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Int Neurourol J > Volume 28(Suppl 1); 2024 > Article
Faria-Costa, Oliveira, Vilas-Boas, Campelo, Silva, Brás-Silva, Silva, Antunes-Lopes, and Charrua: The Ketone Bridge Between the Heart and the Bladder: How Fast Should We Go?

ABSTRACT

Metabolic syndrome (MS) is associated with both cardiovascular and bladder dysfunction. Insulin resistance (IR) and central obesity, in particular, are the main risk factors. In these patients, vicious pathological cycles exacerbate abnormal carbohydrate metabolism and sustain an inflammatory state, with serious implications for both the heart and bladder. Ketone bodies serve as an alternative energy source in this context. They are considered a “super-fuel” because they generate adenosine triphosphate with less oxygen consumption per molecule, thus enhancing metabolic efficiency. Ketone bodies have a positive impact on all components of MS. They aid in weight loss and glycemic control, lower blood pressure, improve lipid profiles, and enhance endothelial function. Additionally, they possess direct anti-inflammatory, antioxidant, and vasodilatory properties. A shared key player in dysfunction of both the heart and bladder dysfunction is the formation of the NLRP3 inflammasome, which ketone bodies inhibit. Interventions that elevate ketone body levels—such as fasting, a ketogenic diet, ketone supplements, and sodium-glucose cotransporter 2 inhibitors—have been shown to directly affect cardiovascular outcomes and improve lower urinary tract symptoms derived from MS. This review explores the pathophysiological basis of the benefits of ketone bodies in cardiac and bladder dysfunction.

INTRODUCTION

Energy metabolism is fueled by various substrates, including carbohydrates, fatty acids, amino acids, and ketone bodies. While all of these substrates ultimately generate the energy molecule adenosine triphosphate (ATP), their metabolic pathways are distinct and have significant differences [1]. An imbalance in these metabolic pathways can have detrimental effects on human health. Metabolic syndrome (MS) is one such example [2]. MS affects one-quarter of the global population, constituting a global pandemic [3]. A diagnosis of MS must include at least 3 of the following cardiovascular risk factors: elevated fasting glucose levels, hypertension, high triglyceride levels, reduced high-density lipoprotein (HDL) cholesterol levels, and central obesity [4]. These components of MS are known to interact within a shared pathophysiology, predisposing individuals to not only an increased cardiovascular risk but also to noncardiovascular diseases [5-7]. In this context, urologic symptoms have been associated with MS [8]. Therefore, understanding the relationship between the components of MS, cardiovascular health, and urologic health is of the utmost importance.
In this paper, we explore the impact of MS on the cardiovascular and urinary systems, as well as the potential benefits of ketone bodies as an alternative energy source in mitigating these adverse effects. We also review the effects of currently available interventions that modulate serum ketone body concentrations.

CARDIOVASCULAR IMPACT OF METABOLIC SYNDROME

Insulin resistance (IR) and obesity, particularly visceral adiposity, are common in patients with MS and are the primary predictors of cardiovascular mortality associated with this syndrome [2, 4, 6]. IR is linked to the disruption of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway, which affects the expression of glucose transporter type 4, thereby reducing glucose metabolism in muscle and fat cells [7]. Consequently, fat cells resort to lipolysis, releasing free fatty acids (FFAs) that are re-esterified in the liver. This process results in elevated triglyceride levels and subsequent increases in very low-density lipoprotein (LDL) and HDL, which accounts for the dyslipidemia profile observed in MS patients [2]. Furthermore, the dysfunction of the PI3K-Akt pathway leads to reduced phosphorylation of nitric oxide synthase (eNOS), diminishing nitric oxide production, which in turn causes endothelial dysfunction and hypertension [7]. The increase in visceral adiposity also triggers an overproduction of proinflammatory adipokines and a decrease in anti-inflammatory adipokines, as well as activating the reninangiotensin system [9]. These effects contribute to the persistence of IR and endothelial dysfunction, creating a self-perpetuating cycle that exacerbates each condition and increases the risk of cardiovascular disease [2].

THE IMPACT OF METABOLIC SYNDROME ON THE BLADDER

The impact of MS on the urinary system is increasingly recognized [10]. Several large population-based studies have linked lower urinary tract symptoms (LUTS) with each of the MS components. The Flint Study found an association between LUTS and both hypertension and diabetes in African American males [11]. Similarly, the HUNT study identified diabetes, body mass index, and waist-to-hip ratio as risk factors for LUTS [12]. Although not formally a component of MS, physical inactivity is a known risk factor for all MS components and has been consistently associated with LUTS in several studies [13, 14]. Moreover, the severity of LUTS correlates with several MS components [5]. Indeed, all MS components are linked to pathological changes in the bladder. Obesity and hyperlipidemia are associated with systemic chronic inflammation, evidenced by bladder leukocyte infiltration and locally enhanced cytokine expression [15]. High glucose concentrations and hyperinsulinemia contribute to oxidative stress, insulin-like growth factor-1–driven mitogenic effects, and increased bladder sympathetic tone [10, 16]. Additionally, hypertension is closely related to the incidence of overactive bladder (OAB) due to elevated sympathetic tone and has been shown to increase hypoxia in the urothelium and detrusor muscle [17]. Kim et al. [18] demonstrated that the incidence of urological diseases in metabolically unhealthy obese individuals within the Korean population was significantly higher than in metabolically unhealthy nonobese individuals or in metabolically healthy obese individuals. These findings highlight the significant role of metabolic disease in influencing bladder function.
Evidence from animal models has detailed the underlying alterations that link MS with LUTS. Myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits exhibit OAB with nonvoiding contractions, which may be due to a reduced area of detrusor smooth muscle cells and urothelial thickness, as well as an increase in peptidergic neurons [19]. Obese B6.VLepob/J mice, used as a model for MS, display increased urinary bladder frequency and voiding impairment, along with an increased volume and inflammation of the prostate [20]. Additionally, in a rabbit model of MS induced by a high-fat diet, animals exhibited bladder fibrosis with signs of hypoxia and inflammation [21]. Although the mechanisms are not fully understood, the association between MS and LUTS appears to be partially related to overactivity of the RhoA/Rho-kinase pathway [21, 22]. In MS-related LUTS, overactivity of the estrogen receptor increases RhoA/ROCK signaling, which promotes bladder overactivity [22]. Within this pathway, androgens may contribute to phosphodiesterase type 5 modulation, enhancing RhoA membrane translocation and ROCK overexpression in bladder smooth muscle cells, thereby promoting detrusor contractility and contributing to bladder inflammation and fibrosis [23]. Beyond the estrogen and androgen-dependent mechanisms, MS-related LUTS may also be associated with impaired neuronal activity. Obese Zucker rats exhibit impaired excitatory neurotransmission due to a decrease in cannabinoid receptor expression in the nerve fibers of the urinary bladder [24].

KETOGENESIS

Under conditions of low carbohydrate availability, such as fasting or a low carbohydrate diet, or when insulin action is impaired (as in IR), fat stores are broken down through lipolysis [25]. The FFAs released during this process are utilized by the liver to produce ketone bodies—acetone, acetoacetate, and β-hydroxybutyrate (β-OHB)—via the metabolic pathway of ketogenesis. This pathway involves the use of acetyl-CoA, which is derived from the β-oxidation of FFAs [26]. Ketone bodies are then released into the bloodstream and can be used as energy sources by tissues outside the liver, where they re-enter the Krebs cycle [27]. The production of ketone bodies is suppressed by insulin and stimulated by glucagon and adrenaline, which regulate the activity of key enzymes involved in ketogenesis [27]. Recently, there has been a surge of interest in ketogenesis due to the beneficial effects of ketone bodies as an “alternative fuel” for tissues outside the liver. β-OHB, being the predominant ketone body in circulation, is the focus of most research in this area [25].

Ketogenesis and Cardiovascular Health

The heart derives most of its energy from fatty acid β-oxidation, which accounts for 50%–65%, and from the oxidation of pyruvate that originates from glucose, which contributes 30%–50% [28]. However, the heart exhibits remarkable metabolic flexibility; during states of ketosis, such as fasting, it can utilize ketone bodies for energy. Likewise, cardiomyocytes in patients with type 2 diabetes also metabolize ketone bodies as an energy source [29].
Ketone bodies have been found to be a more efficient energy source than carbohydrates or fatty acids, as they require less oxygen consumption for the same level of ATP production [28]. Consequently, they have been regarded as a “super-fuel” for the heart [29]. Beyond energy efficiency, ketone bodies also play direct beneficial roles at the subcellular level. β-OHB increases eNOS activity and enhances myocardial blood flow through direct vasodilation [30, 31]. In animal models, β-OHB has been shown to decrease infarct size and reduce ischemia/reperfusion injury. It also significantly reduces myocardial apoptosis and oxidative stress [32]. Furthermore, β-OHB exhibits potent antiinflammatory effects by inhibiting the formation of the NODlike receptor protein 3 inflammasome (NLRP3 inflammasome), a key mediator in the pathological progression of cardiovascular diseases [33, 34]. Notably, β-OHB has been found to reduce maladaptive cardiac remodeling in animal models of heart failure [30]. In humans, supplementation with β-OHB has been shown to lower levels of glucose, FFAs, and triglycerides [35] (Fig. 1). Given these beneficial effects, interventions that regulate the formation of ketone bodies are gaining increasing interest in the context of cardiovascular health and MS.

Ketogenesis and Bladder Health

Ketogenesis has not been extensively studied in the context of urological health. However, managing MS components may be beneficial for LUTS derived from MS. For example, visceral adiposity is associated with an OAB [36], and the metabolic effects of ketone bodies might be helpful. Ketone bodies also have a direct impact on the lower urinary system. β-OHB acts on free fatty acid receptor 3 (FFAR3, also known as GPR41), which is expressed in the urothelium and, to a lesser extent, in the detrusor muscle. In urothelial carcinoma, both β-OHB [37] and FFAR3 are found to be highly expressed [38]. Their elevated levels may be associated with protective mechanisms, as β-OHB regulates gene expression by inhibiting histone deacetylases [39], and FFAR3 activation has anticarcinogenic effects [40]. As previously mentioned, β-OHB has a potent effect on the NLRP3 inflammasome [39]. In the bladder, the NLRP3 inflammasome is associated with various pathologies that induce LUTS. It triggers bladder dysfunction in the aging bladder and in the diabetic bladder [41, 42]. In the latter, it is also associated with bladder denervation, which is characteristic of patients with diabetes [42]. Additionally, in models of bladder outlet obstruction, the NLRP3 inflammasome has been shown to be a primary mediator of bladder decompensation, leading to end-stage damage and fibrosis of the detrusor muscle [43]. This has led some researchers to hypothesize that the NLRP3 inflammasome may be a key factor in the transition from an OAB to an underactive bladder (UAB) phenotype, as seen in the aforementioned models [42, 43]. Furthermore, the NLRP3 inflammasome is also implicated in bladder impairment and the development of pain in animal models of interstitial cystitis/bladder pain syndrome (IC/BPS) [44]. Its inhibition by β-OHB resulted in pain improvement in an animal model of spinal cord injury [45]. Therefore, the influence of β-OHB on the NLRP3 inflammasome makes it a promising therapeutic agent for bladder dysfunction (Fig. 1). However, its effects have yet to be validated.

INTERMITTENT FASTING

Intermittent fasting (IF) involves voluntary periods of abstaining from food and drink. This term encompasses a variety of diets [46, 47], all of which ultimately increase ketone body levels during the fasting period.

IF and Cardiovascular Health

IF benefits cardiometabolic health by addressing the various components of MS. IF promotes significant weight loss and a reduction in waist circumference, which corresponds to a decrease in total fat mass [48, 49]. While some of these effects may be due to a lower caloric intake associated with IF [49], the cardiometabolic benefits of IF persist even without a reduction in calorie consumption [48]. Additionally, IF positively influences glucose and insulin levels [49]. Restricting eating to certain hours of the day may enhance the alignment of metabolism with the body’s circadian rhythms [46]. Moreover, during fasting periods, the use of ketone bodies generates fewer reactive oxygen species, thereby reducing oxidative stress in both the pancreas and target organs. This leads to improved insulin secretion and increased peripheral insulin sensitivity [48, 49]. The impact of IF on the lipid profile is more contentious. Some studies have observed reductions in the LDL/HDL ratio and serum triglycerides [48]. However, a recent meta-analysis found no significant effect of IF on the lipid profile [49]. The lack of consistent findings may be due to the substantial heterogeneity among studies examining different types of IF diets. Lastly, IF lowers blood pressure through complex and multifactorial mechanisms. These include a decrease in sympathetic nervous system activity and an increase in parasympathetic tone, as well as a reduction in the activity of the renin-angiotensin-aldosterone system (RAAS) [47, 50].
Another cardiovascular benefit of IF is related with the regulation and favorable changes in the diversity of the gut microbiome [47]. Obese individuals tend to show a less diverse gut microbiome and strains that allow more energy extraction from the diet [46, 47]. Dysbiosis is also linked to cardiovascular risk factors, such as atherosclerosis, hypertension, heart failure, chronic kidney disease, obesity, and type 2 diabetes mellitus [51]. IF led to an enrichment of Parabacteroides distasonis and Bacteroides thetaiotaomicron, which correlated with cardiovascular risk factor modification in humans [52].

IF and Bladder Health

Many cardiovascular benefits of IF can be applied to the treatment of LUTS. Controlling the RAAS axis may be advantageous, as this system has been found to be overactive in patients with benign prostatic hyperplasia (BPH) [53]. Additionally, the glycemic control achieved through IF may positively influence the progression of BPH/LUTS [54]. However, the most significant impact of IF may be on inflammation, a common feature of LUTS associated with OAB, UAB, and MS [15]. IF reduces levels of the proinflammatory molecule soluble intercellular adhesion molecule-1, thereby decreasing the risk of atherosclerosis by regulating leukocyte-endothelial attachment [55]. Moreover, IF lowers the number of circulating inflammatory cells and modulates the NLRP3 inflammasome, without compromising the immune response in healthy individuals [56, 57]. Consequently, IF could play a role in the symptomatic improvement of patients with OAB and UAB. A case report of a patient with ulcerative colitis, a condition often associated with OAB, demonstrated functional enhancement of inflammation-mediated symptoms following an IF regimen [58], indicating that visceral inflammation can be ameliorated by IF. Furthermore, OAB shares additional characteristics with MS, such as IR and reduced levels of HDL cholesterol, which may also improve with an IF diet [59].
IF also modulates the immune response. IF elevates the levels of ketone bodies, specifically β-OHB and acetoacetate, which in turn trigger a CD8+ T-cell immune response against infections and cancer cells by modulating histone acetylation [60]. Cytotoxic CD8+ T cells are key players in the anti-tumor immune response to bladder cancer [61]. The significance of these cells is underscored by the recent identification of CD8+ T-cell infiltration-related molecular signature clusters, which serve as a prognostic tool with strong clinical potential for identifying patients at high risk of bladder cancer [62]. Therefore, IF may have a significant clinical impact on the treatment of bladder cancer. In fact, recent evidence has demonstrated that IF can inhibit epithelial ovarian tumors in a mouse model by enhancing the activity of both CD8+ T and CD4+ T helper cells [63].
Additionally, IF may confer benefits for urinary pathologies by modulating the interplay among diet, the immune system, and the gut microbiota. Pain syndromes such as chronic prostatitis/chronic pelvic pain syndrome and IC/BPS have been linked to fecal dysbiosis [64]. Since IF can aid in the restoration of the gut microbiome, it may also alleviate the pain experienced by these patients. Furthermore, in a mouse model of urinary incontinence caused by sciatic nerve lesions, an IF diet influenced the metabolism of gram-positive bacteria. This led to the release of molecules that promote neutrophil chemotaxis, resulting in the regeneration of the axonal sciatic nerve [65]. Such an effect could potentially influence bladder activity.
Although IF acts on several pathophysiological aspects of bladder dysfunction, to our knowledge, no studies have directly addressed its effects on LUTS. Further investigation may reveal promising results.

KETOGENIC DIET AND KETONE SUPPLEMENTS

Ketosis can be induced through various dietary modifications. The ketogenic diet (KD) is characterized by low carbohydrate and high-fat intake, which prompts ketosis due to the availability of substrates. Additionally, ketone supplements, including ketone esters and ketone salts, effectively elevate ketone body levels [30].

KD/Ketone Supplements and Cardiovascular Health

One of the primary advantages of the KD in managing cardiovascular risk is its ability to promote weight loss. The consistent weight loss observed across various studies may be partly due to caloric restriction [66]. However, the KD has been shown to have a greater impact on weight loss than low-fat diets, with results that persist even after 1 year [67]. Interestingly, even with equal calorie consumption, a carbohydrate-restricted diet results in a higher resting energy expenditure than a low-fat diet [68]. This observation is corroborated by animal research, which indicates that the KD can increase energy expenditure without increasing caloric intake [69]. Concurrently, the KD is associated with a marked decrease in fasting glucose and HbA1c levels compared to other diets [70]. Therefore, the KD has demonstrated significant benefits in the metabolic management of patients with obesity and diabetes [71].
The KD appears to have a negative impact on the lipid profiles of rodents; however, in humans, the opposite is true, with the KD generally having a beneficial effect [71]. This discrepancy may be due to the high saturated fat content in the diets of animal models, while the human version of the KD typically contains more unsaturated fats. Most randomized controlled trials have demonstrated a significant decrease in total cholesterol and triglyceride levels, along with an increase in HDL [66]. Although some studies have noted a rise in LDL levels, which has prompted skepticism about the benefits of the KD, these findings are inconsistent and do not seem to be associated with adverse cardiovascular outcomes [66]. Similarly to IF, the KD influences the sympathetic nervous system and the RAAS, contributing to the regulation of blood pressure. Various studies have documented a notable reduction in blood pressure following adherence to the KD [66, 72].
Finally, the KD has anti-inflammatory and antioxidant effects, which are primarily attributed to the increase in β-OHB levels. This elevation in β-OHB, in turn, influences the NLRP3 inflammasome and the balance of oxidative stress. Additionally, the restriction of carbohydrates and the high concentration of omega-3 fatty acids may also contribute to the anti-inflammatory effects of the KD [66]. Similarly, the effect of the KD on endothelial function is associated with the impact of β-OHB, as previously described (Fig. 1).
Ketone salts and ketone esters represent alternative methods for elevating β-OHB levels. Clinical trials have demonstrated their efficacy in improving glycemic and lipid control, as well as enhancing myocardial blood flow [30]. Notably, in a study involving heart failure patients, a ketone supplement prompted a significant, dose-dependent increase in cardiac output [73].

KD/Ketone Supplements and Bladder Health

The KD was utilized to treat urinary infections long before the advent of antibiotics. In 1933, Fuller reported a high success rate of the KD in treating these infections, attributing the effectiveness to the presence of β-OHB in the acidic urine [74]. The KD has also been investigated as a therapeutic option in other areas of urology. For example, it has been shown to be effective in improving stress urinary incontinence in obese women, primarily through the control of risk factors [75]. Additionally, in an animal model of BPH, the KD significantly reduced prostate size and markers of oxidative stress [76]. Similarly, the KD has been found to significantly alleviate symptoms in patients with male accessory gland inflammation and is associated with an increased rate of α-blocker discontinuation [77]. Further research is necessary to fully understand the effects of the KD and ketone supplements on LUTS stemming from various etiologies. Nevertheless, the aforementioned effects on the cardiovascular control of MS components are promising for the treatment of LUTS (Fig. 1).

SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITORS

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a class of antidiabetic drugs that function by inhibiting glucose reabsorption in the proximal tubule, thereby enhancing glucose excretion in the urine. This leads to reduced plasma glucose levels, which in turn decreases the insulin/glucagon ratio and stimulates ketogenesis, causing an elevation in β-OHB. Following long-term SGLT2i treatment, β-OHB levels can increase by up to 78% [78].

SGLT2i and Cardiovascular Health

SGLT2i have a broad spectrum of actions that are beneficial to cardiovascular health, which helps to explain their remarkable outcomes in heart failure trials. In addition to improving glycemic control, SGLT2i contribute to weight loss, reduction in blood pressure, better lipid profile management, and decreased levels of inflammation and oxidative stress [79]. They also have direct subcellular effects that support cardiac ion homeostasis [79]. However, it is thought that their metabolic actions are of greatest significance. The “thrifty substrate” hypothesis suggests that SGLT2i shift the body’s energy source from carbohydrates to lipids. This shift leads to an increase in β-OHB, providing the heart with an alternative and advantageous fuel source, as previously described [80]. Consequently, it is an intriguing proposition that β-OHB may act as a mediator for the effects of SGLT2i. Furthermore, the role of SGLT2i in cardiac remodeling could be partially attributed to β-OHB’s inhibition of class I histone deacetylases and the NLRP3 inflammasome [78].

SGLT2i and Bladder Health

SGLT2i treatment has diuretic effect, which increases urine volume. This effect may be problematic and potentially aggravate LUTS. In fact, some studies report an increased daytime frequency and nocturia associated with the beginning of the treatment [81, 82]. However, the diuretic effect of SGLT2i is transitory because a new hemodynamic, renal and neurohumoral adaptation is established [83] and the distal nephron compensates for the lack of sodium absorption in the proximal tubule [84]. Therefore, it remains unknown whether the increased LUTS reported with the beginning of SGTLT2i treatment persist with the long-term use of the drug. Moreover, given the similarities between heart failure and bladder myogenic dysfunction pathophysiology, SGLT2i long-term use may prove to be valuable in the treatment of LUTS arising from bladder dysfunction [85]. SGLT2i counteract ischemia, inflammation, oxidative stress, apoptosis and fibrosis which are all pathological processes of bladder damage [85]. Additionally, the SGLT2i induced increase of β-OHB may also exert actions over the urological system, as already discussed previously (Fig. 1). However, further studies are needed to better characterize the role of SGLT2i in LUTS and to what extent ketogenesis enhancement is involved in the molecular pathways.

KETOACIDOSIS RISK

Rising the circulating levels of ketone bodies increases the risk o ketoacidosis. This is a state where the buffering capacity of ketone acids has been outreached and therefore the blood pH drops [25]. All the above-mentioned interventions (intermittent fasting, ketogenic diet/supplements and SGLT2i treatment) carry the potential risk of ketoacidosis induction. IF and KD prescribed by a trained physician have very low risk of ketoacidosis [25]. However, there are reports of self-administered regimens of IF and KD resulting in ketoacidosis [86-88]. Furthermore, SGTLT2i may induce an euglycemic ketoacidosis, not only because of ketone bodies increase but also due to volume depletion [84]. Once more, this is a predictable and preventable complication that physicians should be aware before starting this treatment [89].

CONCLUSIONS

Ketogenesis is a metabolic process that offers benefits for heart and bladder health by managing components of MS. β-OHB appears to be a crucial molecule in the involved pathways. Interventions that elevate serum β-OHB levels—such as fasting, a KD, ketone supplementation, and SGLT2i—have shown significant cardiovascular advantages and offer promising prospects for treating bladder dysfunction associated with MS.

NOTES

Conflict of Interest
No potential conflict of interest relevant to this article was reported.
AUTHOR CONTRIBUTION STATEMENT
·Conceptualization: GFC, TAL, AC
·Writing - original draft: GFC, JO, IVB, IC, EAS, CBS, SMS, TAL, AC
·Writing - review & editing: GFC, JO, IVB, IC, EAS, CBS, SMS, TAL, AC

REFERENCES

1. Efeyan A, Comb WC, Sabatini DM. Nutrient-sensing mechanisms and pathways. Nature 2015;517:302-10. PMID: 25592535
crossref pmid pmc pdf
2. Fahed G, Aoun L, Bou Zerdan M, Allam S, Bou Zerdan M, Bouferraa Y, et al. Metabolic syndrome: updates on pathophysiology and management in 2021. Int J Mol Sci 2022;23:786. PMID: 35054972
crossref pmid pmc
3. Saklayen MG. The global epidemic of the metabolic syndrome. Curr Hypertens Rep 2018;20:12. PMID: 29480368
crossref pmid pmc pdf
4. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120:1640-5. PMID: 19805654
crossref pmid
5. Pashootan P, Ploussard G, Cocaul A, de Gouvello A, Desgrandchamps F. Association between metabolic syndrome and severity of lower urinary tract symptoms (LUTS): an observational study in a 4666 European men cohort. BJU Int 2015;116:124-30. PMID: 25229124
pmid
6. Li X, Zhai Y, Zhao J, He H, Li Y, Liu Y, et al. Impact of metabolic syndrome and it’s components on prognosis in patients with cardiovascular diseases: a meta-analysis. Front Cardiovasc Med 2021;8:704145. PMID: 34336959
crossref pmid pmc
7. Huang PL. A comprehensive definition for metabolic syndrome. Dis Model Mech 2009;2:231-7. PMID: 19407331
crossref pmid pmc pdf
8. Antunes-Lopes T, Vasconcelos A, Costa D, Charrua A, Neves J, Silva J, et al. The impact of chronic pelvic ischemia on LUTS and urinary levels of neuroinflammatory, inflammatory, and oxidative stress markers in elderly men: a case-control study. Urology 2019;123:230-4. PMID: 30219559
crossref pmid
9. Rochlani Y, Pothineni NV, Kovelamudi S, Mehta JL. Metabolic syndrome: pathophysiology, management, and modulation by natural compounds. Ther Adv Cardiovasc Dis 2017;11:215-25. PMID: 28639538
crossref pmid pmc pdf
10. Russo GI, Castelli T, Urzi D, Privitera S, La Vignera S, Condorelli RA, et al. Emerging links between non-neurogenic lower urinary tract symptoms secondary to benign prostatic obstruction, metabolic syndrome and its components: a systematic review. Int J Urol 2015;22:982-90. PMID: 26193757
crossref pmid
11. Wallner LP, Hollingsworth JM, Dunn RL, Kim C, Herman WH, Sarma AV, et al. Hyperglycemia, hyperinsulinemia, insulin resistance, and the risk of BPH/LUTS severity and progression over time in community dwelling black men: the Flint Men’s Health Study. Urology 2013;82:881-6. PMID: 23915515
crossref pmid
12. Seim A, Hoyo C, Ostbye T, Vatten L. The prevalence and correlates of urinary tract symptoms in Norwegian men: the HUNT study. BJU Int 2005;96:88-92. PMID: 15963127
crossref pmid
13. Penson DF, Munro HM, Signorello LB, Blot WJ, Fowke JH, et al. Obesity, physical activity and lower urinary tract symptoms: results from the Southern Community Cohort Study. J Urol 2011;186:2316-22. PMID: 22014824
crossref pmid pmc
14. Park HJ, Park CH, Chang Y, Ryu S. Sitting time, physical activity and the risk of lower urinary tract symptoms: a cohort study. BJU Int 2018;122:293-9. PMID: 29557554
crossref pmid pdf
15. Morelli A, Comeglio P, Filippi S, Sarchielli E, Cellai I, Vignozzi L, et al. Testosterone and farnesoid X receptor agonist INT-747 counteract high fat diet-induced bladder alterations in a rabbit model of metabolic syndrome. J Steroid Biochem Mol Biol 2012;132:80-92. PMID: 22406511
crossref pmid
16. Russo GI, Cimino S, Fragala E, Privitera S, La Vignera S, Condorelli R, et al. Insulin resistance is an independent predictor of severe lower urinary tract symptoms and of erectile dysfunction: results from a cross-sectional study. J Sex Med 2014;11:2074-82. crossref
17. Morelli A, Filippi S, Comeglio P, Sarchielli E, Chavalmane AK, Vignozzi L, et al. Acute vardenafil administration improves bladder oxygenation in spontaneously hypertensive rats. J Sex Med 2010;7:107-20. crossref
18. Kim JK, Lee YG, Han K, Han JH. Obesity, metabolic health, and urological disorders in adults: a nationwide population-based study. Sci Rep 2021;11:8687. PMID: 33888807
crossref pmid pmc pdf
19. Yoshida M, Masunaga K, Nagata T, Satoji Y, Shiomi M. The effects of chronic hyperlipidemia on bladder function in myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits. Neurourol Urodyn 2010;29:1350-4. PMID: 20127840
crossref pmid pdf
20. He Q, Babcook MA, Shukla S, Shankar E, Wang Z, Liu G, et al. Obesity-initiated metabolic syndrome promotes urinary voiding dysfunction in a mouse model. Prostate 2016;76:964-76. PMID: 27040645
crossref pmid pmc
21. Vignozzi L, Morelli A, Sarchielli E, Comeglio P, Filippi S, Cellai I, et al. Testosterone protects from metabolic syndrome-associated prostate inflammation: an experimental study in rabbit. J Endocrinol 2012;212:71-84. PMID: 22010203
crossref pmid
22. Chavalmane AK, Comeglio P, Morelli A, Filippi S, Fibbi B, Vignozzi L, et al. Sex steroid receptors in male human bladder: expression and biological function. J Sex Med 2010;7:2698-713. PMID: 20412431
crossref pmid
23. Vignozzi L, Filippi S, Comeglio P, Cellai I, Morelli A, Maneschi E, et al. Tadalafil effect on metabolic syndrome-associated bladder alterations: an experimental study in a rabbit model. J Sex Med 2014;11:1159-72. PMID: 24612540
crossref pmid
24. Blaha I, Recio P, Martinez MP, Lopez-Oliva ME, Ribeiro AS, AgisTorres A, et al. Impaired excitatory neurotransmission in the urinary bladder from the obese zucker rat: role of cannabinoid receptors. PLoS One 2016;11:e0157424. crossref pmc
25. Kolb H, Kempf K, Rohling M, Lenzen-Schulte M, Schloot NC, Martin S. Ketone bodies: from enemy to friend and guardian angel. BMC Med 2021;19:313. crossref pmc pdf
26. Dhillon KK, Gupta S. Biochemistry, ketogenesis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.
27. Mohammadifard N, Haghighatdoost F, Rahimlou M, Rodrigues APS, Gaskarei MK, Okhovat P, et al. The effect of ketogenic diet on shared risk factors of cardiovascular disease and cancer. Nutrients 2022;14:3499. PMID: 36079756
crossref pmid pmc
28. Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC. Myocardial fatty acid metabolism in health and disease. Physiol Rev 2010;90:207-58. PMID: 20086077
crossref pmid
29. Mizuno Y, Harada E, Nakagawa H, Morikawa Y, Shono M, Kugimiya F, et al. The diabetic heart utilizes ketone bodies as an energy source. Metabolism 2017;77:65-72. crossref
30. Yurista SR, Chong CR, Badimon JJ, Kelly DP, de Boer RA, Westenbrink BD. Therapeutic potential of ketone bodies for patients with cardiovascular disease: JACC state-of-the-art review. J Am Coll Cardiol 2021;77:1660-9. PMID: 33637354
pmid
31. Gormsen LC, Svart M, Thomsen HH, Sondergaard E, Vendelbo MH, Christensen N, et al. Ketone body infusion with 3-hydroxybutyrate reduces myocardial glucose uptake and increases blood flow in humans: a positron emission tomography study. J Am Heart Assoc 2017;6:e005066. PMID: 28242634
crossref pmid pmc
32. Yu Y, Yu Y, Zhang Y, Zhang Z, An W, Zhao X. Treatment with Dbeta-hydroxybutyrate protects heart from ischemia/reperfusion injury in mice. Eur J Pharmacol 2018;829:121-8. PMID: 29679541
pmid
33. Bae HR, Kim DH, Park MH, Lee B, Kim MJ, Lee EK, et al. betaHydroxybutyrate suppresses inflammasome formation by ameliorating endoplasmic reticulum stress via AMPK activation. Oncotarget 2016;7:66444-54. PMID: 27661104
crossref pmid pmc
34. Zheng Y, Xu L, Dong N, Li F. NLRP3 inflammasome: the rising star in cardiovascular diseases. Front Cardiovasc Med 2022;9:927061. PMID: 36204568
crossref pmid pmc
35. Stubbs BJ, Cox PJ, Evans RD, Santer P, Miller JJ, Faull OK, et al. On the metabolism of exogenous ketones in humans. Front Physiol 2017;8:848. PMID: 29163194
crossref pmid pmc
36. Otsubo A, Miyata Y, Matsuo T, Mukae Y, Mitsunari K, Ohba K, et al. Excessive accumulation of visceral fat is associated with lower urinary symptoms including overactive bladder in female patients. Int J Urol 2021;28:397-403. PMID: 33377223
crossref pmid pdf
37. Cao M, Zhao L, Chen H, Xue W, Lin D. NMR-based metabolomic analysis of human bladder cancer. Anal Sci 2012;28:451-6. PMID: 22687923
crossref pmid pdf
38. Akanksha M, Sandhya S. Role of FGFR3 in urothelial carcinoma. Iran J Pathol 2019;14:148-55. PMID: 31528172
crossref pmid pmc
39. Qi J, Gan L, Fang J, Zhang J, Yu X, Guo H, et al. Beta-hydroxybutyrate: a dual function molecular and immunological barrier function regulator. Front Immunol 2022;13:805881. PMID: 35784364
crossref pmid pmc
40. Cosin-Roger J, Ortiz-Masia D, Barrachina MD, Calatayud S. Metabolite sensing GPCRs: promising therapeutic targets for cancer treatment? Cells 2020;9:2345. PMID: 33113952
crossref pmid pmc
41. Chen L, He PL, Yang J, Yang YF, Wang K, Amend B, et al. NLRP3/ IL1beta inflammasome associated with the aging bladder triggers bladder dysfunction in female rats. Mol Med Rep 2019;19:2960-8. PMID: 30720125
pmid pmc
42. Hughes FM Jr, Odom MR, Cervantes A, Purves JT. Inflammation triggered by the NLRP3 inflammasome is a critical driver of diabetic bladder dysfunction. Front Physiol 2022;13:920487. PMID: 36505062
crossref pmid pmc
43. Hughes FM Jr, Sexton SJ, Jin H, Govada V, Purves JT. Bladder fibrosis during outlet obstruction is triggered through the NLRP3 inflammasome and the production of IL-1beta. Am J Physiol Renal Physiol 2017;313:F603-10. PMID: 28592436
pmid pmc
44. Butler DSC, Ambite I, Nagy K, Cafaro C, Ahmed A, Nadeem A, et al. Neuroepithelial control of mucosal inflammation in acute cystitis. Sci Rep 2018;8:11015. PMID: 30030504
crossref pmid pmc pdf
45. Qian J, Zhu W, Lu M, Ni B, Yang J. D-beta-hydroxybutyrate promotes functional recovery and relieves pain hypersensitivity in mice with spinal cord injury. Br J Pharmacol 2017;174:1961-71. PMID: 28320049
pmid pmc
46. Patterson RE, Sears DD. Metabolic effects of intermittent fasting. Annu Rev Nutr 2017;37:371-93. PMID: 28715993
crossref pmid pdf
47. Varady KA, Cienfuegos S, Ezpeleta M, Gabel K. Cardiometabolic benefits of intermittent fasting. Annu Rev Nutr 2021;41:333-61. PMID: 34633860
crossref pmid
48. Dong TA, Sandesara PB, Dhindsa DS, Mehta A, Arneson LC, Dollar AL, et al. Intermittent fasting: a heart healthy dietary pattern? Am J Med 2020;133:901-7. PMID: 32330491
crossref pmid pmc
49. Kamarul Zaman M, Teng N, Kasim SS, Juliana N, Alshawsh MA. Effects of time-restricted eating with different eating duration on anthropometrics and cardiometabolic health: a systematic review and meta-analysis. World J Cardiol 2023;15:354-74. PMID: 37576544
crossref pmid pmc
50. Povoa R. Intermittent fasting and blood pressure reduction: related mechanisms. Arq Bras Cardiol 2023;120:e20230265. PMID: 37341296
pmid pmc
51. Nesci A, Carnuccio C, Ruggieri V, D’Alessandro A, Di Giorgio A, Santoro L, et al. Gut microbiota and cardiovascular disease: evidence on the metabolic and inflammatory background of a complex relationship. Int J Mol Sci 2023;24:9087. PMID: 37240434
crossref pmid pmc
52. Hu X, Xia K, Dai M, Han X, Yuan P, Liu J, et al. Intermittent fasting modulates the intestinal microbiota and improves obesity and host energy metabolism. NPJ Biofilms Microbiomes 2023;9:19. PMID: 37029135
crossref pmid pmc pdf
53. Singh Y, Gupta G, Sharma R, Matta Y, Mishra A, Pinto TJA, et al. Embarking effect of ACE2-angiotensin 1-7/Mas receptor axis in benign prostate hyperplasia. Crit Rev Eukaryot Gene Expr 2018;28:115-24. PMID: 30055537
crossref pmid
54. Breyer BN, Sarma AV. Hyperglycemia and insulin resistance and the risk of BPH/LUTS: an update of recent literature. Curr Urol Rep 2014;15:462. PMID: 25287259
crossref pmid pmc pdf
55. Stekovic S, Hofer SJ, Tripolt N, Aon MA, Royer P, Pein L, et al. Alternate day fasting improves physiological and molecular markers of aging in healthy, non-obese humans. Cell Metab 2019;30:462-76.e6. PMID: 31471173
crossref pmid
56. Meydani SN, Das SK, Pieper CF, Lewis MR, Klein S, Dixit VD, et al. Long-term moderate calorie restriction inhibits inflammation without impairing cell-mediated immunity: a randomized controlled trial in non-obese humans. Aging (Albany NY) 2016;8:1416-31. PMID: 27410480
crossref pmid pmc
57. Wang C, Liu Z, Cai J, Xu X. The regulatory effect of intermittent fasting on inflammasome activation in health and disease. Nutr Rev 2023 Aug;27:nuad104. doi: 10.1093/nutrit/nuad104. [Epub]. crossref pdf
58. Roco-Videla A, Villota-Arcos C, Pino-Astorga C, Mendoza-Puga D, Bittner-Ortega M, Corbeaux-Ascui T. Intermittent fasting and reduction of inflammatory response in a patient with ulcerative colitis. Medicina (Kaunas) 2023;59:1453. PMID: 37629743
crossref pmid pmc
59. Uzun H, Yilmaz A, Kemik A, Zorba OU, Kalkan M. Association of insulin resistance with overactive bladder in female patients. Int Neurourol J 2012;16:181-6. PMID: 23346484
crossref pmid pmc
60. Luda KM, Longo J, Kitchen-Goosen SM, Duimstra LR, Ma EH, Watson MJ, et al. Ketolysis drives CD8(+) T cell effector function through effects on histone acetylation. Immunity 2023;56:2021-35.e8. PMID: 37516105
crossref pmid
61. van Dorp J, van der Heijden MS. The bladder cancer immune micro-environment in the context of response to immune checkpoint inhibition. Front Immunol 2023;14:1235884. PMID: 37727793
pmid pmc
62. Lin F, Ke ZB, Xue YT, Chen JY, Cai H, Lin YZ, et al. A novel CD8(+) T cell-related gene signature for predicting the prognosis and immunotherapy efficacy in bladder cancer. Inflamm Res 2023;72:1665-87. PMID: 37578544
crossref pmid pdf
63. Udumula MP, Singh H, Faraz R, Poisson L, Tiwari N, Dimitrova I, et al. Intermittent fasting induced ketogenesis inhibits mouse epithelial ovarian tumors by promoting anti-tumor T cell response. bioRxiv [Preprint] 2023 Mar;10:2023.03.08.531740. https://doi.org/10.1101/2023.03.08.531740. crossref
64. White B, Welge M, Auvil L, Berry M, Bushell C, Schaeffer AJ, et al. Microbiota of chronic prostatitis/chronic pelvic pain syndrome are distinct from interstitial cystitis/bladder pain syndrome. medRxiv [Preprint] 2021:2021.03.04.21252926. https://doi.org/10.1101/2021.03.04.21252926. crossref
65. Serger E, Luengo-Gutierrez L, Chadwick JS, Kong G, Zhou L, Crawford G, et al. The gut metabolite indole-3 propionate promotes nerve regeneration and repair. Nature 2022;607:585-92. PMID: 35732737
crossref pmid pdf
66. Dynka D, Kowalcze K, Charuta A, Paziewska A. The ketogenic diet and cardiovascular diseases. Nutrients 2023;15:3368. PMID: 37571305
crossref pmid pmc
67. Bueno NB, de Melo IS, de Oliveira SL, da Rocha Ataide T. Verylow-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials. Br J Nutr 2013;110:1178-87. PMID: 23651522
crossref pmid
68. Ebbeling CB, Swain JF, Feldman HA, Wong WW, Hachey DL, Garcia-Lago E, et al. Effects of dietary composition on energy expenditure during weight-loss maintenance. JAMA 2012;307:2627-34. PMID: 22735432
crossref pmid pmc
69. Jornayvaz FR, Jurczak MJ, Lee HY, Birkenfeld AL, Frederick DW, Zhang D, et al. A high-fat, ketogenic diet causes hepatic insulin resistance in mice, despite increasing energy expenditure and preventing weight gain. Am J Physiol Endocrinol Metab 2010;299:E808-15. PMID: 20807839
crossref pmid pmc
70. Choi YJ, Jeon SM, Shin S. Impact of a ketogenic diet on metabolic parameters in patients with obesity or overweight and with or without type 2 diabetes: a meta-analysis of randomized controlled trials. Nutrients 2020;12:2005. PMID: 32640608
crossref pmid pmc
71. Kosinski C, Jornayvaz FR. Effects of ketogenic diets on cardiovascular risk factors: evidence from animal and human studies. Nutrients 2017;9:517. PMID: 28534852
crossref pmid pmc
72. Castellana M, Conte E, Cignarelli A, Perrini S, Giustina A, Giovanella L, et al. Efficacy and safety of very low calorie ketogenic diet (VLCKD) in patients with overweight and obesity: a systematic review and meta-analysis. Rev Endocr Metab Disord 2020;21:5-16. PMID: 31705259
crossref pmid pdf
73. Nielsen R, Moller N, Gormsen LC, Tolbod LP, Hansson NH, Sorensen J, et al. Cardiovascular effects of treatment with the ketone body 3-hydroxybutyrate in chronic heart failure patients. Circulation 2019;139:2129-41. PMID: 30884964
crossref pmid pmc
74. Fuller A. The ketogenic diet. Nature of the bactericidal agent. Lancet 1933;224:855-6. crossref
75. Sun Y, Chen H, Bai Y, Zhang T, Bai W, Jiang B. Ketogenic diet may be a new approach to treatment stress urinary incontinence in obese elderly women: report of five cases. BMC Womens Health 2022;22:402. PMID: 36195868
crossref pmid pmc pdf
76. Kayode OT, Owolabi AV, Kayode AAA. Biochemical and histomorphological changes in testosterone propionate-induced benign prostatic hyperplasia in male Wistar rats treated with ketogenic diet. Biomed Pharmacother 2020;132:110863. PMID: 33113424
crossref pmid
77. Condorelli RA, Aversa A, Basile L, Cannarella R, Mongioi LM, Cimino L, et al. Beneficial effects of the very-low-calorie ketogenic diet on the symptoms of male accessory gland inflammation. Nutrients 2022;14:1081. PMID: 35268056
crossref pmid pmc
78. Saucedo-Orozco H, Voorrips SN, Yurista SR, de Boer RA, Westenbrink BD. SGLT2 Inhibitors and Ketone Metabolism in Heart Failure. J Lipid Atheroscler 2022;11:1-19. PMID: 35118019
crossref pmid pmc pdf
79. Kaplan A, Abidi E, El-Yazbi A, Eid A, Booz GW, Zouein FA. Direct cardiovascular impact of SGLT2 inhibitors: mechanisms and effects. Heart Fail Rev 2018;23:419-37. PMID: 29322280
crossref pmid pdf
80. Ferrannini E, Mark M, Mayoux E. CV protection in the EMPAREG OUTCOME Trial: a “thrifty substrate” hypothesis. Diabetes Care 2016;39:1108-14. PMID: 27289126
crossref pmid pdf
81. Chilelli NC, Bax G, Bonaldo G, Ragazzi E, Iafrate M, Zattoni F, et al. Lower urinary tract symptoms (LUTS) in males with type 2 diabetes recently treated with SGLT2 inhibitors-overlooked and overwhelming? A retrospective case series. Endocrine 2018;59:690-3. PMID: 28421418
crossref pmid pdf
82. Shikuma J, Ito R, Sasaki‐Shima J, Teshima A, Hara K, Takahashi T, et al. Changes in overactive bladder symptoms after sodium glucose cotransporter‐2 inhibitor administration to patients with type 2 diabetes. Practical Diabetes 2018;35:47-50. crossref pdf
83. Ansary TM, Nakano D, Nishiyama A. Diuretic effects of sodium glucose cotransporter 2 inhibitors and their influence on the reninangiotensin system. Int J Mol Sci 2019;20:629. PMID: 30717173
crossref pmid pmc
84. Peters AL, Buschur EO, Buse JB, Cohan P, Diner JC, Hirsch IB. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care 2015;38:1687-93. PMID: 26078479
crossref pmid pmc pdf
85. Faria-Costa G, Charrua A, Martins-Silva C, Leite-Moreira A, Antunes-Lopes T. Myogenic underactive bladder and heart failure resemblance: a novel role for SGLT2 Inhibition? Eur Urol Focus 2022;8:1783-6. PMID: 35599200
crossref pmid
86. Fernández-Cardona A, González-Devia D, Mendivil CO. Intermittent fasting as a trigger of ketoacidosis in a patient with stable, longterm type 1 diabetes. J Endocr Soc 2020;4:bvaa126. PMID: 33033790
pmid pmc
87. Blanco JC, Khatri A, Kifayat A, Cho R, Aronow WS. Starvation ketoacidosis due to the ketogenic diet and prolonged fasting - a possibly dangerous diet trend. Am J Case Rep 2019;20:1728-31. PMID: 31756175
crossref pmid pmc
88. Bashir B, Fahmy AA, Raza F, Banerjee M. Non-diabetic ketoacidosis: a case series and literature review. Postgrad Med J 2021;97:667-71. PMID: 33246966
crossref pmid pdf
89. Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care 2015;38:1638-42. PMID: 26294774
crossref pmid pdf

Fig. 1.
Effects of interventions that increase ketone bodies levels. β-OHB, β-hydroxybutyrate; SGLT2i, sodium-glucose cotransporter 2 inhibitors; RAAS, renin-angiotensin-aldosterone system; BP, blood pressure; IR, insulin resistance. This figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license (https://creativecommons.org/licenses/by/3.0/) and using images from Flaticon.com.
inj-2346250-125f1.jpg
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