The mystery of the ketogenic diet: benevolent pseudo-diabetes

Abstract

Designed a century ago to treat epilepsy, the ketogenic diet (KD) is also effective against obesity and diabetes. Paradoxically, some studies in rodents have found that the KD seemingly causes diabetes, contradicting solid clinical data in humans. This paradox can be resolved by applying the concept of starvation pseudo-diabetes, which was discovered in starved animals almost two centuries ago, and has also been observed in some rapamycin-treated rodents. Intriguingly, use of the KD and rapamycin is indicated for a similar spectrum of diseases, including Alzheimer’s disease and cancer. Even more intriguingly, benevolent (starvation) pseudo-diabetes may counteract type 2 diabetes or its complications.

Rapamycin for longevity: opinion article

“…The obligatory symptom of starvation is ketosis, as ketones substitute for glucose as the main fuel for the brain. The ketogenic diet, a promising treatment for diabetes and obesity in humans, can cause symptoms of SPD in rodents (see for references [64]). Once again, some researchers warned that the ketogenic diet can favor type 2 diabetes [65].…”

“…Once again, some researchers warned that the ketogenic diet can favor type 2 diabetes [65]. As discussed, such warnings may not be justified [64,66–68].…”

In silico clinical trials for anti-aging therapies

“…( C ) The cellular epigenome landscape directs cell fate and reflects its health and biological age. Certain dietary interventions (e.g., ketogenic diets), by altering the availability of key regulators for chromatin-modifying enzymes (e.g., the histone deacetylases inhibitor β-hydroxybutyrate), may provide a direct link between metabolism and epigenomic remodeling to extend healthspan and longevity [54,55]. Given the ability of dietary interventions and DRMs to affect the epigenome [31,56–58] and to suppress the development of senescence [59–62], an intriguing possibility is that dietary, pharmacological, and behavioral strategies targeting nutrient-sensing pathways might synergistically interact with cellular reprogramming strategies to provide better anti-aging outcomes.…”

Pseudodiabetes—not a contraindication for metabolic interventions

“…In spite of the undoubtable antidiabetic effects of the aforementioned interventions, many of them induce a phenomenon that can be referred to as “pseudo-diabetes” (Fig. 1), namely a change in laboratory parameters that are indicative of diabetes: glycosuria, hyperglycemia, glucose intolerance, hyperinsulinemia, and insulin resistance, as recently brought up by Blagosklonny 8,11 . Indeed, the French physiologist Claude Bernard was the first to note in 1846 that rabbits that were on a starvation diet developed glycosuria after having been refed with carrots, hence developing a “starvation diabetes”.…”

“…Similarly, ketogenic diets induce glucose intolerance and insulin resistance in mice, a phenomenon that is reversed upon cessation of the diet. Hence, ketogenic diets also induce pseudo-diabetes 11 . In response to chronic rapamycin treatment, a mild hyperglycemia, glucose intolerance, and insulin resistance is observed, again revealing signs of pseudo-diabetes 8 .…”