Article Type : Short commentary
Authors : Bando H
Keywords : Ketone bodies (KB); Hydroxybutyrate (HB); Low carbohydrate diet (LCD); Ketogenic diet (KD); Endocrine Care
The inaugural issue of “SunText Review of Endocrine Care”
has been published. As the sun and moon shine during the day and at night, this
journal will illuminate the world's medical community for long. When looking
back the history of human being, the evolution of metabolic programs was
observed. Under favourable and unfavourable environment, anabolic and
maintenance program were continued, respectively. Food deficiency resulted in
elevated ketone bodies (KB), which became important energy producing system in
addition to glucose metabolism. Recent topics concerning KB include beneficial
mechanism for cardiovascular disease, efficacy for neurodegenerative diseases
and supplementation with exogenous KB.
Congratulations for the
inaugural issue of “SunText Review of Endocrine Care” [1]. As the sun and moon
shine during the day and at night, this journal will illuminate the world's
medical community for long. When looking back the long history, human beings
have showed evolution for long years associated with metabolic change [2]. In
favorable environment, growth and reproduction programs had been continued,
which were anabolic metabolism. Under unfavorable environment, maintenance
programs were engaged including dormancy and defence. Dormancy is induced by
nutrient shortage relying on energy preserving catabolic metabolism. Defense is
induced by infections and other aggressive factors with supporting anabolic
metabolism [2].
Regarding human
evolution, metabolic programs have changed during 4-7 million years [2]. There
has been comparative perspective on two situations on fasting and binge eating
[3]. Food deficiency resulted in elevated ketone bodies (KB), enhanced
cognition, synaptic plasticity, neurogenesis, and neuro protection. This
mechanism demonstrates optimal cognitive function and resistance to injury and
illness. On the other hand, the latter has been recently observed in medical
and health issues related to non-communicable diseases (NCDs) worldwide. Food
abundance results in increased insulin resistance and cognitive complacency,
leading to synaptic dysfunction, neurogenesis disorders, and neuro
degeneration. This mechanism demonstrates suboptimal cognition and
vulnerability to injury and disease [3].
From historical and
medical points of view, recent topics would be described in this article
concerning diabetes, KB, ?-hydroxybutyrate (?HB), fatty acids, low carbohydrate
diet (LCD), ketogenic diet (KD) and cardiovascular disease.
As an important study
for diabetes, EMPA-REG OUTCOME has been known. Empagliflozin showed slower
progression of CKD and lower rates of clinical events than control [4].
Regarding the protection efficacy for renal problem, KB seemed to be involved
in the mechanism [5]. During the treatment of SGLT2i, rather persistent and
mild hyperketonemia would be observed. In such circumstances, ?-HB is taken up
freely especially by the heart and is oxidized in predominance to free fatty
acids (FFA). This automatic selection may improve the transduction of oxygen
consumption for the efficient work at the mitochondrial level. Furthermore, the
cardiorenal beneficial mechanism of empagliflozin would be from a shift in
myocardial and renal fuel metabolism. This change seems to be from fat and
glucose oxidation with inefficient energy of heart and kidney, toward KB system
with energy-efficient super fuel [6].
When insulin levels
decrease or exercise is performed for a long time, free fatty acids (FFA) are
mobilized from adipose tissue into the blood. From FFA, liver produces KB that
exhibit beneficial effects on the heart with heart failure situation. Regarding
the metabolism of KB, the fuel profiles of the heart and leg were investigated
[7]. The human arterial-venous metabolomics were measured by the simultaneous
blood sampling from radial artery, coronary sinus and femoral vein. As a
result, the leg obtained about 90% of carbons from KB and glucose. In contrast,
the leg released most carbons as lactate, FFA, and amino acids. In detail, approximately
half of released FFA was C18:2 (linoleate), essential FFA, suggesting active
lipolysis from adipose tissue. On the other hand, the heart showed that most
carbons are from FFAs. KB were accounted for about 15% of carbon uptake in the
heart, and acetate were about 2%, which is most abundant short-chain fatty acid
[7]. As to clinically important point, the energy source would be switched from
FFA to KB in the heart disease such as heart failure.
Thus, in heart failure,
KB metabolism in the heart would be stimulated. It is not completely clarified
whether this finding means protective to the heart, or conversely harmful to
remodeling. According to the recent report, continuous intravenous infusion of
KB improved cardiac output without increasing energy and oxygen demand [8]. In
other words, KB can improve cardiac function without imposing a burden on
cardiomyocytes. Furthermore, continuous intravenous infusion of KB has been
reported to improve cardiac blood flow [9]. Thus, KB are considered to have a
potential therapeutic effect on heart diseases centered on heart failure.
Therefore, measures to increase the blood KB level may be effective.
As to cardiac function,
hyperketonemia would bring several mechanisms with beneficial effects for
protecting human organs [10]. There are 10 related factors in the following: i)
elevation of cardiac energetics, endothelial function mitochondrial function,
ii) reduction of cardiac remodelling, inflammation, oxidative stress, Histone
deacetylase (HDAC, iii) related mechanism of blood pressure, body weight, blood
glucose and lipid profile.
In addition to the
above-mentioned cardiovascular system, KB have also been reported to be
effective against neurodegenerative diseases. KD has been known to have
historically efficacy for epilepsy and GLUT-1 deficiency [11,12]. It is also
expected to be effective against mild cognitive impairment (MCI), Alzheimer's
disease, and Parkinson's disease [13]. There was an impressive report that KB
was effective against acromegaly, which is one of the endocrine diseases [14].
From the above, it can be considered that the protective effect of ketone
bodies on brain cells can be observed.
Such an investigation
would provide some answer for various inquiries. One question would be which is
more effective, i) stabilization of glycemic fluctuations by LCD or ii)
maintenance of hyperketonemia by some agent [15]. It has been reported that
supplementation with ketone esters improved early insulin secretory response
for 75gOGTT with alleviation of impaired glucose tolerance (IGT) [16]. For the
background of this mechanism, hyperketonemia itself may contribute to the
stabilization of glycemic fluctuations. From meta-analysis of RCTs, LCD showed
better result than KD [17]. This reason would be probably easy continuation for
the patients. Consequently, it would be a gospel method, if diabetic patient
can have some medicine of KB precursors, associated with loose dietary
restriction life.
In recent report,
supplementation with exogenous ?HB was provided [18]. Subjects included 22
healthy male and female adolescents, who consumed ?HB 3.75g or maltodextrin
placebo twice daily for 90 days. The analyzed factors were blood test, bone
density, emotional intelligence and happiness surveys and blood pressure checked
at 0, 45 day and 90 day. The result was well-tolerated and safe in the case of
adolescence subjects [18].
In summary, several impressive information was
commented. This report will hopefully become a reference for clinical practice
and research development.