Abstract
Cognitive dysfunction is an increasingly recognized complication of diabetes, contributing substantially to morbidity in the aging population, yet disease-modifying therapies remain scarce. Dietary intervention, a cornerstone of diabetes management, may offer neuroprotective potential. Low-carbohydrate ketogenic diets (LCKDs), typically restricting carbohydrates to < 50 g/day, effectively improve glycemic control and metabolic health. Emerging preclinical and clinical evidence suggests that LCKDs may also confer cognitive benefits through mechanisms including enhanced mitochondrial bioenergetics, reduced neuro-inflammation, and modulation of the gut-brain axis. This narrative review critically evaluates the current evidence regarding the efficacy, mechanisms, and safety of LCKDs for managing diabetes-associated cognitive dysfunction, identifies key limitations in the existing literature, and proposes a framework for future research to enhance translational value.
1 Introduction
The global prevalence of diabetes, particularly type 2 diabetes mellitus (T2DM), continues to rise, driven largely by population aging and the obesity epidemic (GBD 2021 Diabetes Collaborators, 2023; Sun et al., 2022; Antza et al., 2021; Lauder et al., 2023). This escalating trend contributes to a growing burden of diabetic complications on healthcare systems worldwide. Common macrovascular and microvascular complications, such as cardiovascular disease, nephropathy, and retinopathy, have long been the focus of clinical attention (Luk et al., 2025; Iwasaki et al., 2025; Alrubaiee, 2025; Nokihara et al., 2025). In recent years, however, cognitive dysfunction has emerged as a significant and increasingly recognized complication of diabetes. Epidemiological evidence indicates that among individuals aged 60 years and older with T2DM, the prevalence of dementia approaches 20% (Srikanth et al., 2020). Compared with normoglycemic counterparts, this population exhibits a 1.44-fold increased risk of mild cognitive impairment (MCI) (Jia et al., 2020) and a 2.8-fold higher risk of dementia (Schnaider Beeri et al., 2004). These findings highlight the pressing need for effective strategies to prevent and treat cognitive decline in diabetic patients, an area that remains largely unmet and warrants urgent investigation.
Despite growing recognition of this clinical challenge, several critical gaps persist in the existing literature. First, the pathophysiological mechanisms linking diabetes to cognitive impairment-encompassing insulin resistance, chronic neuro-inflammation, mitochondrial dysfunction, and vascular damage-are complex and incompletely understood, complicating the development of targeted interventions. Second, while dietary approaches have shown promise, most evidence derives from preclinical models or studies in non-diabetic populations with mild cognitive impairment or Alzheimer's disease, limiting direct applicability to diabetic cohorts. Third, available human studies are characterized by substantial heterogeneity in intervention protocols-including variations in carbohydrate thresholds, dietary fat composition, ketosis monitoring, and duration-as well as inconsistent outcome measures, which hinder cross-study comparison and synthesis. Fourth, safety considerations specific to diabetic patients, particularly regarding medication interactions (e.g., insulin, sodium-glucose cotransporter 2 inhibitors), renal function, and long-term metabolic effects, remain inadequately addressed. These gaps underscore the need for a critical evaluation of current evidence and a structured framework to guide future research.
Current management approaches for cognitive dysfunction in diabetes encompass multifactorial risk factor modification, treatment of underlying pathologies, and symptomatic interventions (Yang et al., 2022b; Sjöholm et al., 2025; Liu et al., 2020; Xu et al., 2025). Dietary patterns are increasingly recognized as modifiable risk factors, with healthy diets holding significant potential for neuroprotection. The low-carbohydrate ketogenic diet (LCKD), historically used for epilepsy, has demonstrated efficacy in improving hyperglycemia, facilitating weight loss, and ameliorating metabolic dysregulation in diabetes (Bruci et al., 2020; Ren et al., 2024; Merovci et al., 2024; Leung et al., 2025). Emerging evidence suggests that nutritional ketosis, characterized by beta-hydroxybutyrate (BHB) concentrations typically ranging from 0.5 to 5 mmol/L, confers dual benefits: it optimizes systemic metabolism and directly supports brain health by providing an alternative fuel source (Lennerz et al., 2021; Tosefsky et al., 2026). This review compiles and evaluates the evidence for LCKDs as a neuroprotective intervention for cognitive dysfunction in diabetes, with a focus on mechanistic pathways, clinical evidence, intervention heterogeneity, and safety considerations.
2 Defining the intervention and the target condition
2.1 Low-carbohydrate ketogenic diets: a spectrum of interventions
Dietary regimens restricting carbohydrates are heterogeneous. A daily carbohydrate intake below 130 g is generally classified as low-carbohydrate, while intakes ≤ 50 g per day is typically required to induce and maintain nutritional ketosis, defining a ketogenic diet (Charlot and Zoll, 2022; Sakr et al., 2023). Critically, not all low-carbohydrate diets are ketogenic. Moreover, ketogenic diets themselves vary considerably in their macronutrient composition. These include classic low-carbohydrate ketogenic diets (LCKDs), which are high in fat and moderate in protein; modified Mediterranean-ketogenic diets (MMKDs); and very-low-calorie ketogenic diets (VLCKDs) (Sukkar and Muscaritoli, 2021; Di Renzo et al., 2023; Calcaterra et al., 2023). These variations in macronutrient composition, calorie prescription, and duration significantly influence ketosis depth, metabolic effects, and tolerability, necessitating careful consideration when interpreting study outcomes.
2.2 Diabetes-associated cognitive dysfunction: phenotypes and outcomes
Cognitive dysfunction in diabetes represents a multifactorial continuum, typically classified into asymptomatic decline, MCI, and dementia. The associated dementia phenotypes are broadly categorized into two types: vascular dementia (VaD), resulting from cerebrovascular damage, and Alzheimer's disease (AD)-like pathology, driven by neurodegenerative alterations potentially accelerated by diabetes (Li et al., 2023; van Sloten et al., 2020; Zhang et al., 2023). Key cognitive domains affected include information processing speed, executive function, and memory (Murali et al., 2025; Palta et al., 2014), with assessment relying on standardized neuropsychological tools such as the Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), and domain-specific tests (Wang and Chen, 2025; Wei et al., 2025; Carlew et al., 2021). Interpretation of intervention effects requires simultaneous consideration of diabetes-related parameters, including hypoglycemia history (Lee et al., 2014), microvascular burden (Satapathy et al., 2025), and neuroimaging markers like white matter hyperintensities (WMH) (Lee et al., 2014; Sugimoto et al., 2025) and cerebral blood flow (CBF) (Li et al., 2024; Mondal et al., 2024; Chen et al., 2025). To structure the evidence, Table 1 summarizes the key cognitive outcomes and relevant diabetes-related parameters reported in clinical studies.
Table 1
| Author/Year/[reference] | Diabetes or not | Types of animal/participants | Data of laboratory/ clinical | Types of ketogenic diets | Neurological assessment tools | Relevant diabetes/CNS parameters | Effect (conclusion) |
|---|---|---|---|---|---|---|---|
| (Tosefsky et al. 2026) | Not | Participants | Clinical | MeDi-MCT vs. MeDi-KD | MDS-UPDRS, MoCA, PD-CRS | BHB, Brain BHB, plasma medium chain fatty acids, MDS-UPDRS | MeDi-MCT(Positive) MeDi-KD(Negative) |
| (Luong et al. 2025a) | Not | Participants | Clinical | KD | Neuropsychological test | HbA1c, BHB, BDNF, CBF | Positive |
| (Patoine et al. 2025) | Prediabetic adults | Participants | Clinical | MMKD MD | MoCA | BMI/DCCS, FName, Flanker, LSWM, PSMT, RAVLD, rey auditory verbal Learning Delay, Speed Matching Test | Obesity (Positive); Not-obesity: (Negative) |
| (Roslund et al. 2025) | Not | Middle-aged female mice | Laboratory | KD | Not mentioned | BHB, glucose catabolism, glucose-alanine cycle, brain glucose-dependent energy metabolism, lactate production downstream from glucose/hippocampus metabolome, cortex metabolome, hippocampal metabolites involved in myelinogenesis | Positive |
| Arabacı Tamer et al. (2025) | Diabetes | Adult male Wistar rats | Laboratory | KD | Hole-board test, Elevated plus maze test, Object recognition test | MDA, GSH, S100β, TNF-α, IL-6, BDNF, 8-OHdG, Ketone levels, Fasting glucose levels/Neuronal integrity (histopathological and immune-histochemical analyses of CA1, CA3, and dentate gyrus regions) | Positive |
| Abdel-Kareem et al. (2025) | Insulin-resistant | Rats | Laboratory | KD | MWM | IR index (homeostasis model assessment), BDNF, IDE activity, GSK3β activity, Tau protein, Aβ | Negative |
| (Park et al. 2024) | Not | Mice | Laboratory | MMKD | Neurocognitive and neuromuscular function | GTT, ITT, object Recognition Test, location Memory Test, T-maze Spontaneous Test, neuromuscular and motor function test | Positive |
| (Ren et al. 2024) | Diabetes | db/db mice | Laboratory | KD | Not mentioned | Fasting blood glucose, body weights/mRNA-seq analysis of brain gene expressions, DEGs in the brain, GSEA Proteasomal activity in the brain | Positive |
| Acuña-Catalán et al. (2024) | Not | aged mice | Laboratory | KD | Elevated plus maze, Novel object recognition, Open field, Y-maze, Barnes maze, Rotarod | Glycemia, BHB blood concentration/Elevated plus maze, open field, Y-maze, Barnes maze, Rotarod, novel object recognition, hippocampal slices electrophysiology, golgi staining, morphometric analysis of pyramidal neurons | Positive |
| (Di Lucente et al. 2024) | Not | Aged C57BL/6 mice | Laboratory | KD | Open field, Y-maze, Barnes maze | BHB/LTP, BDNF, p-ERK, p-CREB, glutamate release | Positive |
| (Gureev et al. 2024) | Not | Mice | Laboratory | BHB | MWM, String Test | String test, Rod test, Rotarod test, MWM, Mitochondrial metabolism, Tissue ATP levels, Nrf2/ARE signaling pathway activity, Antioxidant defenses, Inflammation status | Positive |
| (Jiang et al. 2023) | Not | APP/PS1 mice | Laboratory | KD | NORT,Y-maze spontaneous alternation test | Blood sugar levels, hyperinsulinemia, glucose metabolism, insulin sensitivity/Recognition index, Y-maze spontaneous alternation, Aβ deposition, GFAP expression, Iba1 expression, Nrf2 protein level HO-1 protein level, Phospho-IκBα protein level, NF-κB p65 protein level, Learning and memory capacity | Positive |
| (Rutkowsky et al. 2024) | Not | TgF344-AD rats | Laboratory | KD | Elevated plus maze, open field, grip strength, rotarod, Barnes maze | Glucose, ketone measurements/Barnes maze performance, rotarod test performance, grip strength, Aβ40, Aβ42, pTau, total Tau | Negative |
| (Dilmore et al. 2023) | Prediabetic adults | participants | Clinical | MMKD | Not mentioned | Hb1Ac,insulin/Aβ42, tau, cerebral ketone body uptake, cerebral perfusion | Positive |
| (Qin et al. 2023) | Not | APP/PS1mice | Laboratory | KD | MWM,Y maze | BHB/learning and memory ability, Brain iron deposition, Aβ, Neuronal ferroptosis, Nrf2-mediated ferroptosis pathway activity | Positive |
| (Di Renzo et al. 2023) | Not | Participants | Clinical | MMKD | Fibromyalgia Tests | EQ-5D | Positive |
| (Yang et al. 2022a) | Not | Female C57BL/6 mice | Laboratory | KD | MWM | BHB, Blood glucose/Aβ, p-tau, BACE1, BDNF, DCX, Iron deposition, Lipid peroxides accumulation, MDA, GSH, GPX4 | Positive |
| (Kumar et al. 2022) | Not | Participants | Clinical | MMKD vs. AHAD | ADNI-2, NIA-AA, LP, MRI | Aβ1-42, p181-tau, NfL, Ng, glutamate, glutamate receptor ionotropic NMDA1, glutamate receptor ionotropic NMDA2A, glutamate receptor ionotropic NMDA2B, glutamate receptor ionotropic AMPA type subunit 1, AGEs, MCT2 | Positive |
| (Brinkley et al. 2022) | Not | Participants | Clinical | MMKD vs. AHAD | ADNI-2, NIA-AA | Aβ42, Aβ40, total tau, tau-p181, Ng, sTREM2, YKL40, NfL, AChE activity, BChE activity, Aβ42/Aβ40 ratio, Aβ42/tau-p181 ratio, tau-p181/tau ratio, AChE/BChE activity | Positive |
| (Wang et al. 2021) | Not | PTZ-induced and kindled rats | Laboratory | KD | MWM | GluR1 (mRNA and protein expression), NR2B (mRNA and protein expression), MAPK activity, CAMKII activity | Positive |
| (Neth et al. 2020) | Not | Participants | Clinical | MMKD | FCSRT, WMS-R, ADAS-Cog12 | HbA1c, Glucose, Insulin/Aβ42, tau, Ng, Cerebral perfusion, Cerebral 11C-AcAc uptake, Executive function, attention, verbal abilities, emory, Capillary BHB | Positive |
| (Siegmann et al. 2019) | Prediabetic adults and diabetes | Participants | Clinical | Nutritional ketosis | PSQI | Weight, fasting blood glucose, HbA1c, HOMA-IR, BHB and hsCRP | Positive |
| (Nagpal et al. 2019) | Not | Participants | Clinical | MMKD vs. AHAD | Not mentioned | Aβ42, Aβ40, total tau, tau-p181 | Positive |
| (Xu et al. 2010) | Not | Aged rats | Laboratory | KD | Object recognition test, T-maze test, Inclined screen test | Blood ketone levels, BHB/Cognitive performance, T-maze test: alternation rate, time to choose arms, Object recognition test, new object exploration percent, Motor performance, Inclined-screen test, Brain cortex parameters, HIF-1a protein levels, Capillary density | Positive |
Summary of key outcomes in studies of ketogenic diets for cognitive dysfunction.
3 Neuroprotective mechanisms of ketogenic diets
The pathogenesis of diabetic cognitive dysfunction involves complex interactions between metabolic dysfunction and neurodegeneration. Key contributors include insulin resistance, cerebral microvascular damage, chronic neuroinflammation, oxidative stress, mitochondrial dysfunction, and dysregulation of the gut-brain axis (Yang et al., 2022b; Li et al., 2023; Wang et al., 2022; Little et al., 2022; Yue et al., 2024; Elzinga et al., 2025; Chen et al., 2023). Emerging evidence suggests that ketogenic diets may mitigate cognitive decline by targeting these interconnected pathways (Figure 1). This section synthesizes the evidence for these mechanisms, integrating recent findings and calibrating conclusions to the strength of the available data.
Figure 1
3.1 Amelioration of insulin resistance
Insulin resistance is a core pathophysiological feature linking T2DM to cognitive impairment. In the brain, insulin resistance disrupts signaling pathways crucial for neuronal survival, synaptic plasticity, and energy homeostasis. Notably, insulin-degrading enzyme (IDE) is responsible for cleaving both insulin and amyloid-beta (Aβ); hyperinsulinemia can competitively inhibit Aβ clearance (Kellar and Craft, 2020). The phosphatidylinositol-3 kinase/protein kinase B (PI3K/Akt) pathway, a key downstream insulin signaling cascade, is implicated in both diabetes and cognitive function (Constantino et al., 2018).
Preclinical studies indicate that ketogenic diets may modulate these pathways. In a rodent model of bipolar disorder, a ketogenic diet modulated the PI3K/Akt/HIF-1α pathway, coinciding with improved insulin sensitivity and cognitive performance (Campbell and Campbell, 2020). Short-term carbohydrate restriction in patients with MCI has been associated with reduced insulin resistance and neuroinflammation, alongside memory improvements (Gibas, 2017; Carneiro and Leloup, 2020). Mechanistically, studies in epileptic rats suggest that ketogenic diets may enhance cognitive function by modulating glutamate receptor expression and suppressing excessive MAPK pathway activation (Wang et al., 2021). Recent evidence further demonstrates that BHB directly inhibits class I histone deacetylases (HDACs), thereby upregulating genes associated with oxidative stress resistance and potentially influencing insulin sensitivity at the transcriptional level (Shimazu et al., 2013; Pali et al., 2025). While these findings are promising, direct evidence within diabetic populations remains limited and warrants further investigation.
3.2 Modulation of brain structure, metabolism, and perfusion
Cognitive dysfunction is underpinned by structural and functional cerebral alterations, including neuronal loss, impaired synaptic plasticity, and reduced cerebral blood flow (Liu Q. et al., 2025). Ketone bodies, particularly BHB, serve not only as an efficient brain fuel but also as signaling molecules that may influence these processes.
In aged mice, a ketogenic diet modulated the cortical synaptic proteome via the PKA signaling pathway, enhancing synaptic organization and improving memory (Acuña-Catalán et al., 2024). In APP/PS1 mice, a model of AD, a ketogenic diet restored hippocampal long-term potentiation (LTP)-a cellular correlate of learning and memory-through a BHB-mediated mechanism involving enhanced synaptic plasticity, reduced microglial inflammation, and increased brain-derived neurotrophic factor (BDNF) (Di Lucente et al., 2024). Ketogenic diets have also been shown to upregulate BDNF in the mouse cerebral cortex and reduce Aβ deposition and blood-brain barrier damage (Di Lucente et al., 2024; Al-Kuraishy et al., 2024; Yang et al., 2022a). In aged rats, cognitive improvement following a ketogenic diet was associated with elevated hypoxia-inducible factor-1α (HIF-1α) and subsequent cerebrovascular angiogenesis (Xu et al., 2010).
The latest clinical studies also provide evidence for the neuroprotective mechanism of LCKD. A modified Mediterranean-ketogenic diet (MMKD) has been associated with improved metabolic profiles, elevated cerebrospinal fluid Aβ42 levels, reduced tau protein, and increased whole-brain perfusion in neuroimaging studies (Neth et al., 2020). Furthermore, a 3-week intervention study with LCKD was shown to significantly increase plasma BHB levels, raise cerebral blood flow by 22%, and elevate plasma BDNF levels by 47% in healthy subjects (Luong et al., 2025a). These findings indicate that LCKD may serve as a potential approach for preventing and managing cognitive decline. These findings collectively suggest that ketogenic diets may exert neuroprotective effects through direct modulation of brain structure, metabolism, and perfusion.
3.3 Attenuation of neuroinflammation and oxidative stress
Chronic neuroinflammation and oxidative stress are pivotal in the pathogenesis of diabetic cognitive dysfunction. Hyperglycemia promotes oxidative stress and the accumulation of advanced glycation end products (AGEs), contributing to neurovascular injury (Michailidis et al., 2022). Microglia, the brain's resident immune cells, can become chronically activated, shifting to a pro-inflammatory (M1) phenotype and releasing cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), which exacerbate neuronal damage (Hou et al., 2025; Adamu et al., 2024).
Ketone bodies exhibit anti-inflammatory and antioxidant properties. In a mouse model of ischemic stroke, administration of BHB improved cognitive performance post-stroke, an effect attributed to enhanced neuronal plasticity, anti-inflammatory activity, and antioxidant capacity (Gureev et al., 2024). A 3-month ketogenic intervention in APP/PS1 mice reduced cerebral Aβ deposition and decreased pro-inflammatory cytokine levels, correlating with improved learning and memory (Jiang et al., 2023). Mechanistically, these benefits were linked to suppression of the nuclear factor-κB (NF-κB) inflammatory pathway and concurrent activation of the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) antioxidant axis (Shippy et al., 2025). Recent evidence extends these findings, demonstrating that BHB suppresses NLRP3 inflammasome activation in microglia, thereby attenuating neuroinflammatory responses (Shippy et al., 2020). While compelling, these findings require replication in models of diabetic cognitive dysfunction specifically.
3.4 Restoration of mitochondrial function
Mitochondrial dysfunction is a hallmark of both diabetes and neurodegenerative diseases. Impaired mitochondrial bioenergetics and defective mitophagy-the selective clearance of damaged mitochondria-contribute to neuronal stress and death (Carvalho and Moreira, 2023; Shafiee et al., 2025). In the BTBR mouse model of neurodevelopmental disorders, a 2-week ketogenic diet improved mitochondrial function and ameliorated behavioral and cognitive deficits (Ahn et al., 2020). The neuroprotective effects are hypothesized to stem from ketosis-induced enhancement of mitochondrial efficiency, reduced oxidative stress, and modulation of inflammatory pathways (Pawłowska et al., 2025; Paoli et al., 2024; Jang et al., 2023).
Recent advances have elucidated more specific mechanisms. Ketone bodies have been shown to enhance mitochondrial respiration and reduce reactive oxygen species (ROS) production by increasing the oxidized-to-reduced coenzyme Q (CoQ) ratio (Sato et al., 1995; Veech et al., 2001; Puchalska and Crawford, 2017). Additionally, BHB promotes mitochondrial biogenesis via activation of the PGC-1α pathway (Gómora-García et al., 2023; Hasan-Olive et al., 2019; Nesterova et al., 2024). A recent study in aged mice demonstrated that intermittent ketogenic feeding preserved mitochondrial function and neuromuscular junction integrity, correlating with improved cognitive and physical performance (Rutkowsky et al., 2024; Wallace et al., 2021; Roslund et al., 2025). However, direct evidence linking ketogenic diet-induced changes in mitochondrial function to cognitive outcomes in diabetes-specific models remains an important research priority.
3.5 Regulation of the gut-brain axis
The gut microbiota and its metabolites are increasingly recognized as modulators of brain function via the gut-brain axis. In older adults with MCI, a MMKD intervention altered gut microbiota composition, increasing the abundance of specific taxa (e.g., Enterobacteriaceae, Akkermansia) and increasing fecal short-chain fatty acid (propionate, butyrate) levels (Nagpal et al., 2019). These changes correlated with reduced AD pathological markers in cerebrospinal fluid and improved cognition. In MCI patients, a ketogenic diet reduced levels of GABA-producing gut microbes and fecal GABA, while increasing GABA-lowering taxa, suggesting modulation of GABA signaling as a potential mechanism for cognitive improvement (Dilmore et al., 2023).
More recent research has identified that ketogenic diets increase the Akkermansia muciniphila abundance, which is associated with improved gut barrier function and reduced systemic inflammation (Tang et al., 2025; Chelakkot et al., 2018; Paone et al., 2026). The resulting reduction in peripheral inflammatory cytokines may subsequently decrease neuroinflammation via the vagus nerve and circumventricular organs (Hosoi et al., 2002; Dantzer et al., 2000). These findings highlight the gut-brain axis as a promising therapeutic target, though the specific contribution of these microbial shifts to cognitive outcomes in diabetic populations requires further exploration.
3.6 Inhibition of ferroptosis
Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a potential mechanism in neurodegenerative diseases (Ursini and Maiorino, 2020; Xu et al., 2024; Liu et al., 2024; Wang et al., 2025; Kazmirczak et al., 2024; Chen et al., 2022a; Liu and Wang, 2022). Its relevance to cognitive dysfunction is supported by studies showing that inhibiting ferroptosis alleviates cognitive deficits in rodent models of ischemia-reperfusion injury and AD (Wang et al., 2023; Naderi et al., 2025; Sousa et al., 2023; Chen et al., 2022b; Fu et al., 2022; Lu et al., 2025; Li et al., 2025). A recent study reported that a low-carbohydrate diet suppressed ferroptosis, activated the hippocampal Sirt1-Nrf2 axis, and ameliorated sleep deprivation-induced cognitive dysfunction and AD-like pathology in mice (Yang et al., 2022a). In APP/PS1 mice, a 12-week low-carbohydrate diet intervention improved cognitive function, an effect potentially mediated by BHB-induced Nrf2 activation and subsequent regulation of neuronal ferroptosis and Aβ accumulation (Qin et al., 2023).
Collectively, these convergent mechanisms position ketone bodies as pleiotropic metabolites restoring cellular homeostasis under metabolic stress. In diabetes, where chronic hyperglycemia disrupts multiple adaptive pathways, nutritional ketosis recalibrates redox balance, energy availability, and inflammatory tone-systems-level determinants of neuronal resilience. This mechanistic breadth supports ketogenic metabolic therapy as a disease-modifying strategy warranting prioritized investigation in diabetic populations at risk for cognitive decline.
4 Safety and clinical considerations in diabetes
Implementing ketogenic diets in individuals with diabetes requires rigorous safety monitoring due to potential interactions with glucose-lowering medications and the presence of underlying comorbidities. Short-term adverse effects commonly include gastrointestinal disturbances and electrolyte imbalances collectively termed “keto flu” (Dyńka et al., 2026; Bostock et al., 2020; Sáenz de Pipaón et al., 2020). Long-term risks, however, necessitate more nuanced consideration in this population.
4.1 Medication interactions
Concomitant use of insulin or insulin secretagogues (e.g., sulfonylureas) with carbohydrate restriction significantly elevates hypoglycemia risk, mandating dose reductions upon diet initiation and continued adjustment throughout the intervention. The combination with sodium-glucose cotransporter-2 inhibitors warrants particular caution due to an increased, albeit rare, risk of euglycemic diabetic ketoacidosis (Long et al., 2021; Peters et al., 2015; Nasa et al., 2021). Recent evidence from a long-term case report demonstrated a 43% reduction in daily insulin requirements with ketogenic diet implementation, underscoring the necessity for substantial dose adjustments upon diet initiation (Koutnik et al., 2024; Gardemann et al., 2023; Wolver et al., 2021). Clinical practice guidelines emphasize the importance of close glucose monitoring and individualized insulin modification to mitigate hypoglycemia risk.
4.2 Dyslipidemia
Ketogenic diets high in saturated fat may elevate low-density lipoprotein cholesterol in susceptible individuals termed “hyper-responders,” potentially exacerbating cardiovascular risk (Norwitz et al., 2021; Budoff et al., 2024). Lipid profiles should be monitored at baseline and periodically during intervention (Kirkpatrick et al., 2019), with emphasis on dietary fat quality prioritizing monounsaturated and polyunsaturated fats over saturated fats (Liu Y. et al., 2025).
4.3 Renal considerations
High dietary protein intake, common in some low-carbohydrate ketogenic diet versions, may increase glomerular pressure and warrants caution in patients with chronic kidney disease (de Lorenzo et al., 2024). Nephrolithiasis represents a recognized risk, particularly attributable to urinary pH changes and hypocitraturia, with adequate hydration and potassium citrate supplementation potentially mitigating this risk (Ko et al., 2020).
4.4 Nutrient deficiencies
Long-term carbohydrate restriction may precipitate deficiencies in vitamins (e.g., B vitamins, vitamin D), minerals (e.g., magnesium, selenium), and fiber, necessitating supplementation or structured dietary planning with a registered dietitian (Churuangsuk et al., 2019; Tay et al., 2020).
4.5 Contraindications
Absolute contraindications include pregnancy, lactation, eating disorders, pancreatitis, liver failure, and specific metabolic disorders such as carnitine deficiency, porphyria, and pyruvate carboxylase deficiency (Tay et al., 2020; Barrea et al., 2024). Relative contraindications require careful risk-benefit assessment on an individual basis. These safety considerations collectively underscore the necessity of multidisciplinary management when implementing ketogenic interventions in diabetic populations.
5 Limitations and future directions
This review synthesizes current evidence positioning ketogenic metabolic therapy as a potential neuroprotective strategy for diabetes-associated cognitive dysfunction, yet several limitations warrant acknowledgment. The existing literature remains predominantly preclinical, with human studies confined to small samples, short durations, and heterogeneous interventions that impede cross-study comparison. Most clinical evidence derives from mild cognitive impairment or Alzheimer's disease populations rather than diabetic cohorts, limiting direct translatability. Furthermore, the absence of standardized cognitive endpoints and inconsistent reporting of diabetes- relevant parameters-such as hypoglycemia history, microvascular burden, and neuroimaging markers-precludes definitive conclusions regarding efficacy.
Moreover, the ε4 allele of apolipoprotein E (APOE4) represents the strongest genetic risk factor for Alzheimer's disease (AD), conferring an approximately fourfold increase in AD risk among ~34 million American women and 75 million European women. Metabolic deficits in the brain are detectable in APOE4 carriers decades before clinical symptom onset (Di Lucente et al., 2026). The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) is widely regarded as the gold standard for assessing cognitive impairment in AD. Interventions based on ketogenic diets (KD) or medium-chain triglycerides (MCT) have been associated with improvements in ADAS-Cog scores, particularly in individuals who are APOE4 non-carriers (Taylor et al., 2017; Reger et al., 2004). Specifically, MCT supplementation has been linked to improved ADAS-Cog performance in APOE4-negative individuals, whereas no statistically significant cognitive benefits have been observed among APOE4-positive participants (Reger et al., 2004). In a multicenter, randomized, placebo-controlled trial, supplementation with AC-1202 led to significant improvements in ADAS-Cog scores in individuals who were APOE4-negative with mild-to-moderate Alzheimer's disease, while no significant benefit was detected in those carrying the APOE4 allele (Henderson et al., 2009). Collectively, these findings highlight the critical role of APOE4 genotype in modulating the therapeutic response to ketogenic interventions and underscore the need for genotype-informed, personalized treatment strategies.
Several priorities emerge for future investigation. First, rigorous randomized controlled trials are needed in phenotypically characterized diabetic populations, incorporating standardized cognitive batteries alongside concurrent assessment of glycemic control, vascular status, and brain imaging biomarkers (Luong et al., 2025b; Dyńka et al., 2026). Second, intervention protocols require harmonization regarding carbohydrate thresholds, dietary fat quality, ketosis monitoring, and duration to enable cross-study comparability. Third, mechanistic studies integrated within clinical trials should confirm target engagement-via neuroimaging of brain ketone uptake or cerebrospinal fluid analysis of neurodegenerative and inflammatory markers-and identify response biomarkers to guide patient stratification. Fourth, long-term safety data beyond 12 months are essential, particularly regarding cardiovascular outcomes, renal function, and medication interactions in diabetic patients with varying comorbidities.
Addressing these priorities will determine whether ketogenic metabolic therapy can transition from mechanistic promise to evidence-based clinical application for mitigating cognitive decline in the aging diabetic population.
6 Conclusions and future perspectives
Current evidence suggests ketogenic diets exert neuroprotection against diabetes-associated cognitive dysfunction through synergistic mechanisms-improved insulin sensitivity, reduced neuro-inflammation, enhanced mitochondrial function, and gut-brain axis modulation. Substantial gaps remain, however. The evidence base is predominantly preclinical; human studies are limited by small sample sizes, short durations, and heterogeneous interventions. Inconsistent outcome reporting and insufficient attention to diabetes-specific safety further limit translational value.
Advancing the field requires: (i) rigorous randomized trials in diabetic populations using standardized cognitive endpoints; (ii) harmonized intervention protocols defining carbohydrate thresholds, fat quality, and ketosis monitoring; (iii) evidence-based safety guidelines tailored to diabetes, including long-term data beyond 12 months; and (iv) mechanistic studies integrated within trials to confirm target engagement and identify response biomarkers.
Addressing these priorities is essential to determine whether ketogenic metabolic therapy represents a safe, effective strategy to mitigate cognitive decline in the aging diabetic population.
Statements
Author contributions
YX: Writing – review & editing, Writing – original draft. WZ: Funding acquisition, Writing – review & editing, Writing – original draft.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This work was supported by grants from Zhejiang Province Traditional Chinese Medicine Science and Technology project (Nos. 2023ZL310 and 2025ZL344), Medical and Health Science Program of Zhejiang Province (No. 2025HY0265), Noncommunicable Chronic Diseases-National Science and Technology Major Project (2025ZD0550900 and 2025ZD0550904), and Pre-research project of National Natural Science Foundation of Zhejiang Chinese Medicine University (No. 2018ZG15).
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declared that generative AI was not used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1
Abdel-KareemN. M.ElshazlyS. M.AbdE. F. M. A.ZaitoneS. A.ElmasryT. A.SalehA.et al. (2025). Ramipril and ketogenic diet response in cognitive dysfunction of insulin-resistant rats. Front. Pharmacol.16:1620139. doi: 10.3389/fphar.2025.1620139
2
Acuña-CatalánD.ShahS.WehrfritzC.NomuraM.AcevedoA.OlmosC.et al. (2024). Ketogenic diet administration later in life improves memory by modifying the synaptic cortical proteome via the PKA signaling pathway in aging mice. Cell Rep. Med. 5:101593. doi: 10.1016/j.xcrm.2024.101593
3
AdamuA.LiS.GaoF.XueG. (2024). The role of neuroinflammation in neurodegenerative diseases: current understanding and future therapeutic targets. Front. Aging Neurosci. 16:1347987. doi: 10.3389/fnagi.2024.1347987
4
AhnY.SabounyR.VillaB. R.YeeN. C.MychasiukR.UddinG. M.et al. (2020). Aberrant mitochondrial morphology and function in the BTBR mouse model of autism is improved by two weeks of ketogenic diet. Int. J. Mol. Sci. 21:3266. doi: 10.3390/ijms21093266
5
Al-KuraishyH. M.JabirM. S.AlbuhadilyA. K.Al-GareebA. I.JawadS. F.SwelumA. A.et al. (2024). Role of ketogenic diet in neurodegenerative diseases focusing on Alzheimer diseases: the guardian angle. Ageing Res. Rev. 95:102233. doi: 10.1016/j.arr.2024.102233
6
AlrubaieeG. G. (2025). Prevalence of chronic diabetic complications and associated risk factors among follow-up diabetic patients: estimates from a referral national diabetes center in Yemen. BMC Endocr. Disord. 25:68. doi: 10.1186/s12902-025-01893-5
7
AntzaC.KostopoulosG.MostafaS.NirantharakumarK.TahraniA. (2021). The links between sleep duration, obesity and type 2 diabetes mellitus. J. Endocrinol. 252, 125–141. doi: 10.1530/JOE-21-0155
8
Arabacı TamerS.DoǧanayS.KöseF.BolatI.Ahmed AhmedN. I. (2025). Neuroprotective and Cognitive benefits of a ketogenic diet in a type 2 diabetes rat model. Mol. Neurobiol.63:208. doi: 10.1007/s12035-025-05328-z
9
BarreaL.CaprioM.CamajaniE.VerdeL.PerriniS.CignarelliA.et al. (2024). Ketogenic nutritional therapy (KeNuT)-a multi-step dietary model with meal replacements for the management of obesity and its related metabolic disorders: a consensus statement from the working group of the Club of the Italian Society of Endocrinology (SIE)-diet therapies in endocrinology and metabolism. J. Endocrinol. Invest. 47, 487–500. doi: 10.1007/s40618-023-02258-2
10
BostockE. C. S.KirkbyK. C.TaylorB. V.HawrelakJ. A. (2020). Consumer reports of “Keto Flu” associated with the ketogenic diet. Front. Nutr. 7:20. doi: 10.3389/fnut.2020.00020
11
BrinkleyT. E.LengI.RegisterT. C.NethB. J.ZetterbergH.BlennowK.et al. (2022). Changes in adiposity and cerebrospinal fluid biomarkers following a modified mediterranean ketogenic diet in older adults at risk for Alzheimer's disease. Front Neurosci.16:906539. doi: 10.3389/fnins.2022.906539
12
BruciA.TuccinardiD.TozziR.BalenaA.SantucciS.FrontaniR.et al. (2020). Very low-calorie ketogenic diet: a safe and effective tool for weight loss in patients with obesity and mild kidney failure. Nutrients12:333. doi: 10.3390/nu12020333
13
BudoffM.ManuboluV. S.KinningerA.NorwitzN. G.FeldmanD.WoodT. R.et al. (2024). Carbohydrate restriction-induced elevations in LDL-cholesterol and atherosclerosis: the KETO trial. JACC Adv. 3:101109. doi: 10.1016/j.jacadv.2024.101109
14
CalcaterraV.CenaH.SottotettiF.HrubyC.MadiniN.ZelaschiN.et al. (2023). Low-calorie ketogenic diet: potential application in the treatment of polycystic ovary syndrome in adolescents. Nutrients15:3582. doi: 10.3390/nu15163582
15
CampbellI.CampbellH. (2020). Mechanisms of insulin resistance, mitochondrial dysfunction and the action of the ketogenic diet in bipolar disorder. Focus on the PI3K/AKT/HIF1-a pathway. Med. Hypotheses. 145:110299. doi: 10.1016/j.mehy.2020.110299
16
CarlewA. R.SmithE. E.GoetteW.LippeB.LacritzL.RossettiH.et al. (2021). Montreal cognitive assessment (MoCA) scores in medically compromised patients: a scoping review. Health Psychol. 40, 717–726. doi: 10.1037/hea0001138
17
CarneiroL.LeloupC. (2020). Mens sana in corpore sano: does the glycemic index have a role to play?Nutrients12:2989. doi: 10.3390/nu12102989
18
CarvalhoC.MoreiraP. I. (2023). Metabolic defects shared by Alzheimer's disease and diabetes: a focus on mitochondria. Curr. Opin. Neurobiol. 79:102694. doi: 10.1016/j.conb.2023.102694
19
CharlotA.ZollJ. (2022). Beneficial effects of the ketogenic diet in metabolic syndrome: a systematic review. Diabetologia2022:292–309. doi: 10.3390/diabetology3020020
20
ChelakkotC.ChoiY.KimD. K.ParkH. T.GhimJ.KwonY.et al. (2018). Akkermansia muciniphila-derived extracellular vesicles influence gut permeability through the regulation of tight junctions. Exp. Mol. Med. 50:e450. doi: 10.1038/emm.2017.282
21
ChenJ.GuoP.HanM.ChenK.QinJ.YangF.et al. (2023). Cognitive protection of sinomenine in type 2 diabetes mellitus through regulating the EGF/Nrf2/HO-1 signaling, the microbiota-gut-brain axis, and hippocampal neuron ferroptosis. Phytother. Res. 37, 3323–3341. doi: 10.1002/ptr.7807
22
ChenJ.LiX.GeC.MinJ.WangF. (2022a). The multifaceted role of ferroptosis in liver disease. Cell Death Differ. 29, 467–480. doi: 10.1038/s41418-022-00941-0
23
ChenL.DarN. J.NaR.McLaneK. D.YooK.HanX.et al. (2022b). Enhanced defense against ferroptosis ameliorates cognitive impairment and reduces neurodegeneration in 5xFAD mice. Free Radic. Biol. Med. 180, 1–12. doi: 10.1016/j.freeradbiomed.2022.01.002
24
ChenX.HuangY.XiongX. (2025). Mechanisms underlying cognitive impairment and management strategies in type 2 diabetes. Front. Endocrinol. 16:1655768. doi: 10.3389/fendo.2025.1655768
25
ChuruangsukC.GriffithsD.LeanM. E. J.CombetE. (2019). Impacts of carbohydrate-restricted diets on micronutrient intakes and status: a systematic review. Obes. Rev. 20, 1132–1147. doi: 10.1111/obr.12857
26
ConstantinoL. C.BinderL. B.Vandresen-FilhoS.ViolaG. G.LudkaF. K.LopesM. W.et al. (2018). Role of phosphatidylinositol-3 kinase pathway in NMDA preconditioning: different mechanisms for seizures and hippocampal neuronal degeneration induced by quinolinic acid. Neurotox Res. 34, 452–462. doi: 10.1007/s12640-018-9903-5
27
DantzerR.KonsmanJ. P.BluthéR. M.KelleyK. W. (2000). Neural and humoral pathways of communication from the immune system to the brain: parallel or convergent?Auton. Neurosci. 85, 60–65. doi: 10.1016/S1566-0702(00)00220-4
28
de LorenzoA.BombackA. S.MihicN. (2024). High protein diets and glomerular hyperfiltration in athletes and bodybuilders: is chronic kidney disease the real finish line?Sports Med. 54, 2481–2495. doi: 10.1007/s40279-024-02086-1
29
Di LucenteJ.PersicoG.ZhouZ.JinL. W.RamseyJ. J.RutkowskyJ. M.et al. (2024). Ketogenic diet and BHB rescue the fall of long-term potentiation in an Alzheimer's mouse model and stimulates synaptic plasticity pathway enzymes. Commun. Biol. 7:195. doi: 10.1038/s42003-024-05860-z
30
Di LucenteJ.RutkowskyJ. M.Errico ProvenzanoA.et al. (2026). A ketogenic diet improves memory in females in the APOE4 mouse model of Alzheimer's disease. Geroscience48, 1937–1954. doi: 10.1007/s11357-025-01998-8
31
Di RenzoL.GualtieriP.ZomparelliS.De SantisG. L.SeracenoS.ZuenaC.et al. (2023). A modified mediterranean-ketogenic diet and carboxytherapy as personalized therapeutic strategies in lipedema: a pilot study. Nutrients15:3654. doi: 10.3390/nu15163654
32
DilmoreA. H.MartinoC.NethB. J.WestK. A.ZemlinJ.RahmanG.et al. (2023). Alzheimer's Gut Microbiome Project Consortium. Effects of a ketogenic and low-fat diet on the human metabolome, microbiome, and foodome in adults at risk for Alzheimer's disease. Alzheimers Dement. 19, 4805–4816. doi: 10.1002/alz.13007
33
DyńkaD.RodzeńŁ.RodzeńM.ŁojkoD.Karakuła-JuchnowiczH.EdeG.et al. (2026). The ketogenic diet is not for everyone: contraindications, side effects, and drug interactions. Ann. Med. 58:2603016. doi: 10.1080/07853890.2025.2603016
34
ElzingaS. E.GuoK.TurfahA.HennR. E.Webber-DavisI. F.HayesJ. M.et al. (2025). Metabolic stress and age drive inflammation and cognitive decline in mice and humans. Alzheimers Dement. 21:e70060. doi: 10.1002/alz.70060
35
FuC.WuY.LiuS.LuoC.LuY.LiuM.et al. (2022). Rehmannioside A improves cognitive impairment and alleviates ferroptosis via activating PI3K/AKT/Nrf2 and SLC7A11/GPX4 signaling pathway after ischemia. J. Ethnopharmacol. 289:115021. doi: 10.1016/j.jep.2022.115021
36
GardemannC.KnowlesS.MarquardtT. (2023). Managing type 1 diabetes mellitus with a ketogenic diet. Endocrinol. Diabetes Metab. Case Rep. 2023, 1–7. doi: 10.1530/EDM-23-0008
37
GBD 2021 Diabetes Collaborators. (2023). Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet402, 203–234. doi: 10.1016/S0140-6736(23)01301-6
38
GibasK. J. (2017). The starving brain: overfed meets undernourished in the pathology of mild cognitive impairment (MCI) and Alzheimer's disease (AD). Neurochem Int. 110, 57–68. doi: 10.1016/j.neuint.2017.09.004
39
Gómora-GarcíaJ. C.MontielT.HüttenrauchM.Salcido-GómezA.García-VelázquezL.Ramiro-CortésY.et al. (2023). Effect of the ketone body, D-β-hydroxybutyrate, on sirtuin2-mediated regulation of mitochondrial quality control and the autophagy-lysosomal pathway. Cells12:486. doi: 10.3390/cells12030486
40
GureevA. P.SadovnikovaI. S.ChernyshovaE. V.TsvetkovaA. D.BabenkovaP. I.NesterovaV. V.et al. (2024). Beta-hydroxybutyrate mitigates sensorimotor and cognitive impairments in a photothrombosis-induced ischemic stroke in mice. Int. J. Mol. Sci. 25:5710. doi: 10.3390/ijms25115710
41
Hasan-OliveM. M.LauritzenK. H.AliM.RasmussenL. J.Storm-MathisenJ.BergersenL. H. A.et al. (2019). Ketogenic diet improves mitochondrial biogenesis and bioenergetics via the PGC1α-SIRT3-UCP2 Axis. Neurochem. Res. 44, 22–37. doi: 10.1007/s11064-018-2588-6
42
HendersonS. T.VogelJ. L.BarrL. J.GarvinF.JonesJ. J.CostantiniL. C.et al. (2009). Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer's disease: a randomized, double-blind, placebo-controlled, multicenter trial. Nutr. Metab. 6:31. doi: 10.1186/1743-7075-6-31
43
HosoiT.OkumaY.NomuraY. (2002). The mechanisms of immune-to-brain communication in inflammation as a drug target. Curr. Drug Targets Inflamm. Allergy1, 257–262. doi: 10.2174/1568010023344599
44
HouY.ChenZ.ChengJ.LiG.YinL.GaoJ.et al. (2025). The mechanism and treatment of cognitive dysfunction in diabetes: a review. Exp. Clin. Endocrinol. Diabetes133, 64–72. doi: 10.1055/a-2480-7826
45
IwasakiH.YagyuH.ShimanoH. A. (2025). Comprehensive analysis of diabetic complications and advances in management strategies. J. Atheroscler. Thromb. 32, 550–559. doi: 10.5551/jat.65551
46
JangJ.KimS. R.LeeJ. E.LeeS.SonH. J.ChoeW.et al. (2023). Molecular mechanisms of neuroprotection by ketone bodies and ketogenic diet in cerebral ischemia and neurodegenerative diseases. Int. J. Mol. Sci. 25:124. doi: 10.3390/ijms25010124
47
JiaL.DuY.ChuL.ZhangZ.LiF.LyuD.et al. (2020). Prevalence, risk factors, and management of dementia and mild cognitive impairment in adults aged 60 years or older in China: a cross-sectional study. Lancet Public Health5, e661–e671. doi: 10.1016/S2468-2667(20)30185-7
48
JiangJ.PanH.ShenF.TanY.ChenS. (2023). Ketogenic diet alleviates cognitive dysfunction and neuroinflammation in APP/PS1 mice via the Nrf2/HO-1 and NF-κB signaling pathways. Neural. Regen. Res. 18, 2767–2772. doi: 10.4103/1673-5374.373715
49
KazmirczakF.VogelN. T.PriscoS. Z.PattersonM. T.AnnisJ.MoonR. T.et al. (2024). Ferroptosis-mediated inflammation promotes pulmonary hypertension. Circ. Res. 135, 1067–1083. doi: 10.1161/CIRCRESAHA.123.324138
50
KellarD.CraftS. (2020). Brain insulin resistance in Alzheimer's disease and related disorders: mechanisms and therapeutic approaches. Lancet Neurol. 19, 758–766. doi: 10.1016/S1474-4422(20)30231-3
51
KirkpatrickC. F.BolickJ. P.Kris-EthertonP. M.SikandG.AspryK. E.SofferD. E.et al. (2019). Review of current evidence and clinical recommendations on the effects of low-carbohydrate and very-low-carbohydrate (including ketogenic) diets for the management of body weight and other cardiometabolic risk factors: a scientific statement from the National Lipid Association Nutrition and Lifestyle Task Force. J. Clin. Lipidol. 13, 689–711, e1. doi: 10.1016/j.jacl.2019.08.003
52
KoG. J.RheeC. M.Kalantar-ZadehK.JoshiS. (2020). The effects of high-protein diets on kidney health and longevity. J. Am. Soc. Nephrol. 31, 1667–1679. doi: 10.1681/ASN.2020010028
53
KoutnikA. P.KleinS.RobinsonA. T.WatsoJ. C. (2024). Efficacy and safety of long-term ketogenic diet therapy in a patient with type 1 diabetes. JCEM Case Rep. 2:luae102. doi: 10.1210/jcemcr/luae102
54
KumarA.SharmaM.SuY.SinghS.HsuF. C.NethB. J.et al. (2022). Small extracellular vesicles in plasma reveal molecular effects of modified Mediterranean-ketogenic diet in participants with mild cognitive impairment. Brain Commun.4:fcac262. doi: 10.1093/braincomms/fcac262
55
LauderL.MahfoudF.AziziM.BhattD. L.EwenS.KarioK.et al. (2023). Hypertension management in patients with cardiovascular comorbidities. Eur. Heart J. 44, 2066–2077. doi: 10.1093/eurheartj/ehac395
56
LeeJ. H.ChoiY.JunC.HongY. S.ChoH. B.KimJ. E.et al. (2014). Neurocognitive changes and their neural correlates in patients with type 2 diabetes mellitus. Endocrinol. Metab. 29, 112–121. doi: 10.3803/EnM.2014.29.2.112
57
LennerzB. S.KoutnikA. P.AzovaS.WolfsdorfJ. I.LudwigD. S. (2021). Carbohydrate restriction for diabetes: rediscovering centuries-old wisdom. J. Clin. Invest. 131:e142246. doi: 10.1172/JCI142246
58
LeungL. Y.TamH. L.HoJ. K. (2025). Effects of ketogenic and low-carbohydrate diets on the body composition of adults with overweight or obesity: a systematic review and meta-analysis of randomised controlled trials. Clin Nutr. 46, 10–18. doi: 10.1016/j.clnu.2025.01.017
59
LiH.RenJ.LiY.WuQ.WeiJ. (2023). Oxidative stress: the nexus of obesity and cognitive dysfunction in diabetes. Front. Endocrinol. 14:1134025. doi: 10.3389/fendo.2023.1134025
60
LiM.LiY.ZhaoK.QinC.ChenY.LiuY.et al. (2024). Abnormal cerebral blood flow and brain function in type 2 diabetes mellitus. Endocrine85, 433–442. doi: 10.1007/s12020-023-03342-6
61
LiQ.HeB.XiongY. (2025). Calycosin attenuates neuronal ferroptosis in Alzheimer's disease mice by activating the Nrf2/HO-1 pathway. Gen. Physiol. Biophys. 44, 363–375. doi: 10.4149/gpb_2025021
62
LittleK.Llorián-SalvadorM.ScullionS.HernándezC.Simó-ServatO.Del MarcoA.et al. (2022). Common pathways in dementia and diabetic retinopathy: understanding the mechanisms of diabetes-related cognitive decline. Trends Endocrinol. Metab. 33, 50–71. doi: 10.1016/j.tem.2021.10.008
63
LiuQ.DaiS.LiX.ChenY.WangN.WuJ.et al. (2025). A review of brain research on T2DM-related cognitive dysfunction. Open Med. 20:20251253. doi: 10.1515/med-2025-1253
64
LiuY.FengD.ShuiL.WangY. J.YuL.LiuY. Q.et al. (2024). The research landscape of ferroptosis in neurodegenerative disease: a bibliometric analysis. Front. Aging Neurosci. 16:1417989. doi: 10.3389/fnagi.2024.1417989
65
LiuY.WangJ. (2022). Ferroptosis, a rising force against renal fibrosis. Oxid. Med. Cell Longev. 2022:7686956. doi: 10.1155/2022/7686956
66
LiuY.WangJ.ChangX.RenX.WangG.LiuJ.et al. (2025). Association between saturated and polyunsaturated fatty acid proportions in total fat intake and mortality risk: mediation by the neutrophil percentage-to-albumin ratio. Lipids Health Dis. 24:175. doi: 10.1186/s12944-025-02592-9
67
LiuZ.DaiX.ZhangH.ShiR.HuiY.JinX.et al. (2020). Gut microbiota mediates intermittent-fasting alleviation of diabetes-induced cognitive impairment. Nat. Commun. 11:855. doi: 10.1038/s41467-020-14676-4
68
LongB.LentzS.KoyfmanA.GottliebM. (2021). Euglycemic diabetic ketoacidosis: etiologies, evaluation, and management. Am. J. Emerg. Med. 44, 157–160. doi: 10.1016/j.ajem.2021.02.015
69
LuQ.ShaoN.FangZ.OuyangZ.ShenY.YangR.et al. (2025). The anti-Alzheimer's disease effects of ganoderic acid A by inhibiting ferroptosis-lipid peroxidation via activation of the NRF2/SLC7A11/GPX4 signaling pathway. Chem. Biol. Interact. 412:111459. doi: 10.1016/j.cbi.2025.111459
70
LukA.WildS. H.JonesS.AnjanaR. M.HivertM. F.McCaffreyJ.et al. (2025). Early-onset type 2 diabetes: the next major diabetes transition. Lancet405, 2313–2326. doi: 10.1016/S0140-6736(25)00830-X
71
LuongT.SvartM.GormsenL. C.SøndergaardE. (2025b). Ketogenic diet in the management of disease. Curr. Opin. Clin. Nutr. Metab Care28, 477–482. doi: 10.1097/MCO.0000000000001158
72
LuongT. V.HansenK. V.HansenA. K.CunnaneS. C.MøllerN.SøndergaardE.et al. (2025a). 3-week ketogenic diet increases global cerebral blood flow and brain-derived neurotrophic factor. J. Clin. Endocrinol. Metab. 110, e4176–e4181. doi: 10.1210/clinem/dgaf207
73
MerovciA.FinleyB.Hansis-DiarteA.NeppalaS.Abdul-GhaniM. A.CersosimoE.et al. (2024). Effect of weight-maintaining ketogenic diet on glycemic control and insulin sensitivity in obese T2D subjects. BMJ Open Diabetes Res. Care12:e004199. doi: 10.1136/bmjdrc-2024-004199
74
MichailidisM.MoraitouD.TataD. A.KalinderiK.PapamitsouT.PapaliagkasV.et al. (2022). Alzheimer's disease as type 3 diabetes: common pathophysiological mechanisms between Alzheimer's disease and type 2 diabetes. Int. J. Mol. Sci. 23:2687. doi: 10.3390/ijms23052687
75
MondalR.DebS.ChowdhuryD.SarkarS.Guha RoyA.ShomeG.et al. (2024). Neurometabolic substrate transport across brain barriers in diabetes mellitus: implications for cognitive function and neurovascular health. Neurosci. Lett. 843:138028. doi: 10.1016/j.neulet.2024.138028
76
MuraliN. V.JosephN.GangadharaV. K. (2025). Determinants of selective domains of cognitive impairment among diabetes mellitus patients: a primary health care setting-based study in India. Sci. Rep. 15:44891. doi: 10.1038/s41598-025-28613-2
77
NaderiS.KhodagholiF.JanahmadiM.MotamediF.TorabiA.BatoolZ.et al. (2025). Ferroptosis and cognitive impairment: unraveling the link and potential therapeutic targets. Neuropharmacology263:110210. doi: 10.1016/j.neuropharm.2024.110210
78
NagpalR.NethB. J.WangS.CraftS.YadavH. (2019). Modified Mediterranean-ketogenic diet modulates gut microbiome and short-chain fatty acids in association with Alzheimer's disease markers in subjects with mild cognitive impairment. EBioMed. 47, 529–542. doi: 10.1016/j.ebiom.2019.08.032
79
NasaP.ChaudharyS.ShrivastavaP. K.SinghA. (2021). Euglycemic diabetic ketoacidosis: a missed diagnosis. World J. Diabetes. 12, 514–523. doi: 10.4239/wjd.v12.i5.514
80
NesterovaV. V.BabenkovaP. I.BrezgunovaA. A.SamoylovaN. A.SadovnikovaI. S.SemenovichD. S.et al. (2024). Differences in the effect of beta-hydroxybutyrate on the mitochondrial biogenesis, oxidative stress and inflammation markers in tissues from young and old rats. Biochemistry89, 1336–1348. doi: 10.1134/S0006297924070149
81
NethB. J.MintzA.WhitlowC.JungY.Solingapuram SaiK.RegisterT. C.et al. (2020). Modified ketogenic diet is associated with improved cerebrospinal fluid biomarker profile, cerebral perfusion, and cerebral ketone body uptake in older adults at risk for Alzheimer's disease: a pilot study. Neurobiol. Aging. 86, 54–63. doi: 10.1016/j.neurobiolaging.2019.09.015
82
NokiharaM.FujiharaK.YaguchiY.TakizawaH.KhinL.FerreiraE. A.et al. (2025). The associations of body mass index and waist circumference with the risk of diabetic complications in people with type 2 diabetes mellitus. Diabetes Obes. Metab. 27, 4259–4267. doi: 10.1111/dom.16461
83
NorwitzN. G.FeldmanD.Soto-MotaA.KalayjianT.LudwigD. S. (2021). Elevated LDL cholesterol with a carbohydrate-restricted diet: evidence for a “lean mass hyper-responder” phenotype. Curr. Dev. Nutr. 6:nzab144. doi: 10.1093/cdn/nzab144
84
PaliD. V.KimS.MantikK. E. K.LeeJ. B.SoC. Y.MoonS.et al. (2025). Unraveling the translational relevance of β-hydroxybutyrate as an intermediate metabolite and signaling molecule. Int. J. Mol. Sci. 26:7362. doi: 10.3390/ijms26157362
85
PaltaP.SchneiderA. L. C.BiesselsG. J.TouradjiP.Hill-BriggsF. (2014). Magnitude of cognitive dysfunction in adults with type 2 diabetes: a meta-analysis of six cognitive domains and the most frequently reported neuropsychological tests within domains. J. Int. Neuropsychol. Soc. 20, 278–291. doi: 10.1017/S1355617713001483
86
PaoliA.TinsleyG. M.MattsonM. P.De VivoI.DhawanR.MoroT.et al. (2024). Common and divergent molecular mechanisms of fasting and ketogenic diets. Trends Endocrinol. Metab. 35, 125–141. doi: 10.1016/j.tem.2023.10.001
87
PaoneP.PetitfilsC.PuelA.LatousakisD.de VosW. M.DelzenneN. M.et al. (2026). Akkermansia muciniphilamodulates intestinal mucus composition to counteract high-fat diet-induced obesity in mice. Gut Microbes18:2612580. doi: 10.1080/19490976.2025.2612580
88
ParkG.KadyanS.HochuliN.PollakJ.WangB.SalazarG.et al. (2024). A modified Mediterranean-style diet enhances brain function via specific gut-microbiome-brain mechanisms. Gut Microbes16:2323752. doi: 10.1080/19490976.2024.2323752
89
PatoineC.ShefflerJ.SimsT.GutierrezV.ParkG.MayonuM.et al. (2025). Obesity-associated gut microbiome influences diet-induced metabolic and cognitive outcomes in older adults. Gut Microbes Rep.3:2605879. doi: 10.1080/29933935.2025.2605879
90
PawłowskaM.KruszkaJ.PorzychM.GarbarekJ.NuszkiewiczJ. (2025). Ketogenic metabolism in neurodegenerative diseases: mechanisms of action and therapeutic potential. Metabolites15:508. doi: 10.3390/metabo15080508
91
PetersA. L.BuschurE. O.BuseJ. B.CohanP.DinerJ. C.HirschI. B.et al. (2015). Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care. 38, 1687–1693. doi: 10.2337/dc15-0843
92
PuchalskaP.CrawfordP. A. (2017). Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab. 25, 262–284. doi: 10.1016/j.cmet.2016.12.022
93
QinY.BaiD.TangM.ZhangM.ZhaoL.LiJ.et al. (2023). Ketogenic diet alleviates brain iron deposition and cognitive dysfunction via Nrf2-mediated ferroptosis pathway in APP/PS1 mouse. Brain Res. 1812:148404. doi: 10.1016/j.brainres.2023.148404
94
RegerM. A.HendersonS. T.HaleC.et al. (2004). Effects of beta-hydroxybutyrate on cognition in memory-impaired adults. Neurobiol Aging. 25, 311–314. doi: 10.1016/S0197-4580(03)00087-3
95
RenQ.FuJ.DuanX.SunL.MuZ.LiangW.et al. (2024). The effects of ketogenic diet on brain gene expressions in type 2 diabetes background. Neuroscience549, 101–109. doi: 10.1016/j.neuroscience.2024.04.008
96
RoslundK. J.RamseyJ. J.RutkowskyJ. M.ZhouZ.SlupskyC. M. (2025). Two-month ketogenic diet alters systemic and brain metabolism in middle-aged female mice. Geroscience47, 935–952. doi: 10.1007/s11357-024-01314-w
97
RutkowskyJ. M.RolandZ.ValenzuelaA.NguyenA. B.ParkH. H.SixN.et al. (2024). The impact of continuous and intermittent ketogenic diets on cognitive behavior, motor function, and blood lipids in TgF344-AD rats. Aging16, 5811–5828. doi: 10.18632/aging.205741
98
Sáenz de PipaónM.Flores-RojasK.GilA.Gil-CamposM. (2020). Commentary: consumer reports of “Keto Flu” associated with the ketogenic diet. Front. Nutr. 7:113. doi: 10.3389/fnut.2020.00113
99
SakrH. F.SirasanagandlaS. R.DasS.BimaA. I.ElsamanoudyA. Z. (2023). Low-carbohydrate ketogenic diet for improvement of glycemic control: mechanism of action of ketosis and beneficial effects. Curr. Diabetes Rev. 19:e110522204580. doi: 10.2174/1573399818666220511121629
100
SatapathyP.PratimaP.GaidhaneA. M.VadiaN.MenonS. V.ChennakesavuluK.et al. (2025). Prevalence and impact of microvascular complications in type 2 diabetes mellitus on cognitive impairment and depression: a systematic review and meta-analysis. Diabetol. Metab. Syndr. 17:187. doi: 10.1186/s13098-025-01759-9
101
SatoK.KashiwayaY.KeonC. A.TsuchiyaN.KingM. T.RaddaG. K.et al. (1995). Insulin, ketone bodies, and mitochondrial energy transduction. FASEB J. 9, 651–658. doi: 10.1096/fasebj.9.8.7768357
102
Schnaider BeeriM.GoldbourtU.SilvermanJ. M.NoyS.SchmeidlerJ.Ravona-SpringerR.et al. (2004). Diabetes mellitus in midlife and the risk of dementia three decades later. Neurology63, 1902–1907. doi: 10.1212/01.WNL.0000144278.79488.DD
103
ShafieeA.AkhlaghiA. A.EllstromA.MohammadiS. O.ShafieeA.SathyamoorthyM.et al. (2025). Molecular aspects of mitochondrial dysfunction in diabetes, pearson and kearns-sayre syndromes, and neurodegenerative disorders. Int. J. Gen. Med. 18, 5355–5366. doi: 10.2147/IJGM.S539967
104
ShimazuT.HirscheyM. D.NewmanJ.HeW.ShirakawaK.Le MoanN. Jr. et al. (2013). Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science339, 211–214. doi: 10.1126/science.1227166
105
ShippyD. C.EveredA. H.UllandT. K. (2025). Ketone body metabolism and the NLRP3 inflammasome in Alzheimer's disease. Immunol. Rev. 329:e13365. doi: 10.1111/imr.13365
106
ShippyD. C.WilhelmC.ViharkumarP. A.RaifeT. J.UllandT. K. (2020). β-Hydroxybutyrate inhibits inflammasome activation to attenuate Alzheimer's disease pathology. J. Neuroinflammation. 17:280. doi: 10.1186/s12974-020-01948-5
107
SiegmannM. J.AthinarayananS. J.HallbergS. J.McKenzieA. L.BhanpuriN. H.CampbellW. W.et al. (2019). Improvement in patient-reported sleep in type 2 diabetes and prediabetes participants receiving a continuous care intervention with nutritional ketosis. Sleep Med.55, 92–99. doi: 10.1016/j.sleep.2018.12.014
108
SjöholmÅ.BennetL.NilssonP. M. (2025). Cognitive dysfunction in diabetes - the ‘forgotten' diabetes complication: a narrative review. Scand. J. Prim. Health Care43, 448–454. doi: 10.1080/02813432.2025.2455136
109
SousaR. A. L.YehiaA.AbulseoudO. A. (2023). Attenuation of ferroptosis as a potential therapeutic target for neuropsychiatric manifestations of post-COVID syndrome. Front. Neurosci. 17:1237153. doi: 10.3389/fnins.2023.1237153
110
SrikanthV.SinclairA. J.Hill-BriggsF.MoranC.BiesselsG. J. (2020). Type 2 diabetes and cognitive dysfunction-towards effective management of both comorbidities. Lancet Diabetes Endocrinol. 8, 535–545. doi: 10.1016/S2213-8587(20)30118-2
111
SugimotoT.OmuraT.ArakiA.HanedaC.HondaK.KishiM.et al. (2025). Differential effects of a multidomain intervention on cognitive decline in older adults with type 2 diabetes according to white matter hyperintensity status: a secondary analysis of the J-MIND-Diabetes. Diabetes Obes. Metab. 27, 5576–5586. doi: 10.1111/dom.16605
112
SukkarS. G.MuscaritoliM. A. (2021). Clinical perspective of low carbohydrate ketogenic diets: a narrative review. Front. Nutr. 8:642628. doi: 10.3389/fnut.2021.642628
113
SunH.SaeediP.KarurangaS.PinkepankM.OgurtsovaK.DuncanB. B.et al. (2022). Diabetes atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res. Clin. Pract. 183:109119. doi: 10.1016/j.diabres.2021.109119
114
TangM.ZhangZ.LinL.NiuJ.MengG.WangW.et al. (2025). Comparative analysis of growth dynamics and relative abundances of gut microbiota influenced by ketogenic diet. Phenomics5, 65–75. doi: 10.1007/s43657-025-00228-7
115
TayJ.ThompsonC. H.Luscombe-MarshN. D.NoakesM.BuckleyJ. D.WittertG. A.et al. (2020). Nutritional adequacy of very low- and high-carbohydrate, low saturated fat diets in adults with type 2 diabetes: a secondary analysis of a 2-year randomised controlled trial. Diabetes Res. Clin. Pract. 170:108501. doi: 10.1016/j.diabres.2020.108501
116
TaylorM. K.SullivanD. K.MahnkenJ. D.BurnsJ. M.SwerdlowR. H. (2017). Feasibility and efficacy data from a ketogenic diet intervention in Alzheimer's disease. Alzheimers Dement. 4, 28–36. doi: 10.1016/j.trci.2017.11.002
117
TosefskyK.LamJ. S.WangY. N.KeymaneshS.KuanA. J.Metcalfe-RoachA.et al. (2026). randomized safety and feasibility crossover trial of two Mediterranean-ketogenic interventions in individuals with Parkinson's disease. J. Parkinsons Dis. 16, 332–350. doi: 10.1177/1877718X261418986
118
UrsiniF.MaiorinoM. (2020). Lipid peroxidation and ferroptosis: the role of GSH and GPx4. Free Radic. Biol. Med. 152, 175–185. doi: 10.1016/j.freeradbiomed.2020.02.027
119
van SlotenT. T.SedaghatS.CarnethonM. R.LaunerL. J.StehouwerC. D. A. (2020). Cerebral microvascular complications of type 2 diabetes: stroke, cognitive dysfunction, and depression. Lancet Diabetes Endocrinol. 8, 325–336. doi: 10.1016/S2213-8587(19)30405-X
120
VeechR. L.ChanceB.KashiwayaY.LardyH. A.CahillG. F.Jr. (2001). Ketone bodies, potential therapeutic uses. IUBMB Life. 51, 241–247. doi: 10.1080/152165401753311780
121
WallaceM. A.AguirreN. W.MarcotteG. R.MarshallA. G.BaehrL. M.HughesD. C.et al. (2021). The ketogenic diet preserves skeletal muscle with aging in mice. Aging Cell20:e13322. doi: 10.1111/acel.13322
122
WangJ.LiL.ZhangZ.ZhangX.ZhuY.ZhangC.et al. (2022). vesicles mediate the communication of adipose tissue with brain and promote cognitive impairment associated with insulin resistance. Cell Metab. 34, 1264–1279.e8. doi: 10.1016/j.cmet.2022.08.004
123
WangN.ChenX. (2025). Diagnostic value of Montreal cognitive assessment combined with olfactory tests for mild cognitive impairment in older adult patients with type 2 diabetes. Eur. Geriatr. Med. 16, 1639–1646. doi: 10.1007/s41999-025-01223-x
124
WangX.HuangS.LiuY.LiD.DangY.YangL.et al. (2021). Effects of ketogenic diet on cognitive function in pentylenetetrazol-kindled rats. Epilepsy Res. 170:106534. doi: 10.1016/j.eplepsyres.2020.106534
125
WangY.LvM. N.ZhaoW. J. (2023). Research on ferroptosis as a therapeutic target for the treatment of neurodegenerative diseases. Ageing Res. Rev. 91:102035. doi: 10.1016/j.arr.2023.102035
126
WangZ.WuC.YinD.DouK. (2025). Ferroptosis: mechanism and role in diabetes-related cardiovascular diseases. Cardiovasc. Diabetol. 24:60. doi: 10.1186/s12933-025-02614-x
127
WeiX.LiuY.LiJ.ZhuY.LiW.ZhuY.et al. (2025). MoCA and MMSE for the detection of post-stroke cognitive impairment: a comparative diagnostic test accuracy systematic review and meta-analysis. J. Neurol. 272:407. doi: 10.1007/s00415-025-13146-5
128
WolverS.FadelK.FiegerE.AburishZ.O'RourkeB.ChandlerT. M.et al. (2021). Clinical use of a real-world low carbohydrate diet resulting in reduction of insulin dose, hemoglobin A1c, and weight. Front. Nutr. 8:690855. doi: 10.3389/fnut.2021.690855
129
XuC.MiaoH.ChenY.LiaoL. (2025). Crosstalk of kidney and brain in diabetes-related cognitive impairment and therapeutic strategies. Front. Endocrinol. 16:1562518. doi: 10.3389/fendo.2025.1562518
130
XuK.SunX.ErokuB. O.TsipisC. P.PuchowiczM. A. (2010). LaManna JC. Diet-induced ketosis improves cognitive performance in aged rats. Adv. Exp. Med. Biol. 662, 71–75. doi: 10.1007/978-1-4419-1241-1_9
131
XuX.XuX. D.MaM. Q.LiangY.CaiY. B.ZhuZ. X.et al. (2024). The mechanisms of ferroptosis and its role in atherosclerosis. Biomed. Pharmacother. 171:116112. doi: 10.1016/j.biopha.2023.116112
132
YangY.WangX.XiaoA.HanJ.WangZ.WenM.et al. (2022a). Ketogenic diet prevents chronic sleep deprivation-induced Alzheimer's disease by inhibiting iron dyshomeostasis and promoting repair via Sirt1/Nrf2 pathway. Front. Aging Neurosci. 14:998292. doi: 10.3389/fnagi.2022.998292
133
YangY.ZhaoJ. J.YuX. F. (2022b). Expert consensus on cognitive dysfunction in diabetes. Curr. Med. Sci. 42, 286–303. doi: 10.1007/s11596-022-2549-9
134
YueD.WangR.ZhaoY.WuB.LiS.ZengW.et al. (2024). Investigating the molecular mechanisms between type 1 diabetes and mild cognitive impairment using bioinformatics analysis, with a focus on immune response. Int. Immunopharmacol. 142:113256. doi: 10.1016/j.intimp.2024.113256
135
ZhangS.ZhangY.WenZ.YangY.BuT.BuX.et al. (2023). dysfunction in diabetes: abnormal glucose metabolic regulation in the brain. Front. Endocrinol. 14:1192602. doi: 10.3389/fendo.2023.1192602
Summary
Keywords
cognitive dysfunction, diabetes mellitus, gut-brain axis, LCKDs, low-carbohydrate ketogenic diet, mild cognitive impairment, nutritional ketosis
Citation
Xun Y and Zeng W (2026) Ketogenic metabolic therapy: low-carbohydrate interventions as novel neuroprotective strategies for cognitive dysfunction in diabetes. Front. Aging Neurosci. 18:1777834. doi: 10.3389/fnagi.2026.1777834
Received
30 December 2025
Revised
03 April 2026
Accepted
07 April 2026
Published
24 April 2026
Volume
18 - 2026
Edited by
Bruce Alan Watkins, University of California, Davis, Davis, United States
Reviewed by
Francisco Capani, Universidad Abierta Interamericana, Argentina
Shanshan Huang, Huashan Hospital, Fudan University, China
Updates
Copyright
© 2026 Xun and Zeng.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Wenqing Zeng, 17580658@qq.com
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.