Keto diets may drop some weight, but cause hyperlipidemia, liver/heart disease, and even diabetes type I

   October 3, 2025  Posted in Science
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This is probably one of the most controversial posts I have made in a long time. It pretty much disproves keto diets as interventions that can improve long-term health, despite the initial (and transitory) weight loss such diets may induce. Keto diets, which I first tried more than a decade ago (and deeply regretted doing so) are all the rage now and it seems every public health agency out there (globally) is recommending them not only for weight loss but for improving systemic health and reducing risks of future chronic disease such as diabetes, liver and heart disease (CVD). Well, there is indeed some weight loss over the first 2-3 months on keto diets. However, most of that weight loss seems to be in the form of intracellular water, since cutting carbs works similarly to diuretics. There is also some fat loss, but multiple studies have shown that muscle loss is also increased and over time dwarfs the fat loss aspect of the diet, thus making the initial problem much worse. Why? Well, the resting metabolic rate (RMR) is determined primarily by the ratio of lean mass to fat mass. Thus, as the amount of muscle loss overtakes the amount of fat loss with chronic ingestion of keto diets, the RMR drops significantly. As such, after the person stops the keto diet and goes back to even low-to-moderate carb diets, the formerly keto diet patient rapidly regains the weight lost as a result of the keto diet, and regains it mostly in the form of fat. Since fat is not nearly as metabolically active as muscle tissue, the newly re-obesified person not only regains all of the lost weight, but almost always exceed the initial weight before the keto diet was started and finds that they keep gaining weight even if they restrict the calories way below what they used to consume prior to the keto diet. That is due to the fact that the RMR dropped as a result of the keto diet (and muscle loss) and the regular diet, which the former keto patient used to consume and maintain a stable (though high) weight on, becomes directly obesogenic due to the much lower RMR. Please note, that this is not a theory but has actually been confirmed by numerous animal and humans studies, and perhaps exemplified best by the so-called “Biggest Loser” contest and studies on those participants. Those poor souls who lost weight as a result of exercise, low-carbing, fasting, etc all regained and then exceeded their original weights before the contest began. The study based on them also concluded that the diet and exercise regimen tanked the contestants’ RMR and resulted in something called “sarcopenic obesity” – colloquially known as “skinny-fat” – a condition of obesity combined with and low muscle mass. This outcome is, without a doubt, a much worse condition to be in compared to being obese but with significant muscle mass, and the latter is what most obese people are prior to commencing keto diets. In the study’s own words – keto diets can provide some weight loss, but cannot reverse the metabolic dysfunction that led to the obesity in the first place, and in fact worsen said dysfunction. In addition, they can cause de-novo liver disease or worsen already present liver disease. In contrast, study subjects who were fed low-fat-low-protein or low-fat-medium-protein diets, lost much more weight than the subjects on the keto diet and actually saw reversal of the metabolic dysfunction that caused the obesity in the first place. Perhaps most worryingly, the mice on the keto diet seemed to have damaged pancreas glands, since they released very little insulin when challenged with a glucose load. That is effectively a precursor state of diabetes I, where the organism cannot produce enough of its own insulin, and the study agrees that keto diets seem to directly induce such a state of pancreatic insufficiency in regards to insulin production. As such, the low insulin touted by keto diet proponents turns out to be a very bad sign – i.e. a “bug” instead of a “feature” of the diet. This should not come as a surprise considering that multiple studies have shown it is precisely elevated fatty acids in the blood (as seen in keto diets and diabetes I/II) that damage not only the pancreas, but other organs such as the kidneys, liver, heart, brain, etc.

Staying on the keto diet long term could carry health risks

“…In the ketogenic diet, fat is king, and carbs are public enemy number one. Going keto means restricting carbs to the bare minimum and replacing those lost calories with fat. It’s the antithesis of the low-fat diet craze of the 1990s. Losing fat on keto diets typically means eating fat — and lots of it. The idea may sound paradoxical. But without our typical go-to energy source (sugar), our bodies learn to rely on a different type of fuel. In keto dieters, the liver converts fat into molecules called ketone bodies, which the body can burn instead of sugar. That can lead to weight loss, despite an unusually high intake of fat. Such results may explain why so many Americans have tried the keto diet on for size. “I think a lot of people look at a ketogenic diet and think, ‘I’ll lose weight, I’ll be healthier,’” says Molly Gallop, a physiologist at Earlham College in Richmond, Ind. On the surface, they may be right. But staying on the diet long-term could carry some risks, a new study in mice suggests. Mice fed a ketogenic diet for up to about a year — decades in human time — experienced health problems including glucose intolerance and signs of liver and cardiovascular disease, Gallop and her colleagues report September 19 in Science Advances. The work uncovers some potential hidden costs to going keto, says physiologist Amandine Chaix, at the University of Utah in Salt Lake City. “It’s a cautionary tale,” she says. People sticking to this high-fat plan need to be careful, she says, “because this is not a magical dietary approach.”

https://www.science.org/doi/10.1126/sciadv.adx2752

“…The ketogenic diet has grown in popularity over the past several decades as a tool for improving weight and metabolic health. While a KD benefits in treating epilepsy are concrete, its effects on metabolic health have been largely understudied. In particular, changes in glucose metabolism upon KD are not fully understood. As most people who go on a KD will likely consume glucose eventually due to the difficulty to strictly adhere to a KD long term (3), this is of critical importance for patients using a KD to treat obesity and related metabolic conditions such as type 2 diabetes. In addition, the very high-fat content of the diet can challenge whole body regulation of lipid homeostasis and may increase the risk of cardiovascular events (15).”

“…Our study is one of few long-term KD interventions (almost 1 year) in which mice had ad libitum access to KD without calorie restriction. We incorporated two low fat diets, a standard LFD with 20% kcal from proteins and a LFMP with a lower 10% kcals from proteins that matches KD protein content to control for the potential confounding effects of reduced proteins. Throughout our investigations, we found that the LFD and LFMP produced virtually identical phenotypes, suggesting that the effects of KD are independent of the more moderate protein content and consistent with studies showing that 10% protein is enough to support normal physiology in B6 mice (42, 43). We also included a comparison group on 60% HFD, the gold standard model of diet-induced obesity for which metabolic disturbances are well described and a group on 60% HFD with very low 0.1% carbohydrate. Our study was powered to detect significant differences, and our results were replicated in two to three independent cohorts. We performed extensive characterization of whole-body metabolic parameters, including state of the art, hyperglycemic clamp, dynamic GSIS, and electron microscopy (EM) experiments. Last, we included both sexes and carefully profiled the diet:sex interaction known to affect metabolic outcomes (44, 45). For the most part, the phenotypic effects of KD followed the same patterns in male and female mice, yet interesting differences were observed as discussed below. Our results set the ground for future investigations into the molecular determinants of KD-mediated insulin secretion defects.”
“…Prior research has led to conflicting findings on weight regulation on KDs. In our study, both male and female B6 mice fed a KD ad libitum gained less weight than mice on an obesogenic 60% HFD but more than mice on a LFD. Several rodent studies reported similar prevention of excessive weight gain on a KD as compared to an HFD (9, 18, 20, 27). Weight gain between KD and chow fed rodents has led to more discordant results, with several studies describing lower BW under KD (19, 22, 29, 46). Two lifelong studies of mice on KD, noted the necessity of restricting caloric intake (23) or cycling the KD with a LFD (9) to prevent obesity (9, 23), and another 8-week study in middle-aged females also reported using pair feeding to prevent weight obesity (47). The long-term duration of our study and differences in diet compositions across studies, for all diets, can all also affect the phenotypic outcomes (7, 48–50). Future studies could directly investigate these parameters that were not explored here.”
“…In our study, reduced caloric intake of KD and LFD/LFMP groups compared to HFD can at least partially explain the lower weight, although concomitant changes in energy expenditure were not assessed systematically. During our WL intervention, we observed a marked decrease in food intake during the first couple of weeks that matches the initial drop in weight. However, weight stabilized after mice increased their ad libitum caloric intake to levels that were slightly below mice maintained on HFD, suggesting that food intake was the main driver of weight changes. KD was less effective than chow diets at inducing WL as mice on LFD/ LFMP lost more than double the weight that mice on KD lost. Moreover, KD did not cure obesity but merely cause a transient WL that was reversed upon resumption of an HFD.”
“…Despite being lighter than mice fed a 60% HFD, males and females on KD had significant increases in plasma TGs and NEFA. KD-fed males also show hepatic steatosis and increased plasmatic ALT activity, suggestive of liver dysfunction. Those findings are in agreement with most other studies of KD (18, 20, 22). With the increasing prevalence of metabolic dysfunction–associated steatohepatitis and especially in people with obesity, the potential of KD to cause or worsen pre-existing hepatic dysfunction is of utmost concern.”
“…In our study, in vivo GSIS revealed a lack of insulin secretion in KD-fed mice in contrast to LFD and HFD groups. Reviewing the literature highlighted that regardless of the positive or negative effects of KD on GTT, insulin levels in KD mice were low across the board, irrespective of diet composition, age, or study duration (18, 19, 46, 51). While this is often pointed to as a positive effect (i.e., prevention or reversal of hyperinsulinemia), we posit that low-insulin levels on a KD are a hallmark of β cell dysfunction and can lead to other detrimental metabolic effects. Accordingly, two prior studies described reduced β cell mass as a cause of low insulin levels (30, 31). In our study, however, extensive characterization of islets mass did not point at differences in islets mass as the underlying determinants of KD-linked insulin secretion defect.”
“…Hyperglycemic clamp further uncovered inefficient rapid insulin secretion in KD-fed mice, a phenomenon that has not been described to the best of our knowledge. In mice on KD, insulin levels did not rise significantly until 90 min into the 120-min clamp study while mice on HFD and KD had an immediate rise in plasma insulin that peaked at 15 min. The exocytosis of insulin containing secretory granules docked at the plasma membrane (40, 52) is incriminated in the early insulin response to glucose, suggesting that this population of insulin granules may be specifically affected by a KD. To assess cell autonomous defects in insulin secretion, β cells were isolated and tested in an ex vivo dynamic GSIS assay. Both HFD and KD islets had reduced insulin secretion under high glucose compared to LFD islets. Upon KCl-induced depolarization, HFD islets secreted significantly more insulin suggestive of impaired glucose sensing. In contrast, islets from KD-fed mice released similarly low levels of insulin whether stimulated by glucose or KCl, indicating defective insulin secretory machinery.”
“…Transcriptomics analysis highlighted alterations in translation, protein transport, Golgi function, and ER/Golgi stress specific to KD islets. Pathways and genes associated with ER transport, COPI and II transport, and secretion from the Golgi were all elevated suggesting increased protein transport pre-Golgi. The transcriptional repression of Rab30 and Rab39, which are important for Golgi organization (38, 39, 56), suggested Golgi disorganization, and repression of Rab8b impaired Golgi vesicle secretion. From these data, we suggest a model in which Golgi-related defects lead to a traffic jam of proteins in the Golgi and a compensatory upregulation of pre-Golgi transport. ER/Golgi stress markers were also up-regulated under KD. For instance, Creb3l3, an ER/Golgi stress marker (57), was the most up-regulated gene in KD islets. CREB3 (of the same family as Creb3l3) is up-regulated by palmitate in human β cells where it attenuates palmitate toxicity and is hypothesized to act as a mediator of the Golgi stress response (58). Overall, we speculate that high lipids on KD lead to the development of a lipotoxicity stress, which has previously been shown to cause ER stress and disrupt ER to Golgi protein transport in islets (59, 60). Electron microscopy images further confirmed aberrations in the Golgi that appeared dilated and vesiculating in mice on a KD. A recent study characterized the disrupted protein trafficking observed in islets of diabetic leptin receptor KO db/db mice and uncovered distended and vesiculated Golgi very similar to what we see in our KD mice (61). Misfolded proinsulin released from the ER is put forth as cause of Golgi dilation and altered morphology (61). Incidentally, misfolded proinsulin has been suggested to occur in early stages of type 2 diabetes (T2D) (62), so it is possible that increases in misfolded proinsulin cause Golgi swelling and further impair insulin trafficking and secretion. Overall, we propose that extremely high-lipid levels under KD lead to ER/Golgi stress in islets, thereby disrupting protein trafficking and causing a traffic jam of vesicles in the Golgi. With impaired protein transport and ER stress, the pool of readily releasable insulin available may be insufficient for the islets to rapidly secrete insulin in response to glucose, thus leading to the observed glucose intolerance. It has been postulated that, early on, lipotoxicity induces an expansion of β cell that precedes β cell failure (63). We hypothesize that the extra high fat of a KD as compared to an HFD causes mice on KD to bypasses the islet proliferative phase as observed in HFD-fed mice and go straight to early β cell failure. Future experiments will be conducted to test this hypothesis.”
“…Many studies have shown that a KD can lower insulin levels in humans (64–68) and mice (19, 46), and while this is generally taken as a sign of improved glycemic control and remission of diabetes, our results led us to question whether low-insulin levels are safe and whether they actually indicate improved glycemic control. Insulin is crucial not only for glucose regulation but also for lipid homeostasis through stimulation of plasma lipid clearance and inhibition of lipolysis (69–71). Insulin resistance is accompanied by elevated blood lipids and ectopic lipid deposition (72, 73), as observed in HFD-fed mice. These metabolic alterations were also observed in KD-fed mice, suggesting that their very low levels of insulin might be insufficient to suppress lipolysis and promote the uptake and benign storage of the excess dietary fat in adipose tissues. Thus, while the lack of insulin on a KD may lead to a lower BW and less fat storage, it may worsens metabolic health by destabilizing lipid homeostasis.”
“…While our findings show that a KD both prevents and causes WL, a KD does not lead to permanent reductions in BW and, thus, should not be treated as a “cure” for obesity or diabetes. Moreover, we observed worsening glucose intolerance and impaired insulin secretion the longer the animals had been on KD, so the vision of KD as a treatment for metabolic disease should be questioned even if initial improvements in health are observed. Although we found that glucose intolerance caused by a KD is reversible, it is possible that other effects may persist. Moreover, in mice with diet-induced obesity, a traditional high-carbohydrate LFD caused greater WL than a KD while improving glucose intolerance.”
“…KD is used to manage refractory epilepsy in children. It is rarely a lifelong intervention as confirmed by a metanalysis of 45 studies reporting that, of children put on a KD, only 45% remain on the diet after 1 year and 29% after 2 years (74). Moreover, an international consensus group statement recommends discontinuing KD by 2 years with some experts recommending discontinuation by 6 months (2). Because KD is predominantly used in children and discontinued after a short time, long-term studies of metabolic effects are generally lacking. Nevertheless, high-plasma lipids, pancreatitis, and cardiac complications have been reported in patients on KD (2, 13, 15, 75–78). Studies around the world have also reported higher than average prevalence of diabetes in people with epilepsy (79–81). The reasons for this co-occurrence are unclear (82, 83), but one hypothesis is that epilepsy treatments increase the likelihood of diabetes (84).
In summary, while a KD can prevent and treat obesity, it causes hyperlipidemia, hepatic steatosis, and glucose intolerance. Unlike mice on HFD, the mice on KD do not have detectable insulin resistance or hyperinsulinemia. Instead, they have impairments in insulin secretion due to a blockade in protein trafficking resulting from dilation of the Golgi apparatus, which also causes ER/Golgi stress.”
“…Our study shows that while C57BL/6J male and female mice on a KD are protected from weight gain as compared to mice on a traditional 60% HFD, the mice experience severe glucose intolerance, high plasma lipids, and impaired insulin secretion with males also developing hepatic steatosis. Further studies in other strains of mice, other animal models, and in humans are necessary to determine whether KD-linked metabolic derangements are universal. Because the KD is not a standardized diet, it has been suggested that saturated versus unsaturated fats and different macronutrient compositions can lead to different metabolic outcomes. While we were able to replicate our results in a group of mice on another type of low-carbohydrate, HFD, future studies to elucidate whether the type of fat and macronutrient composition of the KD influences the metabolic outcomes will be important for making KD safer for all including those who require a KD to treat their epilepsy. Despite these limitations, our findings have relevant translational ramifications. They suggest that a KD used as a long-term dietary intervention may have harmful effects on metabolic health—especially in terms of β cell function, plasma lipid levels, and liver health—and caution against the systematic use of a KD as a health promoting dietary intervention.”
Author: haidut