diabetes and DPN.

Methods

The electronic databases of PubMed and Google Scholar were searched using the keywords "plant-based," "vegetarian," "vegan," "diet," and "diabetic neuropathy."

Results

Only a handful of studies investigated the effects of a plant-based diet on diabetic neuropathy. These studies suggest that a plant-based diet may alleviate pain in affected patients while significantly improving glycemic control, overweight, and serum lipids at the same time. Moreover, a plant-based diet appears to reduce the medication burden in affected patients. However, the results must be interpreted with caution, because the number of clinical trials is limited and all studies have important limitations with regard to their methodology. The dietary intervention was often combined with exercise and other supplemental factors, complicating the interpretation of results. Several potential mechanisms of action including improved blood flow and optimized intake of important nutrients were identified. These factors might complementarily contribute to improved perfusion in the endoneurial microvasculature, thus reducing local hypoxia and improving pain.

Conclusion

Physicians should consider recommending a plant-based diet to patients suffering from DPN, as current studies show favorable effects in terms of pain management, glycemic control, and reduced medication needs. Further well-designed studies are required to confirm the results of this review.

1 INTRODUCTION

The global epidemic of impaired glucose tolerance and diabetes has led to a corresponding epidemic of complications of the aforementioned disorders. ^{1, 2} One of the most prevalent complication is neuropathy—a debilitating condition for which available treatments are limited. ^{1, 3} Diabetic polyneuropathy (DPN) has a lifetime prevalence of approximately 50% and is associated with significant morbidity, including gait disturbances, foot ulcers, amputations, anxiety, depression, and reduced quality of life. ^3-5 According to Greger, DPN can be one of the most painful and frustrating conditions to treat. ⁶ In addition to that, pain is frequently resistant to conventional treatments ⁶ and some authors suggest that none of the existing treatment options are satisfactory. ⁷

Patients suffering from DPN also incur high healthcare costs due to frequent hospitalizations and outpatient visits. ⁸ It has been estimated that approximately 27% of healthcare costs of diabetes can be attributed to DPN. ^{4, 9} A review by Alleman et al revealed that both economic and humanistic burdens increase with higher pain severity. ⁸ Thus, adequate pain control is essential.

Treatment of DPN is based on several major approaches including risk factor management, intensive glycemic control, and symptomatic pain management. ^{7, 10} The latter, however, is frequently a difficult task: a 30% reduction in pain intensity is already considered a "meaningful" reduction in patients with DPN. ¹¹

One potential approach to reduce neuropathic pain is often unknown to clinicians: the use of a whole-food, plant-based or a vegan diet. Plant-based diets restrict or avoid the frequency of animal food consumption and instead emphasize vegetables, legumes, fruits, whole grains, nuts, and seeds. ^{12, 13} Plant-based dietary interventions were frequently shown to ameliorate glycemic control and other factors associated with type 2 diabetes. ^{3, 14-16} Thus, it might be reasonable to assume that a plant-based or a vegan diet could also improve clinical symptoms of DPN.

In fact, more than 25 years ago, Crane and Sample reported regression of neuropathic pain in patients who entered a 25-day lifestyle enhancement program compromising a vegan diet, exercise, and miscellaneous supplemental factors. ¹⁷ Approximately 80% of participants reported complete relief of the neuropathic pain within just 4-16 days.

It is therefore of great interest to examine how plant-based diets perform in clinical studies and whether they constitute an effective treatment option to reduce pain and other symptoms in patients suffering from DPN.

The aim of this review was to investigate on the current role of plant-based diets in DPN management and to summarize the evidence arising from other trials that followed Crane and Sample after 1994. Clinical studies and potential mechanisms of action of this lifestyle approach are examined in this review.

2 METHODS

The review question was structured using the PICOS format; the operationalization of its individual elements is described in Table 1. The electronic database of PubMed was searched using the search string ("plant-based" OR "vegan" OR "vegetarian" OR diet) AND "diabetic neuropathy." In addition to that, Google Scholar was searched utilizing the keywords "vegan," "vegetarian," "plant-based," and "diabetic neuropathy." Studies published within the last 30 years (1990-2020) were included in this review. Only English-language articles were considered for this review. Articles including original articles, review articles, and case reports/series were screened. Both uncontrolled and controlled clinical studies were included. The entire review process was conducted by the authors. Moreover, cross-references and reference lists of the included articles were manually screened for additional articles to ensure that all potentially relevant studies were identified.

TABLE 1. Use of the PICOS format, as applied to this review

PICOS format	Description
Population	Patients with type 2 diabetes aged 18 years or older suffering from diabetic polyneuropathy.
Intervention/Exposure	Dietary modification toward either a whole-food, plant-based diet, a vegetarian diet, or a vegan diet.
Comparison	No changes in diet/no dietary modification. Studies without a control group were included as well.
Outcome	Pain and other symptoms of diabetic polyneuropathy.
Study design	Prospective observational studies (randomized, both controlled and uncontrolled), case reports, and case series published in peer-reviewed journals.

Articles were included if they reported on plant-based, vegan, or vegetarian dietary interventions in patients aged 18 years or older with type 2 diabetes and DPN. Studies were also included in case the dietary component was paired with another lifestyle modification, for example, moderate exercising, to increase the number of search hits. Studies including non-plant-based dietary interventions (eg, weight reduction diets containing processed formula drinks, or fat-reduced animal products) were excluded. Lifestyle intervention studies that did not describe their dietary component in sufficient detail to ensure a vegetarian or vegan character were excluded as well.

3 RESULTS

In total, 1613 articles were retrieved from two databases (PubMed and Google Scholar). An additional seven records were found by scanning reference lists of these articles. Using the reference management software "Zotero," a total of 52 duplicate records were identified and removed. From the remaining 1568 articles, 1509 records were excluded assessing the abstract and title, based on the predefined eligibility criteria. Finally, 59 full-text articles were analyzed. Predefined quality criteria were applied and after further assessment, another 56 articles were excluded from this review (see Figure 1).

PRISMA 2009 flow diagram

The search yielded only a handful of studies that investigated the effects of a plant-based diet on diabetic neuropathy. ^{3, 17, 18} Table 2 provides, in a chronological order, an overview of the study characteristics and the precise interventions performed. Two clinical studies and one case report were identified. The included studies were published between 1994 and 2019. All studies, including the case report, were performed in the United States.

TABLE 2. Plant-based diets in diabetic neuropathy: An overview of included studies

Study	Number of Subjects	Subject type	Design	Intervention	Miscellaneous	Results
Crane and Sample (1994) 17	n = 21	Patients with T2DM and painful systemic distal polyneuropathy of moderate degree or worse.	Uncontrolled intervention study	25-day lifestyle enhancement program including (a) a calorie-reduced, low-fat, high-fiber vegan diet without refined foods and added cholesterol (b) conditioning exercise for 30 min per day	Supplemental factors: Participants were asked to avoid alcohol, tea, and coffee. Group lectures and cooking demonstrations	○ Complete relief of pain in 17 of 21 patients ○ Slight or partial relief of pain in four of 21 patients ○ Significant weight loss in 18 of 21 patients ○ Improved glycemic control ○ Improved blood pressure ○ Improved plasma lipids ○ Reduction in medication needs (antihypertensive agents)
Bunner et al (2015) 3	n = 34	Patients aged 18-65 years with T2DM and painful distal polyneuropathy	Randomized, controlled study design (n = 17 in the intervention group and n = 17 in the control group)	20-week study including a low-fat, plant-based diet. Weekly classes for support.	Vitamin B12 supplementation	○ Significant improvements in pain scores ○ Significant improvements in quality of life ○ Significant improvements in body weight ○ Improved glycemic control ○ Improved electrochemical skin conduction
McGoey-Smith (2019) 18	n = 1	51-year-old Caucasian female with T2DM and severe diabetic neuropathy in both feet	Case report	Dietary modification from a flexitarian diet to a whole-food, plant-based diet including a regimen of six servings of leafy green vegetables a day.	Dietary intervention focusing on nitrate-rich foods.	○ Significantly improved glycemic control ○ Significant weight loss ○ Regression of neuropathic pain ○ Reduction in medication needs

In 1994, Crane and Sample were the pioneers in reporting regression of neuropathic pain after initiation of lifestyle modifications including a plant-based diet. ¹⁷ The authors recruited 21 patients with adult-onset type 2 diabetes mellitus. All participants suffered from painful systemic distal polyneuropathy of moderate degree or worse. The study included 14 women and seven men. The disease had been known for a mean of 3.5 years (SD ± 2.4 years). Ninety percent of the participants were obese and the majority suffered from various other chronic degenerative diseases, including hypertension and coronary artery disease.

The patients entered a 25-day lifestyle enhancement program compromising dietary modifications, exercise, and miscellaneous supplemental factors (see Table 2). The hallmark of this intervention was the calorie-reduced, low-fat vegan diet, which also excluded any refined foods and animal products. For patients suffering from obesity (representing the majority of participants), calories were restricted to 800-1200 kcal/day. In addition to that, participants were asked to walk as briskly as they could for a minimum of 30 min or 2 miles or more per day. Other important supplemental factors can be obtained from Table 2.

Results were remarkable. More than 80% of patients reported a complete relief of their sharp and burning pain within 4-16 days. Essentially all subjects reported a symptomatic increase in the sense of touch. Four participants experienced a partial or slight relief of their symptoms. Glycemic control improved in the majority of participants. Five of 21 subjects no longer required insulin. An average reduction of 54% in insulin or hypoglycemic agent needs was observed in the remaining patients.

Approximately 85% of the participants reported significant weight loss. The average decrease in weight during the first 21 days was 4.9 kg (SD ± 2.7). Moreover, improved blood pressure control and improved serum lipids were observed in many patients. Approximately 50% of the included patients had blood pressure levels below 140/90 mmHg without medication after 3 weeks.

Of note, 17 participants could be followed for a period of 1-4 years. More than 70% of the participants had continued on the aforementioned dietary program satisfactorily. Eleven participants improved further and six remained the same after returning home.

A 2015 study by Bunner and colleagues revealed comparable results. ³ The authors recruited 34 individuals with type 2 diabetes and painful diabetic neuropathy with a minimum duration of at least 6 months. The study cohort included participants between the ages of 18 and 65 years. After an initial screening for vitamin B12 deficiency, patients were randomized either to the study's intervention group or to the control group. The intervention encompassed a low-fat, plant-based diet that excluded animal products. The diet favored low glycemic index foods and daily fat intake was limited to 20-30 g. Furthermore, patients were asked to take 1000 mcg of methylcobalamin per day. The control group was also told to take the vitamin B12 supplement; however, they were not intended to make major dietary changes. Finally, participants in the intervention group received weekly classes including nutrition counseling and counseling as well as social support to increase dietary adherence. Whenever possible, participants were told to keep their diabetes medication constant during the trial; however, in case of hypoglycemia, they were asked to follow the advice of their personal physicians.

To assess the impact of the plant-based diet intervention, the authors gathered both clinical and laboratory data. Moreover, several questionnaires were used to evaluate pain and sensory symptoms (primary outcomes). Questionnaires included the analog "worst pain" scale, Short Form McGill Pain Questionnaire, ¹⁹ Michigan Neuropathy Screening Instrument questionnaire, ²⁰ and global impression scale. ²¹

Upon completion of the study, the authors noted significant improvements in pain among those subjects in the intervention group. ³ Participants who followed a plant-based diet for 20 weeks had significantly lower pain scores on the Short Form McGill Pain Questionnaire. The authors reported a statistically significant decline by 9.1 points in the intervention group and a decline by 0.9 points in the control group. Although not statistically significant, quality of life also improved in the intervention group. Pain, as measured by the Neuropathy Total Symptom Score, improved significantly within the intervention group; however, intergroup differences were not significant.

In addition to that, body weight declined significantly by a mean of 7.0 (SD ±5) kg in the intervention group, as compared to only 0.6 (SD ±3.5) kg in the control group. Serum lipids also improved. Total cholesterol declined by 12.1 mg/dL in the intervention group, but just 2.2 mg/dL in the control group (P = .20). Low-density lipoprotein cholesterol decreased by 7.8 mg/dL in the dietary intervention group and increased by 0.4 mg/dL in the control group. Although hemoglobin A1c remained unchanged in the control group, a significant reduction (mean –0.8%) was observed in the intervention group. The authors also emphasized that electrochemical skin conductance in the foot improved in the intervention group, suggesting that the plant-based diet may have slowed or halted sudomotor nerve function decline.

Finally, the literature research revealed a case report by McGoey-Smith and colleagues. ¹⁸ This recently published case study describes in detail the clinical case of a 51-year-old Caucasian woman who suffered from uncontrolled hypertension, pulmonary hypertension, and type 2 diabetes with a baseline hemoglobin A1c of 15.1%. The patient also reported severe diabetic neuropathy in both feet that was treated with gabapentin.

Regarding her pulmonary hypertension, the patient was prescribed a variety of drugs, including pulmonary arterial vasodilators and diuretics. However, she experienced limited amelioration of her symptoms and looked for other alternative treatment strategies. After consultation of a renowned expert in the field of nutritional medicine (Dr Caldwell B. Esselstyn, Jr.) and after attending a whole-food, plant-based dietary educational program, the patient switched her diet. She subsequently eliminated all animal-derived products and vegetable oils. Besides, she avoided processed foods and added six servings of leafy green vegetables to her diet.

Although this case report focuses on pulmonary hypertension, other beneficial effects of this dramatic dietary changes are described. Within 15 months, hemoglobin A1c levels dropped from 15% to 5.6%. The patient no longer used diabetes medications and lost approximately 50 kg. Of note, regression of the severe neuropathic pain in both feet was reported and the patient no longer required gabapentin.

It has been suggested long ago that lifestyle modifications may beneficially affect peripheral neuropathy in individuals with impaired glucose tolerance and diabetes. Unfortunately, this review revealed that clinical trials specifically including plant-based nutrition as the major component are scarce. Our structured literature research revealed that only one clinical study followed the uncontrolled intervention trial by Crane and Sample. ^{3, 17} The number of studies on this topic is severely limited and only the trial by Bunner and colleagues included a control group. Given the heterogeneity of the studies, the authors refrained from a meta-analysis.

Moreover, this review revealed that none of the aforementioned studies were intended to elucidate the exact molecular mechanisms by which a plant-based dietary intervention can lead to physical and symptomatic improvements. Thus, there is a lot of room for speculations and the authors of the respective articles raised several different potential mechanisms of action.

The literature research for this review also revealed two other important papers with regard to the subject under discussion: a commentary by Greger and a hypothesis paper by McCarthy. ^{6, 17} Both investigated potential mechanisms of action involved, which are presented in the second part of the results section below.

Treatment of DPN is based on several major approaches including risk factor management and intensive glycemic control. ^{7, 10} A low-fat, plant-based diet emphasizing whole grains, fruits, vegetables, and legumes was repeatedly shown to improve insulin sensitivity and leads to better glycemic control. ^22-24 Plant-based diets reduced hemoglobin A1c levels in multiple studies ^{25, 26} and a 2014 meta-analysis indicated that adhering to this diet resulted in a statistically significant lower mean hemoglobin A1c (–0.39 percentage points [95% CI, –0.62 to –0.15], P = .001) when compared to A1C among participants from control diets. ²⁷ Multiple potential mechanisms underlie the benefits of a plant-based diet in ameliorating insulin resistance and glycemic control, including decreased intake of saturated and trans fats and increases intake in fiber, phytonutrients, and polyunsaturated fatty acids. ^{28, 29}

Modifiable risk factors of DPN include hyperglycemia and diabetes duration as well as hypertension, dyslipidemia, and obesity. ^{30, 31} It is of paramount importance that literally all these variables can be ameliorated with a plant-based diet. ^32-35 The participants in the study by Crane and Sample and in the trial of Bunner and colleagues experienced significant improvements in terms of weight, blood pressure, and glycemic control. ^{3, 17} Thus, this could be one potential (indirect) factor for the significant DPN improvements as reported by the study subjects. It is worth considering that other factors might complementarily contribute to pain reduction.

As outlined by Greger, it took approximately 10 days to control the diabetes in the study by Crane and Sample; however, some patients reported pain reduction after only 4 days. ^{6, 17} This is a clear indicator that other (and more immediate) dietary factors may play a crucial role in pain alleviation. According to McCarthy, concurrent marked improvements in glycemic control presumably contributed to this benefit, but were unlikely to be solely responsible. ³⁶

McCarthy suggested that improved blood rheology (mainly due to decreased blood viscosity) played a prominent role in mediating the analgesic effect in Crane's study. ³⁶ There is considerable evidence that both altered blood flow in the endoneurial microvasculature and endoneurial ischemia are important factors in the etiology of diabetic neuropathy. ^36-39

Factors contributing to impaired perfusion and peripheral nerve hypoxia in patients suffering from diabetes include (a) decreased endothelial production of the vasodilator nitric oxide and (b) an increase in blood viscosity constituting an unfavorable rheologic change (see Figure 2). ^{36, 40-42}

Hypoxic nerve damage due to occluded vasa nervorum, decreased endothelial production of nitric oxide, and increased blood viscosity. Modified from refs. 41 and 42

A whole-food, plant-based diet may improve both conditions ¹⁸ and was shown to restore the ability of endothelial cells to produce nitric oxide. ^43-45 Vegetables are the major source of nitrate and a single plate of green leafy vegetables contains more nitrate than is formed endogenously over an entire day by all three nitric oxide synthase isoforms in the human body combined. ^46-48 In the aforementioned case report, the patient consumed at least six servings of green leafy vegetables a day. ¹⁸ The high intake of nitrate-rich green leafy vegetables is a central aspect of many whole-food, plant-based diet treatments and a key feature in many lifestyle programs targeting improved vascular health. ^{18, 49} The latter may allow for improved endoneurial blood flow, thus reducing endoneurial ischemia and subsequently peripheral nerve hypoxia.

In contrast, plant-based diets were reported to improve blood viscosity and filterability. ³⁶ Abnormal hemorheology, and blood hyperviscosity in particular, can substantially impair microcirculatory flow in patients suffering from diabetes, thus contributing to endoneurial ischemia. ^{36, 50, 51} The blood of individuals with diabetes has been frequently reported to be more viscous than that of aged-matched healthy controls. ^{36, 52, 53} This, in turn, may plug capillaries and effectively reduce their diameter, thus promoting local hypoxia and lactic acidosis that both subsequently worsen microangiopathy. ^53-55

Consuming a plant-based diet may also help here. Decades ago, Ernst et al published data on rheological parameters of omnivores and vegetarians. ⁵⁶ The latter had a significantly lower blood viscosity. In vegetarians, values for packed cell volume were lower than those in controls, leading to reduced native blood viscosity. A newer study indicated that regular consumption of a simple vegetable soup for 6 weeks already has the potential to significantly improve blood rheology. ⁵⁷ It is not inconceivable that the rheologic impact of a regular plant-based diet, which maximizes the intake of plants and green leafy vegetables, is even greater.

A study published in the 1980s investigated the effects of another lifestyle program: The Pritikin-program. ^{36, 58} This program combined a quasi-vegan, whole-food diet with walking exercise on a daily basis. ^{59, 60} Noteworthy, this diet allows small amounts of low-fat milk. ⁵⁹ The aforementioned investigation revealed that after 3 weeks on the Pritikin-program, blood viscosity and hematocrit as well as red cell aggregation declined substantially in participating subjects. ⁵⁸ Blood viscosity (in mPa·s at a shear rate of 180/s) decreased significantly (P < .01) from 5.52 (SD ± 0.67) to 5.04 (SD ± 0.75). In contrast to the Pritikin-program, however, the diet used in the study by Crane and Sample is stricter and completely eliminates animal products. Thus, an even great effect is most likely. ³⁶ In light of these findings, it is conceivable that that a plant-based diet may significantly alter blood viscosity and beneficially affects microcirculation in patients suffering from diabetes (see Figure 3).

Restored blood flow using a whole-food, plant-based diet. Improved hemorheology and optimized intake of antioxidants and other important nutrients such as nitric oxide and magnesium complementarily contribute to improved blood flow in the endoneurial microvasculature. Modified from refs. 41 and 42

More recent research emphasizes the role of (low-grade) inflammation in diabetic neuropathy. ^61-63 It becomes more and more apparent that long-term low-grade inflammation has an important role in the pathogenesis of this disease. ^{61, 63} In fact, pro-inflammatory cytokines may lead to neuroinflammation, thus causing direct nerve tissue damage. ⁶² Although mechanisms are still insufficiently understood, it is conceivable that an anti-inflammatory diet could be beneficial in affected patients. A plant-based diet is rich in dietary phenolic compounds and protein from plant sources, which both were associated with beneficial changes in total inflammatory burden. ^{64, 65}

Ultimately, the high magnesium content of plant-based diet is also a crucial factor. ^{66, 67} Hypomagnesemia has been reported at increased frequency among patients with type 2 diabetes. ^{68, 69} Moreover, lower serum magnesium levels were shown to significantly correlate with impaired peripheral nerve function in this cohort. ^{70, 71} Magnesium supplementation can improve both glycemic control and insulin sensitivity ^{72, 73} and can also favorably affect the natural evolution of DPN. ⁷⁴ These findings suggest that the high magnesium content of plant-based diets may also have a beneficial effect on DPN.

4 DISCUSSION

Plant-based nutrition receives more and more attention by the broader medical community. There is now considerable evidence that a plant-based diet is a powerful tool in the prevention and treatment of type 2 diabetes. ^{14, 16, 75, 76} A plant-based diet may also exert beneficial effects with regard to many other chronic lifestyle-related conditions, including obesity and hypertension. ^{32, 35, 33} As such, tackling DPN—one of the most prevalent complications of diabetes—with a plant-based diet seems a reasonable strategy.

This literature review examined how vegan and plant-based diets performed in clinical studies in individuals suffering from DPN and whether they constitute an effective treatment option to reduce pain and other symptoms. The systematic literature research yielded only a handful of studies that investigated the effects of a plant-based diet on diabetic neuropathy. ^{3, 17, 18} Participants frequently reported partial or complete relief of the neuropathic pain; however, the studies are inhomogeneous and have important limitations that are discussed in detail below. This review also revealed that most study participants were able to reduce their daily medication, ^{3, 17, 18} a phenomenon that is consistently observed in patients with type 2 diabetes during plant-based dietary intervention studies. ⁷⁷

Considering these findings, a plant-based diet may help to alleviate pain in DPN while significantly improving glycemic control, overweight, and serum lipids at the same time. ^{3, 17, 18, 36}

Nevertheless, there are several limitations to consider. The number of studies in this particular field is severely limited. Except from the work by Bunner and colleagues, ³ other published data are based on a case report and an uncontrolled intervention study. ^{17, 18} As postulated by McCarthy, some of the literature on that topic is very difficult to locate. ³⁶ For instance, we were not able to trace an older study conducted by DeRose and Charles Marcel that apparently reported clinically and statistically significant effects of a vegan diet along with exercise in the treatment of individuals with diabetic neuropathy. ^{36, 78}

Furthermore, all studies and case reports used the whole-food, plant-based diet as component of a holistic lifestyle medicine approach. The work by Crane and Sample serves as a paradigm for that. ¹⁷ The authors combined the dietary modification with other important lifestyle medicine approaches, including exercise, group sessions, and supplemental factors, such as adequate sunshine and recreation. Regular supervised aerobic exercise itself has been shown to be a safe method that can lead to significant reductions in pain and neuropathic symptoms in individuals with DPN. ^79-82 Regular physical activity was also associated with an increase in nitric oxide bioavailability, which can improve endoneurial blood flow and subsequent peripheral nerve hypoxia. ^{83, 84} It is therefore impossible to determine which part of the intervention in Crane's study promoted the observed clinical improvements. Although the dietary modification was probably the key element, other factors such as abstinence of processed foods and weight loss do play a critical role. From a clinical perspective, both a healthy diet and regular exercise might be key components of a holistic lifestyle medicine approach to tackle DPN. The fact that Bunner and colleagues did not require patients to exercise regularly, however, could serve as an indicator that diet alone may favorably affect symptoms of DPN. Nevertheless, the conditioning exercise component in Crane and Sample's study is an important confounder with regard to the topic of this review.

In addition to that, the study by Crane and Sample included caloric restriction for almost all participants. ¹⁷ Calories were restricted to about 800-1200 kcal/day, which could also be an important confounder. It is now more and more accepted that substantial weight loss—achieved by any means—can bring about significant improvements or even remission of type 2 diabetes. ^85-87 It appears therefore legitimate to argue that the weight loss in Crane's study played a crucial role in the improvements in metabolic control as well as in the amelioration of DPN symptoms in the study participants.

In fact, one could argue that the metabolic improvements associated with weight loss in Crane's study were primarily responsible for the clinical DPN improvements. In support of the vegan diet itself, however, it is important to note that a recent randomized controlled trial of five different diets indicated that vegan diets may result in greater weight loss than more modest dietary recommendations. ⁸⁸ Another recent study by Barnard and colleagues revealed that a low-fat, vegan diet and a portion-controlled eating plan (including a calorie deficit of approximately 500 calories/day) lead to comparable clinical improvements in individuals with type 2 diabetes. ¹⁶ In light of these findings, it might actually be legitimate to recommend a noncalorie-restricted, plant-based diet that induces weight loss while being high in fiber, important micronutrients, and nitric oxide-rich components that were also shown to favorably affect DPN. The anti-inflammatory effects of plant-based diets deserve special mentioning in this discussion, ^89-91 given the central role of inflammation in pathologic changes of DPN. ^{92, 93}

Finally, it is important to note that Bunner and colleagues used a vitamin B12 supplement in their study, which could also have had real effects. ³ On the other hand, a recent review found no evidence that the use of oral vitamin B12 supplements is associated with improvement in the clinical symptoms of diabetic neuropathy. ⁹⁴

In addition to that, the authors noted that the self-reported nature of pain constitutes an intrinsic limitation of pain research. Ultimately, painful diabetic neuropathy as an inclusion criterion was potentially not precise enough. More detailed information on diagnosis, disease duration, and previous treatments could help to determine who benefits the most from this lifestyle intervention.

This review itself has also important limitations and shortcomings that are worth mentioning. First of all, the search strategy of this review implies several limitations. Studies were considered for this review, even though they combined a plant-based diet (or vegan diet, respectively) with exercise or other supplemental factors. The latter might be important confounders that deserve mentioning. The search strategy excluded studies and interventions that contain low amounts of meats and fish, such as the Mediterranean diet. To increase the number of search hits, uncontrolled studies and case reports were included. This decision led to inhomogeneity with regard to the studies included in this review. Another limitation from this review is that, despite plausible inclusion and exclusion criteria as well as a wide search strategy, some articles published in other databases than PubMed and Google Scholar could have been potentially overlooked by both reviewers.

5 CONCLUSION

A plant-based diet may alleviate pain in DPN while significantly improving glycemic control, overweight, and serum lipids at the same time. Moreover, plant-based nutrition may help to reduce the medication burden in patients suffering from diabetes. Considering the evidence for a plant-based diet in the management of DPN, however, the number of studies is severely limited. Only two clinical trials, one of them with an uncontrolled design, were found while conducting this review. None of these studies were intended to elucidate the exact molecular mechanisms by which this dietary modification can lead to physical and symptomatic improvements.

Reviewing the existing literature, we provided several possible explanations. These include improved glycemic control, enhanced risk factor management, improved hemorheology, and optimized intake of antioxidants and important nutrients such as nitric oxide. All factors might complementarily contribute to improved blood flow in the endoneurial microvasculature, thus reducing local hypoxia and improving pain. We also discussed the limited literature on that topic, confounding factors in the study design, and the need for further trials to confirm the findings of this review. This systematic literature review finally revealed that following McCarthy's analysis in 2002, ³⁶ only a limited amounts of direct evidence with respect to plant-based diets and their direct benefits on DPN have arisen. Although plant-based diets have an enormous potential and although the research on plant-based diets is definitely a blossoming field of study, ⁹⁵ more research on its molecular effects and larger trials including plant-based diets in DPN management are desirable.

Referring to the study of Crane and Sample, ¹⁷ McCarthy postulated that the neglect of their important work is "little short of unconscionable," ³⁶ In fact, the number of existing studies on that topic indirectly indicates that this lifestyle medicine approach still receives insufficient attention with regard to that particular disease.

It is the author's hope that this review could contribute to a gradual change here and serve as a stimulus to initiate more clinical trials.

The study of Crane and Sample included patients with painful systemic distal polyneuropathy of moderate degree or worse. They were in desperate need of help—because standard treatments could no longer alleviate their pain. A lifestyle intervention with a plant-based diet as its major component rapidly improved their overall situation. Isn't it worth to try this cost-effective and side-effect-free approach in every patient suffering from DPN?

ACKNOWLEDGMENT

The authors would like to thank Maria Brommer (MD) for providing us with the figures for this publication.

AUTHOR CONTRIBUTIONS

Maximilian Andreas Storz and Onno Küster conceptualized the study. Maximilian Andreas Storz and Onno Küster done the literature research. Maximilian Andreas Storz and Onno Küster contributed with formal analysis. Maximilian Andreas Storz prepared the original draft. Maximilian Andreas Storz and Onno Küster reviewed and edited the manuscript. Maximilian Andreas Storz visualized the study.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

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Can Whole Food Plant Based Diet Reverse Neuropathy

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