Ketogenic diets, which are very low in carbohydrate and high in fat, can help weight loss and are generally considered metabolically healthy, but new research in animal models suggests that they may also increase the risk of type 2 diabetes (TD2). Comparing the metabolic effects of a western-style high-fat diet (HFD) and ketogenic diet (KD) in mice, scientists at the ETH Zurich found that even though KD-fed animals appeared metabolically healthy, within just a few days they exhibited decreased glucose tolerance, which was even more severe than in the HFD animals. “'Diabetes is one of the biggest health issues we face,” comments Christian Wolfrum, Ph.D., co-corresponding author and associate professor of the Institute of Food Nutrition and Health, ETH Zurich.Associate Professor of the Institute of Food Nutrition and Health at the ETH Zurich Associate Professor of the Institute of Food Nutrition and Health at the ETH ZurichAssociate Professor of the Institute of Food Nutrition and Health at the ETH Zurich“Although ketogenic diets are known to be healthy, our findings indicate that there may be an increased risk of insulin resistance with this type of diet that may lead to type 2 diabetes.”
Reporting the findings in the Journal of Physiology, the team says it will be important to try and find out why a short-term ketogenic diet leads to glucose intolerance. “The next step is to try to identify a mechanism for this effect and to address whether this is a physiological adaptation,” says Dr. Wolfrum. “Our hypothesis is that when fatty acids are metabolized, their products might have important signaling roles to play in the brain.” The ETH Zurich researchers, working with colleagues at the University Children’s Hospital, Zurich, describe their findings in a paper titled, “Short-term feeding of a ketogenic diet induces more severe hepatic insulin resistance than a obesogenic high-fat diet.”
T2D is a major healthcare challenge, but we still don’t fully understand its cause, the authors note.The disease has been linked with an unhealthy, characteristically high-fat, high-carbohydrate western diet, and lack of exercise, “whereas the consumption of a low carbohydrate, high-fat ketogenic diet is considered healthy.” The progression of T2D manifests as a gradual downward slide in insulin sensitivity that affects different organs. Blood glucose levels are initially maintained, but this requires increasing levels of insulin to compensate, they explain. Eventually, the pancreatic islets fail.
Studies have shown that rats fed an obesogenic HFD develop poor systemic glucose tolerance and insulin signaling in the brain and liver within just a few days. “These early impairments of glucose homeostasis typically present as a failure of elevated glucose or insulin levels to suppress hepatic glucose output, leading to decreased glucose tolerance,” the researchers point out. It takes much longer for the development of more profound insulin resistance in major organs.
Interestingly, scientists have known for at least a century that starvation, or eating a very low carbohydrate, ketogenic diet for a few days can also result in systemic glucose intolerance, a phenomenon known as starvation diabetes. However, “any mention of the term starvation diabetes or the citation of related studies is absent from the recent literature concerning the effects of longer-term KD feeding on glucose tolerance and insulin sensitivity,” the authors comment. In fact, while a KD is known to effectively aid weight loss, there is “significant controversy about its effect on glucose tolerance and insulin sensitivity.”
To address this controversy, the team compared the short-term effects on glucose tolerance and insulin sensitivity of feeding experimental either a KD or HFD. Using standard metabolic tests and more specialized analyses, the team looked at the effects of glucose production – primarily in the liver – and glucose uptake in the muscle, in parallel with insulin sensitivity.
Their results showed that mice fed a HFD for three days demonstrated slightly impaired insulin signaling, though the measurement didn’t necessarily reflect actual glucose tolerance. In contrast, feeding a KD diet to mice for three days, in the absence of any additional dietary glucose, had a neutral, or even slightly beneficial effect on insulin sensitivity, indicative of a “healthy, glucose-tolerant state.” However, when the animals were given glucose challenge after three days on their respective diets, the KD-fed, as well as HFD-fed animals demonstrated impaired glucose clearance and insulin tolerance. Further tests suggested that reduced insulin sensitivity in the KD mice related primarily to hepatic insulin resistance and so increased glucose output and not to an impaired ability to metabolize glucose, or to changes in glucose uptake by different body tissues.
“The results of the present study demonstrate that, in the context of ad libitum feeding of both HFD or KD for a short period, the effect on systemic glucose tolerance is a result of the inability of insulin to suppress hepatic glucose output, whereas muscle and adipose tissue glucose uptake are completely unperturbed,” the authors state.
They acknowledge that while their results mirror those of some previous research, other studies have shown that KD feeding has “universally beneficial effects on glucose metabolism.” The researchers also state that while there are some metabolic similarities between KD feeding and starvation – both lead the body to switch from carbohydrate to lipid as a primary fuel – there are also major differences. Importantly, the consequences of starvation are due to reduced energy intake, and not specifically to reduced carbohydrate intake that is characteristic of KD, which still provides adequate overall calorie intake.
“Thus it is possible that the symptoms of short-term KD feeding in the present study, and the reported symptoms of starvation diabetes are caused by different mechanisms,” they write. “These data suggest that the early effects of HFD consumption on EGP [endogenous glucose production] may be part of a normal physiological response to increased lipid intake and oxidation, and that systemic insulin resistance results from the addition of dietary glucose to EGP-derived glucose.”