DM and Diabetic Skin Disease
Diabetes mellitus carries with it the risk for skin diseases specific to the diabetic disease process, such as increased risk for bacterial and fungal infections, venous stasis, pruritus (secondary to poor circulation), acanthosis nigricans, diabetic dermopathy, necrobiosis lipoidica diabeticorum, digital sclerosis, and bullosis diabeticorum.11 It is well established that better control of DM results in better disease state outcomes.12 The ketogenic diet has shown itself to be a formidable and successful treatment in the diseases of carbohydrate intolerance (eg, metabolic syndrome, insulin resistance, type 2 DM) because of several known mechanisms, including less glucose entering the body and thus less fat deposition, end-product glycation, and free-radical production (discussed below); enhanced fat loss and metabolic efficiency; increased insulin sensitivity; and decreased inflammation.13 Lowering a patient’s insulin resistance through a ketogenic diet may help prevent or treat diabetic skin disease.
A ketogenic diet has been of interest in oncology research as an adjunctive therapy for several reasons: anti-inflammatory effects, antioxidation effects, possible effects on mammalian target of rapamycin (mTOR) regulation,7 and exploitation of the Warburg effect.14 One article discusses how mTOR, a cell-cycle regulator of particular importance in cancer biology, can be influenced by ketones both directly and indirectly through modulating the inflammatory response.7 It has been shown that suppressing mTOR activity limits and slows tumor growth and spread. Ketones also may prove to be a unique method of metabolically exploiting cancer physiology. The Warburg effect, which earned Otto Warburg the Nobel Prize in Physiology or Medicine in 1931, is the observation that cancerous cells produce adenosine triphosphate solely through aerobic glycolysis followed by lactic acid fermentation.14 This phenomenon is the basis of the positron emission tomography scan. There are several small studies of the effects of ketogenic diets on malignancy, and although none of these studies are of substantial size or control, they show that a ketogenic diet can halt or even reverse tumor growth.15 The hypothesis is that because cancer cells cannot metabolize ketones (but normal cells can), the Warburg effect can be taken advantage of through a ketogenic diet to aid in the treatment of malignant disease.14 If further studies find it a formidable treatment, it most certainly would be helpful for the dermatologist involved in the treatment of cutaneous cancers.
Oxidative stress, a state brought about when reactive oxygen species (ROS) production exceeds the antioxidant capacity of the cell and causes damage, is known to be a central part of certain skin diseases (eg, acne, psoriasis, cutaneous malignancy, varicose ulcers, cutaneous allergic reactions, and drug-induced skin photosensitivity).7 There are 2 proven mechanisms by which a ketogenic diet can augment the body’s innate antioxidation capacity. First, ketones activate a potent antioxidant upregulating protein known as NRF2, which is bound in cytosol and remains inactive until activated by certain stimuli (ie, ketones).16 Migration to the nucleus causes transcriptional changes in DNA to upregulate, via a myriad of pathways, antioxidant production in the cell; most notably, it results in increased glutathione levels.17 NRF2 also targets several genes involved in chronic inflammatory skin diseases that cause an increase in the antioxidant capacity.18 As an aside, several foods encouraged on a ketogenic diet also activate NRF2 independently of ketones (eg, coffee, broccoli).19 Second, a ketogenic diet results in fewer produced ROS and an increase in the nicotinamide adenine dinucleotide ratio produced by the mitochondria; in short, it is a more efficient way of producing cellular energy while enhancing mitochondrial function. When fewer ROS are produced, there is less oxidative stress that needs to be attended to by the cell and less cellular damage. Feichtinger et al19 point out that mitochondrial inefficiency and dysfunction often are overlooked components in several skin diseases, and based on the studies discussed above, these diseases may be aided with a ketogenic diet.
Clearly, a ketogenic diet is therapeutic, and there are many promising potential roles it may play in the treatment of a wide variety of health and disease states through hormonal normalization, antioxidant effects, anti-inflammatory effects, and improvement of metabolic risk factors. However, there are vast limitations to what is known about the ketogenic diet and how it might be employed, particularly by the dermatologist. First, the ketogenic diet lacks a firm definition. Although processed inflammatory vegetable oils and meats are low in carbohydrates and high in fat by definition, it is impossible to argue that they are healthy options for consumption and disease prevention and treatment. Second, nutrigenomics dictates that there must be an individual role in how the diet is employed (eg, patients who are lactose intolerant will need to stay away from dairy). Third, there are no clear proven clinical results from the ketogenic diet in the realm of dermatology. Fourth, as with everything, there are potential detrimental side effects of the ketogenic diet that must be considered for patients (though there are established screening procedures and prophylactic therapies that are beyond the scope of this article). Further, other diets have shown benefit for many other disease states and health promotion purposes (eg, the Mediterranean diet).20 We do not know yet if the avoidance of certain dietary factors such as processed carbohydrates and fats are more beneficial than adopting a state of ketosis at this time, and therefore we are not claiming superiority of one dietary approach over others that are proven to promote health.
Because there are no large-scale studies of the ketogenic diet, there is no verified standardization of initiating and monitoring it, though certain academic centers do have published methods of doing so.21 There are ample anecdotal methods of initiating, maintaining, and monitoring the ketogenic diet.22 In short, drastic restriction of carbohydrate intake and increased fat consumption are the staples of initiating the diet. Medium-chain triglyceride oil supplementation, coffee consumption, intermittent fasting, and low-level aerobic activity also are thought to aid in transition to a ketogenic state. As a result, a dermatologist may recommend that patients interested in this option begin by focusing on fat, fiber, and protein consumption while greatly reducing the amount of carbohydrates in the diet. Morning walks or more intense workouts for fitter patients should be encouraged. Consumption of serum ketone–enhancing foods (eg, coffee, medium-chain triglyceride oil, coconut products) also should be encouraged. A popular beverage known as Bulletproof coffee also may be of interest.23 A blood ketone meter can be used for biofeedback to reinforce these behaviors by aiming for proper β-hydroxybutyrate levels. Numerous companies and websites exist for supporting those patients wishing to pursue a ketogenic state, some hosted by physicians/researchers with others hosted by laypeople with an interest in the topic; discretion should be used as to the clinical and scientific accuracy of these sites. The dermatologist in particular can follow these patients and assess for changes in severity of skin disease, subjective well-being, need for medications and adjunctive therapies, and status of comorbid conditions.
For more information on the ketogenic diet, consider reading the works of the following physicians and researchers who all have been involved with or are currently conducting research in the medical use of ketones and ketogenic diets: David Perlmutter, MD; Thomas Seyfried, PhD; Dominic D’Agostino, PhD; Terry Wahls, MD; Jeff Volek, PhD; and Peter Attia, MD.
Based on the available data, there is potential for use of the ketogenic diet in an adjunctive manner for dermatologic applications, and studies should be undertaken to establish the efficacy or inefficacy of this diet as a preventive measure or treatment of skin disease. With the large push for complementary and alternative therapies over the last decade, particularly for skin disease, the time for research on the ketogenic diet is ripe. Over the coming years, it is our hope that larger clinical, randomized, controlled trials will be conducted for the benefit of dermatology patients worldwide.