Gut Health Series: Diabetic Enteric Neuropathy

Disclaimer:
I am not a medical doctor, and the information presented in this article is for informational and educational purposes only. It is not intended as medical advice, diagnosis, or treatment. Always consult with a qualified healthcare professional before making any changes to your diet, lifestyle, or healthcare regimen. All opinions expressed are my own and do not reflect the views of any organizations or institutions.

Perform a quick google search on diabetic neuropathy, or ask your doctor the top complications you should be concerned about, and these will be top of mind: eyes, fingers, toes. The focus on diabetic retinopathy and diabetic peripheral neuropathy truly dominate the discourse on hyperglycemic-induced nerve damage. This is not surprising, as the idea of losing one’s vision or extremities is daunting. Thus, our endocrinologists always ensure to tap our feet to check for sensation, and prompt us to go to our eye doctor once a year for our full retina scans. Standard patient education and the neuropathy discourse are lacking consideration for the multitude of ways neuropathy can manifest itself in the body – I certainly wasn’t aware before writing this article. Many diabetics are not aware of the complications until it is too late and they get a surprise diagnosis. In this article, I will explore the underlying pathology of diabetic enteric neuropathy, highlight key biological processes that influence everyday health, and share practical preventative measures. We’ll also examine various solutions—including dietary strategies, diabetes management, holistic approaches, and tips for maintaining a healthy lifestyle—to empower you with knowledge and actionable steps.

While neuropathy is a commonly discussed condition, its potential impact on the digestive system was something I had not encountered in conversations with healthcare professionals. While research results vary, the articles I studied reported that 30–70% of diabetic patients showed some form of gut dysfunction or complications. About 50% of people with long-term diabetes experience gastrointestinal symptoms.¹  I had always assumed that research on the gut was limited, so I was surprised to discover the breadth of knowledge available on the subject. Although studies on this topic are complex and multifactorial, researchers are making impressive strides in uncovering the connection between gut health and diabetes—which is linked to premature aging, gastrointestinal issues, and widespread metabolic dysfunction throughout the body.  I don’t know about you, but if my healthcare team had told me when I was diagnosed, “Hey, having high blood sugars will permanently damage your DNA—which, by the way, can be passed on to your children, since we now know that epigenetic changes occurring throughout life can be inherited. Also, it will damage your cellular health. You’ll lose collagen more quickly, making it much harder to age gracefully or replenish your collagen stores—so be prepared to get wrinkly and lose that glow early. If you think you get sore after exercising now, just wait. Your joints will become creakier and stiffer at a rapid rate, right when you should be in your prime. Oh, and elevated TNF levels will weaken your immune system, making you more vulnerable to secondary autoimmune diseases. Think IBS-like symptoms, or feeling like your food just sits painfully in your stomach for hours, causing daily bouts of nausea and constipation.” —well, that might have scared my 15-year-old self straight. Instead, I got: “Oh yea, there will be complications down the line such as vision problems and numbness in fingers and toes…” I mean, which one sounds more imminent and intimidating? A far-off complication, or the idea of your cells exploding, dying, and opening up pathways for inflammation and affecting every single system of your body? The reality is, we need to give extra consideration to reducing inflammation and oxidative stress through pointed measures.

The ENS and AGEs

Neuronal damage culminates in diabetic enteric neuropathy (we’ll refer to as DEN), just the same way that neuronal damage causes diabetic retinopathy and other complications. DEN is generally understood to be caused by hyperglycemia damaging the blood vessels, which impairs nerve functions. It appears to be a starting point for other gastroenterological problems- for example, gastroparesis is just one manifestation of DEN. Adding to the confusion is the fact that the symptoms of DEN can be misconstrued as other conditions or perceived as temporary. These symptoms include nausea, vomiting, early satiety, abdominal bloating, diarrhea, abdominal discomfort, delayed gastric emptying, heartburn, and regurgitation. ^1,4

First, a quick background on how the nervous system works in the gut. Humans have three divisions of the autonomic nervous system: the enteric nervous system (ENS), the parasympathetic nervous system (PSNS) and sympathetic nervous system (SNS). The enteric nervous system is of special interest because it is the only substantial grouping of neurons outside the central nervous system that form circuits capable of autonomous reflex activity. In humans it contains around 500 million neurons that fall into about 20 functional classes. It has been likened to a second brain. The enteric nervous system is composed of thousands of small ganglia, the nerve fibers that connect the ganglia, and nerve fibers that supply the muscle of the gut wall, the mucosal epithelium, arterioles, and other effector tissues. Around 2-600 million neurons are contained in the enteric nervous system, which is comparable to the number of neurons in the spinal cord.²

The most important aspect to remember about the ENS is that its neurotransmitters facilitate the motor, sensory, absorptive, and secretory functions of the gastrointestinal tract. The ENS receives regulatory signals from the central nervous system; however, it is also capable of independent function. These functions range from the propulsion of food to nutrient handling, blood flow regulation, and immunological defense. This chart that follows, gives a brief overview of some illnesses where the ENS is involved and possesses potential therapeutic properties.³

Those are the symptoms, but how is it caused? In type 1 diabetes, enteric neuropathy is often associated with prolonged disease duration and suboptimal glycemic control, where hyperglycemia and autoimmune-related inflammation are primary contributors. A key feature of this alteration is the accumulation of advanced glycation end-products (AGEs).⁴

The biological concept that we’re about to review could save you years of confusion on what is really going on when you have a high blood sugar (and will be a little more detailed than the key and lock analogy).

“The process by which sugar sticks to stuff is called glycation. glycation reactions are reversible, but with enough heat or time, the temporary bonds become permanent due to oxidation reactions. The products of these later oxidation reactions are called advanced glycation end-products, or AGEs. AGEs cross-link normally mobile proteins, hardening your cells and tissues, making them brittle and stiff. At normal blood sugar levels, the reactions occur so slowly that cleanup crews of white blood cells keep them under control by breaking them down. The kidney cleans these AGEs from the blood and excretes them from the body. It follows that the more cross-links you have, the more your immune function is impaired. AGEs are a primary reason diabetics develop circulatory problems. Over the life of a red blood cell (three months or so), the protein-rich red cell sops up sugar like a sponge, growing stiff and bloated. One of the jobs of the spleen is to test the quality of red blood cells in active circulation. Any cell too puffed up with sugar gets destroyed. But when sugar levels are high all the time, the spleen can’t remove all the bloated cells quickly enough, so they wind up clogging tiny capillaries.”⁵

This excerpt taken from Dr. Shanahan’s “Deep Nutrition” was the first I’d ever heard of an advanced glycation end-product, and I think her visual writing is a great way to understand the process. Before you freak out and never eat a carbohydrate again, it is important to know that there are two types of AGEs: endogenous AGEs are formed in the body as part of normal metabolic processes, contribute to normal age-related physiological decline, and are directly involved in the pathogenesis of degenerative musculoskeletal conditions (think of osteoporosis, or your joints getting stiffer and stiffer as you age). The number of these are due in part to glucose concentration, age, and genetics. Exogenous AGEs, however, are entirely in our control, which newer research is finding are primarily from the diet, and are present in particularly high concentrations in foods which have been cooked at high temperatures, are highly processed, or have been prepared for long-term storage, in addition to tobacco and alcohol products.⁶

Us diabetics are often told we can eat anything we like, as long as we administer the correct amount of insulin. While a dietitian might briefly review portions or explain low glycemic index foods to us, the deeper ‘why’ behind food choices draws a blank. What occurs at the cellular level is quite contrary to the ‘just give insulin’ mindset- overlooking metabolic stress, inflammation, and insulin resistance that certain foods can trigger, regardless of insulin dosing.

AGEs: the enemy 

AGEs as a primary source of inflammation is a novel discovery for me, especially considering it is not something discussed in the diabetes canon, nor is reducing inflammation as a whole. In fact, inflammation, glycation, and oxidative stress are the underpinning terms referred to in nearly every article regarding gut health and diabetes complications. Even for non-diabetics, exogenous AGEs can contribute to major epigenetic changes that can culminate in auto-immune conditions and health issues that may have been entirely preventable. These AGEs bind to their specific receptors (RAGE) on neuronal cells, leading to a cascade of oxidative stress and inflammatory responses. This chain of reactions impairs neuronal function and promotes apoptosis, predominantly affecting neurons that regulate GI motility and secretion.⁴  Chronic hyperglycemia can trigger autoimmune responses, resulting in inflammation and subsequent damage to the ENS. The integrity of the GI barrier is compromised in chronic diabetes, partly due to the elevated levels of pro-inflammatory cytokines. These cytokines induce stress and apoptosis in neuronal cells, further exacerbating neuropathic conditions. The resulting inflammation, along with compromised GI mucosal barrier integrity, increases gut permeability, allowing more harmful substances to directly affect the ENS and aggravate neuropathic symptoms. Resultant restricted blood flow impairs essential nutrient and oxygen delivery to enteric neurons and glial cells, exacerbating neuronal damage and dysfunction. This state furthers the degeneration of neural networks in the GI tract, compounding neuropathy’s impact. This interaction is essential for maintaining GI motility and overall gut health. An imbalance in gut microbiome composition has been identified as a key factor influencing both gut motility and neuronal function. This dysregulation presents novel therapeutic targets, offering significant potential for the management of diabetic enteric neuropathy. Epigenetic changes, including DNA methylation and histone acetylation, influence gene expression in diabetic patients. These epigenetic modifications may affect genes crucial for neuronal health and function, thereby playing a significant role in the development and progression of DEN.⁴

Ok- now that we’re past all the really sciency bits, we can discuss what this means in a real-life sense. The personal accounts I’ve read show that diabetics usually get these GI complications in the 10-20 year after diagnosis range, which is confirmed by the research stating prolonged disease duration is a causative factor. Some diabetics get it after fewer years, but with the necessary factor of high A1Cs or other comorbidities. Regardless of duration of diabetes diagnosis, persistent A1Cs over 7.0% are the most important factor. On a human level, diabetics with GI disturbances seem to be very isolated and suffering in a unique way. Some say the diarrhea never stops, even with high amounts of daily imodium supplementation. In addition to close monitoring of their carb count, with many of them barely grazing 60 grams of carbs a day,  they also have to consider the amount of starch and fiber they consume, watch portion sizes, and eliminate most foods. All patients differ, with each patient’s symptoms necessitating a strange cocktail of antiemetics or laxatives. One encouraging sign I’ve seen is in people who once struggled with dangerously high blood sugar levels—experiencing DKA, temporary vision loss, and frequent hospital visits—but who made dramatic lifestyle changes. By cutting out processed foods and establishing consistent eating and exercise routines, they’ve not only reduced their symptoms but, in some cases, even reversed them.⁷ The same has been seen in accounts of peripheral neuropathy. DEN patients seem to go through months of rigorous testing, sometimes never culminating in a single diagnosis– or they don’t fit exactly into the criteria, so the doctors don’t treat them accordingly. In any case, it is a life-long adjustment with diet, various medications, and lifestyle.⁸ Non-specific GI symptoms, the lack of standardized diagnostic criteria, the limited availability of specialized tests, and challenges in interpreting test results all add layers of complexity. Furthermore, the variability in patient presentations, the overlap with other diabetic complications like peripheral neuropathy and autonomic dysfunction, and the potential for psychological factors and functional GI disorders like irritable bowel syndrome to mimic neuropathy symptoms, complicate the diagnosis.⁴ Once the absorption rate of food has become so unpredictable or spontaneous, blood sugar management has to emphasize avoiding hypoglycemia as they try to bring their hypers under control. Seeing how difficult it is living with this condition, my aim is to help even one person avoid it by knowing what steps to take.

Now that we know oxidative stress, glycation, and inflammation are the main culprits behind DEN, the question remains of how we can limit our exposure to these processes to the best of our abilities, in order to prevent the myriad of consequences which we’ve discussed. The solutions I will discuss at great length include: antioxidants, a low-AGE diet, fostering a healthy gut microbiome, maintaining an A1C under 7.0%, vagus nerve stimulation, and limiting smoking and alcohol consumption.

Antioxidants

Dietary antioxidant nutrients, including vitamins and trace elements, play a major role in regulating antioxidant/oxidative stress pathways that have close implications in insulin signaling and glycemic control. Scientific interest has been growing in connecting the role of oxidative stress and the pathogenesis of diabetes and its complications. While there are a lack of studies on type 1 diabetics, this review of copious studies determined an antioxidant-rich diet has been found to decrease oxidative markers and improve insulin sensitivity in type 2 diabetics, and that a diet rich in polyphenolic compounds benefits glucose homeostasis through multiple and complex mechanisms of action in various human body organs such as the intestine, liver, muscle, adipocytes, and pancreatic β-cells.¹⁸  Further, another study showed that biomarkers of oxidative stress are associated with vascular stiffness and diabetic kidney disease (DKD) following acute and chronic hyperglycemic exposure and may predict risk levels for secondary complications of type 1 diabetes. To put this into perspective, imagine if in addition to our standard quarterly lipid panels and A1C, we also did an oxidative stress test that would predict complications and areas that we can improve upon in our diet and lifestyle? My hypothesis is, that as medical technology improves, the number of routine tests will be expanded as patients continue to advocate for preventative medicine practices. After all, the panels a functional medicine doctor performs provide much deeper insight as opposed to the lipid panel ordered by the endocrinologist. While there are not many studies showing a direct correlation to increased antioxidant consumption and improved type 1 diabetic outcomes, there have been a myriad of studies done on high-antioxidant diets, mainly the Mediterranean diet, which we can extrapolate from to draw conclusions about how antioxidants can improve health overall. It is not necessarily groundbreaking information that fruits and vegetables contribute to better health: the Mediterranean diet was recognized in 2003 by the WHO as a model of a healthy diet for both children and adults. The diet has antioxidant, chemopreventive, anti-inflammatory effects, and it decreases triglyceride levels and cholesterol, as well as postprandial hyperglycemia. Thus, it prevents many diseases including atherosclerosis and some cancers.¹⁷ What’s groundbreaking, in my view, is that despite the wealth of information on the healing properties of antioxidants, the first step after a type 1 diabetes diagnosis is not for doctors to recommend an antioxidant-rich diet. The commonalities are striking in the overlap of the Mediterranean diet, the low AGE-diet, and the foods highest in antioxidants. The consensus between many articles seems to be that low-glycemic index, low AGE foods rich in folic acid, zinc, magnesium, iron, and dietary fiber, along with lean meats, animal fats, and healthy oils, protect our cells from oxidative damage in various ways. They also benefit the cardiovascular system, improve LDL and HDL cholesterol levels, and help regulate interprandial blood sugars in type one diabetic children, as highlighted in a Polish research study.¹⁷ How many cases of DEN, in addition to other complications, could have been prevented if this had been instituted by doctors at the beginning of the diabetes journey?

Mechanisms of Antioxidants

Antioxidants have been shown to exert a neuroprotective effect by reducing reactive oxygen species (ROS), modulating inflammation, and supporting neuronal survival. The integration of antioxidant interventions with lifestyle modifications and personalized approaches has led to the development of comprehensive preventive strategies that effectively address the multifactorial nature of neurodegeneration.⁹ Combating oxidative stress through antioxidants is one way to reduce neuronal damage. Oxidative stress, defined as an imbalance between the production of reactive oxygen species (ROS) and the body’s ability to neutralize them with antioxidants, is a key mechanism underlying neuronal damage, loss of nerve connections, and neuroinflammation. Antioxidants being the antithesis of oxidants, therefore delay or prevent the oxidation of other molecules by donating electrons to free radicals. This process helps break chain reactions that can damage cells. In essence, antioxidants are substances that protect cells from damage caused by free radicals, which are unstable molecules produced during normal cell metabolism. Oxidative stress exacerbates neuronal damage by promoting lipid peroxidation, protein misfolding, and DNA damage. Antioxidants, including polyphenols, vitamins, and flavonoids, have been shown to play an important role in modulating the gut microbiota to reduce oxidative stress. One of the main mechanisms by which antioxidants exert their beneficial effects is by promoting the growth of beneficial gut bacteria, such as Bifidobacterium and Lactobacillus. These bacteria are known for their ability to ferment dietary fiber and produce beneficial metabolites, particularly SCFAs (short-chain fatty acids), including acetate, propionate, and butyrate. SCFAs are critical for maintaining gut health by reducing oxidative stress and inflammation in the gut. In particular, SCFAs have been shown to reduce the production of ROS in intestinal cells, thereby protecting intestinal epithelial cells from oxidative damage and helping to maintain a healthy intestinal mucosa.⁹

Foods that stimulate the production of SCFAs include whole grains such as:

• oats
• brown rice
• quinoa

legumes such as:

• beans
• lentils
• peas

fruits and vegetables such as:

• apples
• berries
• asparagus
• onions
• garlic

and nuts and seeds such as:

• almonds
• chia seeds
• flaxseeds

You may notice when simmering fruits such as apples and cranberries that a clear slime will develop; this is the pectin, a soluble fiber, being extracted, and is not only used for jams and jellies, but is converted into SCFAs in your large intestine. (One of my favorite processes in making homemade jams and apple pies, low sugar of course). Foods rich in polyphenols, such as:

• cloves
• blueberries
• plums
• cherries
• apples
• strawberries
• black currants
• black olives
• dark chocolate
• black tea
• hazelnuts
• pecans
• green tea
• blackberries
• walnuts
• pomegranates

promote the growth of beneficial bacteria while suppressing pathogenic species. Polyphenols are metabolized by the gut microbiota into bioactive compounds with potent antioxidant properties. These compounds, including phenolic acids and flavonoids, help to restore microbial balance and reduce inflammation in the gut. By increasing the gut’s ability to produce natural antioxidants, dietary interventions not only improve gut health but also enhance communication along the gut–brain axis, reducing oxidative stress and neuroinflammation in the brain. This includes the use of such molecules as resveratrol, curcumin, vitamin C, vitamin E, and β-carotene, which have been shown to modulate the composition and function of the gut microbiota by reducing ROS levels in the gut and increasing the expression of antioxidant enzymes, such as glutathione peroxidase, in intestinal cells.⁹  Essential oils from spices and herbs, such as:

• oregano
• thyme
• dittany
• marjoram
• lavender
• rosemary

have also been demonstrated to be excellent sources of natural antioxidant molecules.¹⁰ (Please consult with your doctor before experimenting with essential oils, I have experimented with oregano oil and it shoots my blood sugar extremely low). Tea extracts have also been used as sources of natural antioxidants because of their contents of several compounds, such as catechins, tannins and other flavonoids.

All diabetics can take the step of incorporating more antioxidants into their diet through simple swaps like green tea instead of coffee, or making a sandwich at home instead of buying one premade with 50 ingredients that include gums, shelf stabilizers, colorants, flavoring, added sugars, etc. The goal is not to feel limited, but rather to feel empowered to make healthier decisions that will protect your neurons, protect the ENS and CNS, maintain healthy DNA to pass on, and subsequently enjoy a better quality of life that is synonymous with lower inflammation.

Probiotics 

Strategies such as the use of probiotics, prebiotics, and dietary changes are emerging as potential means of restoring the balance of the gut microbiota, which could help reduce neuroinflammation. Probiotics, which introduce beneficial bacteria into the gut, have been shown to reduce systemic inflammation and improve gut–brain communication. Prebiotics, which act as a food source for beneficial gut bacteria, can help increase the growth of these bacteria, further improving the gut–brain connection and potentially reducing neuroinflammation. In addition, dietary changes, such as increasing fiber intake, adopting a Mediterranean diet rich in antioxidants, and including omega-3 fatty acids, can positively influence the composition of the gut microbiota and reduce the risk or progression of neurodegeneration. On the non-immunological front, probiotics participate in digestion and compete with pathogenic bacteria for nutrients. They alter local pH levels to create a hostile environment for pathogens, produce bacteriocins to inhibit harmful bacteria, and scavenge superoxide radicals to reduce oxidative stress. In addition, probiotics stimulate the production of epithelial mucin, which strengthens mucosal defenses, improves the integrity of the intestinal barrier, and reduces intestinal permeability. They also compete with pathogens for adhesion receptors, limiting pathogen colonization, and modify pathogen-produced toxins to mitigate their harmful effects. These combined actions underscore the critical role of probiotics in supporting gut health and overall systemic well-being.⁹

These foods can integrate more probiotics into your diet:

• pineapple
• non-dairy yogurts and milks that have added live and active cultures
• fermented foods made at home with natural yeasts captured in the air

hyperglycemia & a low AGE-diet

Now, for the elephant in the room… hyperglycemia. Arguably, all other therapies are useless to remedy DEN or other GI complications and neuropathies if your A1C is not successfully lowered and steps are not taken to seriously reduce hyperglycemic events. While it may seem confusing, avoiding AGEs in both our diet and from hyperglycemia are the best ways to prevent complications. Elevated AGEs may be a significant risk factor for type 1 diabetes and beta cell injury.  This evidence begs the question of the origin of the large concentrations of AGEs that could induce beta cell toxicity prior to diabetes onset. New studies have proposed that the abundance of pro-oxidant AGEs in the highly industrialized modern food environment could potentially account for the initiation and progression of pre-diabetes to diabetes (referencing type 2, here). Studies have had difficulty showing a direct correlation in the reduction in hyperglycemia reducing AGEs, especially considering part of this management may include a natural reduction of problematic foods. Because hyperglycemia has traditionally been thought to be the principal source of AGEs, intensive control of hyperglycemia was expected to also control the consequences of AGEs on diabetic vascular complications. Recently conducted large studies have, however, failed to produce these long-anticipated results. For instance, measures to assess and modulate exogenously derived AGEs might have influenced these results. Furthermore, well-controlled cellular and animal studies suggest that a chronic exogenous overload of oxidant AGEs can incite β-cell injury and thus the occurrence of T1D and T2D diabetes and their complications.¹¹ This is major. When we’re diagnosed, we’re told “there’s nothing you could have done. We don’t know where it comes from”. This is partially true, as there is still so much to learn. But studies are suggesting that exogenous AGEs, potentially from a Standard American Diet, or ultra-processed foods, or other forms of oxidant loads, could be that “trigger” that causes the autoimmune reaction to kill our beta cells!

It’s important to distinguish what the connection is between antioxidants, hyperglycemia, and nerve death. hyperglycemia leads to polyol and fructose accumulation (fructose is 7 times more reactive than glucose). Fructose is especially reactive and causes more damage than glucose. These byproducts build up and stress the cells. The body uses up important antioxidants trying to deal with all this extra sugar. (Makes sense that a diabetic may need to consume more antioxidants to make up for all of those lost, no?) Without these defenses, cells experience oxidative stress (damage from harmful molecules) and nitrosative stress (a related type of damage). This stress damages the cell’s DNA. In response, the cell activates a repair enzyme called Poly (ADP-ribose) polymerase (PARP) to fix the damage. But PARP ends up shutting down a key step in glycolysis (the process that breaks down sugar for energy). This blockage causes harmful byproducts like Methylglyoxal to build up, leading to even more cell damage. These changes activate a protein called Protein Kinase C beta (PKCβ) in the tiny blood vessels that feed nerves (vasa nervorum). This leads to inflammation, leaky blood vessels, and eventually cell death. At the same time, another protein, Protein Kinase C alpha (PKC alpha), is turned off in nerve cells. That causes the nerves to malfunction.

Back to AGEs: some extent of AGEs are completely unavoidable, (such as those endogenous AGEs) but there are absolute ways in which we can reduce our AGE intake (the exogenous AGEs). Exogenous AGEs are found in ultra-processed food and in meats, most present in red meat.¹² Modern food production utilizes high temperatures, high pressure, dehydration, decompression, irradiation, salt, and preservatives to extend shelf life and palatability. These processes significantly alter proteins and lipids, forming post-translational modifications, including AGEs.  Consumption of energy dense, nutrient poor foods, which are high in sugars and salt, and low in essential nutrients, also contribute to inflammation. As far as preparation goes: grilling, broiling, roasting, searing, and frying propagate and accelerate new AGE formation. According to the study, “Advanced glycation End Products in Foods and a Practical Guide to Their Reduction in the Diet”, when items in the meat category prepared by similar methods were compared, the highest AGE levels were observed in beef and cheeses followed by poultry, pork, fish, and eggs. Lamb ranked relatively low in AGEs compared to other meats.¹³

The importance of cooking methods 

It is noteworthy that even lean red meats and poultry contain high levels of AGEs when cooked under dry heat. This is attributable to the fact that among the intracellular components of lean muscle there exist highly reactive amino-lipids, as well as reducing sugars, such as fructose or glucose-6-phosphate, the combination of which in the presence of heat rapidly accelerates new AGE formation. We can call this the “high heat, low moisture” method of cooking. The article posits that the way to avoid this negative effect is through what we can dub the “low heat, high moisture” method of cooking: brief heating time, low temperatures, high moisture, and/or pre-exposure to an acidified environment (think soaking meat in lime or lemon juice). These are all effective strategies to limit new AGE formation in food. Dairy consumption is a tricky one. Higher-fat and aged cheeses, such as full-fat American and Parmesan, contained more AGEs than lower-fat cheeses, such as reduced-fat mozzarella, 2% milk cheddar, and cottage cheese. Whereas cooking is known to drive the generation of new AGEs in foods, it piqued my interest that even uncooked, animal-derived foods such as cheeses can contain large amounts of AGEs. This is due to pasteurization and/or holding times at ambient room temperatures (eg, as in curing or aging processes).¹³ glycation-oxidation reactions, although at a slower rate, continue to occur over time even at cool temperatures, resulting in large accumulation of AGEs in the long term (while they sit on the shelves).  When attempting to research low-AGE diets, studies seem to be slanted by the non-fat industry, so I will update this article with new recommendations accordingly. For example, high- (healthy) fat foods are considered high in AGEs, yet those that cite the Mediterranean diet place a high emphasis on olive oil and nuts and seeds (foods notoriously high in healthy fats) as contributing to a longer life span. Further, it is worth looking into if unpasteurized dairy has less AGEs as it appears the AGEs stem from the processing of the cheese, not the content of the dairy itself… What is the AGE content of milk made at home and consumed the same day, compared to the processed cheeses that sit on the shelf for months? Goat and sheep’s milk would be worth looking into as well, as sheep’s milk is auto-immune protocol compliant as casein is the inflammatory component of cow’s milk. After all, the Mediterranean diet reveres feta cheese, whose constituents are 70% sheep’s and 30% goat’s milk. These are all questions well-worth some researching. Some of the less controversial foods low in AGEs are vegetables, legumes, and fruits. While more research is needed—and each person’s genetic predispositions and intolerances will influence their dietary choices—an actionable way to reduce AGE consumption is to minimize food processing (for example, replacing packaged snacks with homemade options) and to prepare meats and other foods by boiling, steaming, or stewing them at low temperatures for longer periods. This helps avoid denaturing proteins to the point where toxic byproducts form. Sorry to be the bearer of bad news, but that oh-so-satisfying black char of grilled meat is actually carcinogenic– I wish this wasn’t true!¹⁶ I am further curious about the AGE content of meat, as Dr. Shanahan asserts that meat, not just the muscles but all of the bones, organs, etc.,  make up a large nutritional gap in the Standard American Diet:

“When cooking meat, the more everything stays together—fat, bone, marrow, skin, and other connective tissue—the better. Gentle, moist heating clips just enough peptide bonds to break long protein chains into peptide segments. As long as the meat stays moist, the rows stay neatly aligned and separate. Trouble arises if the meat dries, or if the temperature rises above 170 degrees Fahrenheit. If the chef allows either to happen, hydrolysis stops, the chains themselves curl and bend around creating a tangle, and new, unbreakable bonds form between amino acids in distant chains, between amino acids and sugar, and between amino acids and fats. These undesired reactions create toxins, destroy nutrients, and make the meat tough to cut and chew.” She goes on to discuss the necessity of glycosaminoglycans:

“You will find the three most famous members of this family in nutritional supplements for joints: glucosamine, chondroitin sulfate, and hyaluronic acid. But these processed supplements don’t hold a candle to gelatinous stews, rich with the entire extended family of joint-building molecules. Mineral salts are released from bone and cartilage during stewing. These tissues are mineral warehouses, rich in calcium, potassium, iron, sulfate, phosphate, and, of course, sodium and chloride. Our taste buds can detect more of these ions than previously suspected, including calcium, magnesium, potassium, and possibly iron and sulfate, in addition to the sodium and chloride ions that make up table salt. Overcooking traps these flavorful materials in an indigestible matrix of polymerized flesh that forms when meat begins to dry out. You can only taste, and your body can only make use of, minerals that remain free and available. The health of your joints depends upon the health of the collagen in your ligaments, tendons, and on the ends of your bones. Collagens are a large family of biomolecules, which include the glycosaminoglycans. Bone stock and broth supply our bodies with a whole family of glycosaminoglycans. Now that few people make bone stock anymore, many of us are limping into doctors’ offices for prescriptions, surgeries, and, lately, recommendations to buy over-the-counter joint supplements containing glucosamine. And what is glucosamine? One of the members of the glycosaminoglycan family of joint-building molecules.”

She goes on to discuss the innate need for fat in our diet…

“What are the nutritional benefits of our appetite for fat? For one thing, fat is a source of energy, like sugar. Unlike sugar, however, fat is a major building material for our cells, comprising 30 to 80 percent (dry weight) of our cell membranes. And unlike sugar, fat doesn’t trigger the release of insulin, which promotes weight gain. Furthermore, a high-sugar meal damages our tissues, but a high (natural) fat meal doesn’t. And this is something I was tested on in med school but forgot right after the test: we need fat to be able to absorb most fat-soluble nutrients, including vitamins A, D, E, and K. The fact that the presence of fat in meat also helps protect it during cooking—let’s just call that a happy coincidence.”⁵

Tobacco and Alcohol Consumption

Another notable but unrecognized source of AGEs is cigarette smoking. The processing of curing tobacco involves AGE formation since the plant leaves are heat-dried in the presence of reducing sugars, added for purposes such as taste and smell. Subsequent combustion can lead to the inhalation of AGE derivatives and transfer into the circulation. Levels of serum AGEs or LDL-apolipoprotein-B were found higher in chronic cigarette smokers than in nonsmokers. Also, AGE levels were higher in arterial wall samples or ocular lenses in smokers with diabetes compared to those from non-smoking diabetic persons.¹¹ Chronic and excessive alcohol consumption can alter brain structure and function, causing behavioral, emotional, and intellectual abnormalities. These neurobehavioral changes include the development of alcohol tolerance and addiction, emotional dysregulation, and executive, neurocognitive, and motor dysfunctions with neuroinflammation and/or neurodegeneration. Excessive alcohol exposure increases oxidative stress and the levels of reactive acetaldehyde and lipid aldehydes with a simultaneous decrease in defensive molecules and detoxification enzymes, including GSH and ALDH2.  Ethanol intake or exposure can induce and accelerate AGE production in the brain. Aggregation of cross-linked AGEs further upregulates RAGE expression and activation, contributing to diverse outcomes with neurobehavioral impairment, as observed in people with AUD. These results strongly suggest a contributing role of the AGE-RAGE axis in alcohol-induced neuroinflammation and neurodegeneration through elevated oxidative stress and upregulated cell death pathways in the brain. These changes subsequently lead to the accumulation of acetaldehyde adducts and possibly AGEs in the brain, which has a much lower detoxification capacity than the liver.¹⁴ So, while the general recommendation for daily alcohol consumption for men is two drinks, and one drink for women, I can’t imagine that one drink a day wouldn’t have some negative outcomes.

nVNS Therapies

Now that we’ve covered the ENS and its complexities, let’s discuss the potential importance of the vagus nerve in healing DEN, along with other GI issues. An important component of the parasympathetic nervous system (remember, the PSNS?), the Vagus Nerve is the longest cranial nerve, which acts as a crucial bidirectional conduit between the body and the brain, primarily contributing to homeostasis. This nerve is located in the brainstem, and extends to the proximal two-thirds of the colon, thereby innervating a significant number of thoracic and abdominal viscera. It is a mixed nerve, predominantly composed of afferent fibers, with a smaller proportion of efferent fibers. It is a crucial link and communicates with the ENS, acting as a bridge between the brain and the gut. The vagus nerve transmits signals to and from the ENS, allowing for bidirectional communication between the brain and the digestive system. Disruptions in this pathway—which are frequently associated with alterations in gut microbial composition—contribute to increased oxidative stress, neuronal dysfunction, and inflammation. In normal conditions, the VN exerts its effects through both direct and indirect mechanisms: direct innervation, where it innervates and coordinates the function of smooth muscle cells and intramural ganglia in the gut wall, and paracrine actions, where the VN releases acetylcholine and neuroactive modulators that affect other components of the gut environment, including immune cells in the submucosa. These cells are influenced by vagal activity, which may help maintain the integrity of the epithelial barrier and modulate immune responses, particularly in altered gut microbiota or pathological states. This complex interplay between the VN, the gut microbiota, and the intestinal wall provides insights into mechanisms for maintaining intestinal and systemic homeostasis. Originally developed for neurological conditions such as epilepsy and depression, VNS has been repurposed for its anti-inflammatory potential. By engaging multiple mechanisms—including the cholinergic anti-inflammatory pathway, the vagus-adrenal axis, and the vagus-gut axis—VNS potentially offers a level of precision in modulating systemic inflammation that traditional therapies cannot achieve.⁹   the CAP (cholinergic anti-inflammatory pathway) has an anti-TNF (tumor necrosis factor) effect exerted by the vagus nerve, which dampens peripheral inflammation and decreases intestinal permeability, thus likely modulating microbiota composition. Moreover, the vagus nerve establishes connections between the brain and the gut and transmits information about the state of the gastrointestinal tract to the brain via afferent fibers.  Taking into account the extensive innervation of the gastrointestinal tract, it is not surprising that the vagus nerve appears to play a role in modulating immune activation in the gut wall. The vagus nerve senses microbiota metabolites and generates an adaptive response in the regulation of gastrointestinal motility, acid secretion, food intake, and satiety. Vagal nerve stimulation, sometimes called transcutaneous auricular vagus nerve stimulation (taNVS) or non-invasive vagus nerve stimulation (nVNS), is a method of stimulating the vagus nerve, which runs through the ear, to modulate brain function and potentially treat various conditions. taVNS involves delivering electrical stimulation to the auricular branch of the vagus nerve, a pathway within the ear, to influence brain activity. Therapy is achieved through placing a device on the ear or on the carotid artery for a few minutes while it sends electrical pulses to the nerve. Devices vary and are pricey, so be sure to do your own research on the efficacy and studies behind each product.  Such stimulation might have an anti-inflammatory effect on central serotonin levels and affect the HPA axis and cortisol levels (serotonin and cortisol play a huge role in the gut!). Activation of the vagus nerve may modulate the neuroimmune system, the neuroendocrine system, and brain regions.¹⁵ You may know that your vagus nerve is disrupted if your resting heart rate is consistently above the 60-80 bpm range, aka– your body is very stressed. This is because a stronger/higher vagal tone, which is indicated by a slower heart rate and more variability in the time between heartbeats, suggests a more active vagus nerve. In contrast, a resting heart rate of around 100 beats per minute may indicate a less active vagus nerve or a vagal lesion. Having a higher vagal tone means you may be better able to withstand and recover from stress, you may have improved emotional stability and lower risk for psychological disorders, better regulated digestion, reduced inflammation (and thus a lower risk for chronic diseases), and overall better cardiac health. In addition to products for purchase, free options to regulate the vagus nerve include meditation, deep breathing practices, exercise, vagal massages, yoga, and acupuncture.

Looking forward 

While the multitude of ways that oxidation and inflammation manifest in our bodies may seem entirely overwhelming, the pain of removing some of these pleasures will be far out shadowed by the longevity and vitality we can experience long term by practicing healthy habits. I have found that cutting out certain foods is difficult for the first month, then afterwards the cravings are completely gone and replaced by cravings for the things that nourish my body. It is important for diabetics to know that each decision we make with what we put into our bodies is either helping us live longer and better, or hurting us by contributing to complications such as DEN. Try to find power in the fact that, while we can’t go back in time and change our diagnosis, every single day we are gifted on earth is an opportunity to regain our health through our decisions. And that is the philosophy behind thriving with diabetes— being at peace with what we cannot control, while fiercely fighting to gain knowledge and power of the things we can control. Whether you’re facing a DEN or other neuropathy diagnosis, trying to make sense of how to mitigate the damage done, or seeking ways to prevent these complications, I hope this article has reminded you that you are in control of the daily decisions that shape your health. Significantly reducing (or ideally eliminating) alcohol and tobacco consumption, eating anti-inflammatory foods, using low AGE food preparation methods, reducing A1C, and practicing both vagus nerve stimulation and mindfulness are all showing promising potential for drastically improving our quality of life. Remember to not get overwhelmed, as even the most microscopic achievement today can radically improve your well-being tomorrow. 

Works Cited 

1.Drewes AM, Søfteland E, Dimcevski G, Farmer AD, Brock C, Frøkjær JB, Krogh K, Drewes AM. Brain changes in diabetes mellitus patients with gastrointestinal symptoms. World J Diabetes. 2016 Jan 25;7(2):14-26. doi: 10.4239/wjd.v7.i2.14. PMID: 26839652; PMCID: PMC4724575.

2.  Furness JB (15 April 2008). The Enteric Nervous System. John Wiley & Sons. pp. 35–38. ISBN 978-1-4051-7344-5.

3. Fleming MA 2nd, Ehsan L, Moore SR, Levin DE. The Enteric Nervous System and Its Emerging Role as a Therapeutic Target. Gastroenterol Res Pract. 2020 Sep 8;2020:8024171. doi: 10.1155/2020/8024171. PMID: 32963521; PMCID: PMC7495222.

4. Abdalla MMI. Enteric neuropathy in diabetes: Implications for gastrointestinal function. World J Gastroenterol. 2024 Jun 14;30(22):2852-2865. doi: 10.3748/wjg.v30.i22.2852. PMID: 38947292; PMCID: PMC11212710.

5. Shanahan M D, C., & Shanahan, L. (2008). Deep nutrition. Big Box Books. https://books.apple.com/us/book/deep-nutrition/id1116600019 

6. Phuong-Nguyen, Kate et al. “Advanced glycation End-Products and Their Effects on Gut Health.” Nutrients vol. 15,2 405. 13 Jan. 2023, doi:10.3390/nu15020405

7. Can you please tell me about diabetic digestive neuropathy? [Online forum post]. (n.d.). https://connect.mayoclinic.org/discussion/please-can-you-tell-me-about-diabetic-digestive-neuropathy/?pg=2

8. diabetic enteric neuropathy. (2017, December 27). TuDiabetes Forum. https://forum.tudiabetes.org/t/diabetic-enteric-neuropathy/65156/3

9. Kurhaluk N, Kamiński P, Bilski R, Kołodziejska R, Woźniak A, Tkaczenko H. Role of Antioxidants in Modulating the Microbiota-Gut-Brain Axis and Their Impact on Neurodegenerative Diseases. Int J Mol Sci. 2025 Apr 12;26(8):3658. doi: 10.3390/ijms26083658. PMID: 40332186; PMCID: PMC12027284.

10. Lourenço SC, Moldão-Martins M, Alves VD. Antioxidants of Natural Plant Origins: From Sources to Food Industry Applications. Molecules. 2019 Nov 15;24(22):4132. doi: 10.3390/molecules24224132. PMID: 31731614; PMCID: PMC6891691.

11. Vlassara H, Uribarri J. Advanced glycation end products (AGE) and diabetes: cause, effect, or both? Curr Diab Rep. 2014 Jan;14(1):453. doi: 10.1007/s11892-013-0453-1. PMID: 24292971; PMCID: PMC3903318.

12. Fotheringham, Amelia K et al. “Advanced glycation End Products (AGEs) and Chronic Kidney Disease: Does the Modern Diet AGE the Kidney?.” Nutrients vol. 14,13 2675. 28 Jun. 2022, doi:10.3390/nu14132675

13. Uribarri, Jaime et al. “Advanced glycation end products in foods and a practical guide to their reduction in the diet.” Journal of the American Dietetic Association vol. 110,6 (2010): 911-16.e12. doi:10.1016/j.jada.2010.03.018

14. Rungratanawanich, Wiramon et al. “Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury.” Experimental & molecular medicine vol. 53,2 (2021): 168-188. doi:10.1038/s12276-021-00561-7

15. Liu, CH., Yang, MH., Zhang, GZ. et al. Neural networks and the anti-inflammatory effect of transcutaneous auricular vagus nerve stimulation in depression. J Neuroinflammation17, 54 (2020). https://doi.org/10.1186/s12974-020-01732-5

16. Grilling meat raises cancer risk. Here are ways to lower it. (2023, June 30). UCLA Health. https://www.uclahealth.org/news/article/grilling-meat-raises-cancer-risk-here-are-ways-lower-it

 17. Mańkiewicz-Żurawska, I.,  & Jarosz-Chobot, P. (2019). Nutrition of children and adolescents with type 1 diabetes in the recommendations of the Mediterranean diet. Pediatric Endocrinology Diabetes and Metabolism, 25(2), 74-80. https://doi.org/10.5114/pedm.2019.85817 

18. Krawczyk M, Burzynska-Pedziwiatr I, Wozniak LA, Bukowiecka-Matusiak M. Impact of Polyphenols on Inflammatory and Oxidative Stress Factors in Diabetes Mellitus: Nutritional Antioxidants and Their Application in Improving Antidiabetic Therapy. Biomolecules. 2023 Sep 17;13(9):1402. doi: 10.3390/biom13091402. PMID: 37759802; PMCID: PMC10526737.