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Review
. 2023 Apr 19;15(8):1971.
doi: 10.3390/nu15081971.

The Role of a Ketogenic Diet in the Treatment of Dementia in Type 2 Diabetes Mellitus

Lin Bai  1   2   3 , Yue Zhou  4 , Jie Zhang  2   3 , Junpeng Ma  1
Affiliations
Review

The Role of a Ketogenic Diet in the Treatment of Dementia in Type 2 Diabetes Mellitus

Lin Bai et al. Nutrients. .

Abstract

Type 2 diabetes mellitus (T2DM) shares a common molecular mechanism and underlying pathology with dementia, and studies indicate that dementia is widespread in people with T2DM. Currently, T2DM-induced cognitive impairment is characterized by altered insulin and cerebral glucose metabolism, leading to a shorter life span. Increasing evidence indicates that nutritional and metabolic treatments can possibly alleviate these issues, as there is a lack of efficient preventative and treatment methods. The ketogenic diet (KD) is a very high-fat, low-carbohydrate diet that induces ketosis in the body by producing a fasting-like effect, and neurons in the aged brain are protected from damage by ketone bodies. Moreover, the creation of ketone bodies may improve brain neuronal function, decrease inflammatory expression and reactive oxygen species (ROS) production, and restore neuronal metabolism. As a result, the KD has drawn attention as a potential treatment for neurological diseases, such as T2DM-induced dementia. This review aims to examine the role of the KD in the prevention of dementia risk in T2DM patients and to outline specific aspects of the neuroprotective effects of the KD, providing a rationale for the implementation of dietary interventions as a therapeutic strategy for T2DM-induced dementia in the future.

Keywords: dementia; ketogenic diet; neuroprotective; type 2 diabetes mellitus.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Impaired blood glucose metabolism in T2DM-induced dementia. Patients with dementia from T2DM exhibit systemic hyperglycemia, hyperlipidemia, and hyperinsulinemia. Decreases in insulin resistance and insulin sensitivity are characteristics of T2DM. A lack of insulin sensitivity prevents the liver from absorbing and using glucose from the blood. Defective glucose absorption encourages the liver to speed up gluconeogenesis and glycogenolysis, which raises the level of glucose in the blood. Decreased glucose uptake also causes a dependency on fatty acid metabolism as the main source of energy production. Hepatic fatty acids also encourage the synthesis of triglycerides and ketone bodies, and reactive oxygen species and oxidative imbalance are caused by excess glucose in hepatic mitochondria. In addition, the passive removal of materials from the blood is inhibited by capillarization and inflammatory cytokine release, both of which are promoted by oxidative stress. Finally, the brain also displays insulin resistance with excess glucose through blood, which contributes to increasing neuronal damage and neuroinflammation.
Figure 2
Figure 2
Illustration of the biochemistry of ketogenesis in the liver and brain. Long-term glucose restriction causes the ratio of glucagon to insulin to rise, which causes the release of free fatty acids into the blood. Carnitine acylcarnitine translocase-1 (CAT-1) transports free fatty acids into liver mitochondria, where they are utilized to oxidize fatty acids to produce acetyl coenzyme A (acetyl-CoA). The production of ketone bodies allows these molecules to start the ketogenesis process. Acetyl-CoA is transformed into acetoacetate, which then permits the reversible reduction to acetone and β-hydroxybutyrate (β-OHB). These ketone bodies subsequently leave the liver and travel through the circulation to reach peripheral tissues and the brain, where they are carried in the brain by monocarboxylic acid transporters. In the brain, β-OHB can be changed back into acetoacetate, acting as a potential source of acetyl-CoA to release energy through the tricarboxylic acid cycle. Abbreviations: Acetyl-CoA, acetyl coenzyme A; β-OHB, β-hydroxybutyrate; CAT, carnitine acylcarnitine translocase; CO2, carbon dioxide; FAs, fatty acids; MCT, monocarboxylic acid transporter; TCA, tricarboxylic acid.
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