Scientists at University of Utah Health have released groundbreaking research in Science Advances that delves into the prolonged impacts of the ketogenic diet. These discoveries spark important debates regarding the diet’s safety and efficacy for enhancing metabolic wellness over many months or years. Originally formulated as a therapy for epilepsy, the ketogenic approach has surged in popularity lately as a strategy for shedding pounds and tackling issues like obesity and type 2 diabetes. In their investigation, the researchers employed mice to scrutinize the diet’s influence on metabolic processes across extended durations, uncovering troubling alterations in the body’s management of fats and sugars.
The Fundamentals of the Ketogenic Diet
The ketogenic diet centers on consuming exceptionally high amounts of fats while drastically curtailing carbohydrate intake. It was initially devised to manage epileptic seizures in affected individuals. By minimizing carbs to a bare minimum, this eating pattern forces the body into ketosis—a metabolic state where fats are converted into ketones, which act as an alternative energy source for the brain. This transformation mirrors the effects of fasting and aids in steadying neural activity while curbing seizure occurrences. Although it’s now heavily marketed for slimming down and boosting metabolic function, prior investigations have largely concentrated on immediate results, overlooking sustained consequences.
“Previous research has mostly covered brief periods and fixated on weight reduction alone, without exploring extended timelines or broader aspects of metabolic well-being,” explained Molly Gallop, PhD, currently an assistant professor of anatomy and physiology at Earlham College. She spearheaded the research during her postdoctoral tenure in nutrition and integrative physiology at University of Utah Health.
Details of the Extended Research Effort
To fill this critical knowledge void, Gallop and her colleagues crafted a comprehensive, long-duration trial involving adult male and female mice. The subjects were divided into four distinct dietary groups: a high-fat diet mimicking Western eating patterns, a low-fat diet rich in carbohydrates, a classic ketogenic regimen supplying almost all calories from fats, and a low-fat diet adjusted to match protein levels. The mice had unrestricted access to their assigned foods for a minimum of nine months.
Throughout the experiment, the team diligently monitored shifts in body weight and dietary intake. They assessed blood lipid profiles, hepatic fat accumulation, glucose concentrations, and insulin responses. Furthermore, they analyzed gene expression in pancreatic beta cells responsible for insulin production and utilized cutting-edge microscopy techniques to illuminate the cellular underpinnings of the observed metabolic shifts.
Ketogenic Diet Curbed Weight Gain but Altered Body Makeup
When pitted against mice on the high-fat Western diet, those following the ketogenic plan experienced far less weight increase—a pattern consistent across both genders. That said, the nature of any gained weight was uneven. On the keto diet, increments were predominantly from fat deposits rather than muscle or lean mass.
Development of Fatty Liver Issues Despite Weight Management
While the ketogenic diet succeeded in staving off substantial weight gain, it simultaneously triggered grave metabolic disturbances, some manifesting as early as days into the regimen.
“It’s evident that on an ultra-high-fat diet, those lipids must accumulate somewhere, often flooding the bloodstream and the liver,” noted Amandine Chaix, PhD, assistant professor of nutrition and integrative physiology at University of Utah Health and the study’s senior author.
Hepatic steatosis, or fatty liver disease, stands as a hallmark of metabolic syndrome and frequently correlates with excess body weight. “Far from safeguarding against fatty liver disease, the ketogenic diet proved counterproductive,” Chaix emphasized.
Notably, sex-based disparities emerged prominently. Males exhibited pronounced fatty liver pathology coupled with compromised liver performance—a red flag for metabolic disorders. Females, conversely, displayed negligible hepatic fat deposition. Future inquiries will probe the reasons behind this female resilience.
Impaired Glucose Handling on the Ketogenic Diet
The diet also unleashed surprising disruptions in glycemic control. Following two to three months, keto-fed mice registered depressed blood glucose and insulin readings. Yet, this seeming advantage harbored a perilous flaw.
“The issue arises when you introduce even a modest carbohydrate load—their response is utterly deranged,” Chaix described. “Blood sugar spikes dramatically and persists at elevated levels, posing real hazards.”
Deeper probes revealed deficient insulin secretion from pancreatic cells during glucose challenges. The scientists attribute this to chronic high-fat exposure, which seemingly overburdened these cells, hampering protein trafficking essential for insulin release. Although the exact pathways remain under scrutiny, cellular strain is implicated as a primary culprit in this glucose dysregulation.
Encouragingly, glycemic control normalized after discontinuing the ketogenic diet, indicating that certain metabolic impairments could be reversible with dietary reversal.
Implications for Human Health and Recommendations
While rodent findings don’t invariably mirror human physiology, this work spotlights underexamined long-term metabolic pitfalls of ketosis. It advises caution for those eyeing the ketogenic diet, balancing touted upsides against latent downsides.
“I strongly recommend consulting a healthcare professional before embarking on a ketogenic diet,” Gallop advised.
The full study, titled “A long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin secretion in mice,” is published in Science Advances.
Funding was provided by the National Institutes of Health, encompassing grants from the National Institute on Aging (R01AG065993), National Institute of Diabetes and Digestive and Kidney Diseases (P30DK020579, F32DK137475, T32DK110966, DK108833, DK112826), National Heart, Lung, and Blood Institute (HL170575), and National Cancer Institute (R01CA222570). Supplementary backing included the Damon Runyon-Rachleff Innovation Award (DR 61-20) and American Cancer Society (RSG-22-014-01-CCB). The views expressed are those of the authors and not necessarily those of the funding agencies.
