La miel es un fluido dulce y viscoso

producido por abejas del género

Apis, principalmente la abeja
doméstica, a partir del néctar de las
flores o de secreciones de partes
vivas de plantas o de excreciones de
insectos chupadores de plantas
(áfidos). Estas sustancias son recogidas por las abejas, luego transformadas
al combinarlas con sustancias propias, depositadas, deshidratadas y
almacenadas en los panales para su maduración.

La intervención del hombre en el proceso de explotación de los panales de la

colmena es conocida como apicultura

1
1) Cortés ME, Vigil P, Montenegro G. The medicinal value of honey: a review on its
benefits to human health, with a special focus on its effects on glycemic regulation.
Ciencia e investigación agrarian. 2011[citado 13 jun 2018], 38(2), 303-317.
Disponible en: https://scielo.conicyt.cl/scielo.php?script=sci_arttext&pid=S0718-
16202011000200015

Ciencia e investigación agraria

versión On-line ISSN 0718-1620
Cienc. Inv. Agr. vol.38 no.2 Santiago ago. 2011
http://dx.doi.org/10.4067/S0718-16202011000200015

Cien. Inv. Agr. 38(2):303-317. 2011

HUMAN HEALTH

The medicinal value of honey: a review on its benefits to human health, with a
special focus on its effects on glycemic regulation

Valor medicinal de la miel: beneficios en la salud humana, con especial referencia

en sus efectos sobre la regulación glicémica

Manuel E. Cortés1,2, Pilar Vigil2, and Gloria Montenegro3

1Departamento de Ciencias Animales, Facultad de Agronomía e Ingeniería Forestal,

Pontificia Universidad Católica de Chile. Casilla 306-22, Santiago, Chile.
2Unidad de Reproducción y Desarrollo, Departamento de Fisiología. Facultad de
Ciencias Biológicas, Pontificia Universidad Católica de Chile. Casilla 114D,
Santiago, Chile.
3Departamento de Ciencias Vegetales, Facultad de Agronomía e Ingeniería
Forestal, Pontificia Universidad Católica de Chile. Casilla 306-22, Santiago, Chile.

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Honey, a natural substance produced by honeybees, is composed of a complex
mixture of carbohydrates, water, and a small amount of proteins, vitamins, minerals,
and phenolic compounds. Fructose, glucose and maltose are among the various
types of sugars present in honey. Used for millennia as both food and medicine,
honey has been associated with improved antioxidant capacity, modulation of the
immune system, antimicrobial activities, influence on lipid values (through
antihypercholesterolemic effects) and regulation of glycemic responses, among other
benefits. The aim of this article was to review the effects of natural honey intake on
human health, with particular reference to its influence on glycemic regulation.
Several studies have focused on the potential use of honey as a nutritional
supplement for healthy individuals and for those with impaired glucose tolerance,
diabetes, and their related comorbidities. Such investigations have found that,
compared to glucose and sucrose, the consumption of honey decreases glycemic
levels and blood lipids in healthy, diabetic and hyperlipidemic individuals. Moreover,
long periods of honey intake seem to reduce fasting glucose levels in humans,
suggesting that honey consumption influences plasma glucose regulation, mainly
through a normo- or hypoglycemic effect. Therefore, honey may be proposed as a
nutritional dietary supplement for healthy individuals and for those suffering from
alterations in glycemic regulation.

Key words: Diabetes, flavonoids, glycemic regulation, honey, insulin resistance,

nutraceuticals, nutrition.

Resumen
La miel de abejas es una substancia natural constituida por una mezcla compleja de
carbohidratos, agua y una pequeña proporción de proteínas, vitaminas, minerales y
compuestos fenólicos, entre otros constituyentes minoritarios. Utilizada por milenios
como alimento y medicina, se le atribuye un sinnúmero de efectos beneficiosos, a
saber: aumento de la capacidad antioxidante, modulación del sistema inmune,
actividad antimicrobiana, influencia sobre los niveles lipídicos mediante efectos
antihipercolesterolémicos y regulación de las respuestas glicémicas, entre otros.
Considerando lo anterior, nuestro objetivo es mostrar los efectos de la ingesta de
miel sobre la salud, con especial atención en su influencia sobre la regulación
glicémica. Diversos estudios han investigado si la miel puede constituir un
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suplemento nutricional, tanto para individuos saludables como para aquéllos con
tolerancia reducida a la glucosa, diabetes y comorbilidades asociadas. Estas
investigaciones hanencontrado que el consumo de miel, en comparación a glucosa
y sacarosa, disminuye los niveles glicémicos y los lípidos sanguíneos en sujetos
saludables, diabéticos e hiperlipidémicos. Más aún, su ingesta durante períodos
prolongados puede reducir, según algunos estudios, los niveles glicémicos en
ayunas. Esta evidencia sugiere que el consumo de miel influencia los mecanismos
de regulación de los niveles de glucosa plasmática, principalmente mediante un
efecto normo- o hipoglicemiante. Según lo anterior, la miel podría constituir un
suplemento nutricional en la dieta de individuos saludables y en aquéllos con
alteraciones en la regulación glicémica.

Palabras clave: Compuesto nutracéutico, diabetes, flavonoides, miel, nutrición,

regulación glicémica, resistencia insulínica.

INTRODUCTION
Honey is a natural substance of sweet flavor and viscous consistency produced by
honeybees, especially by the species Apis mellifera.

Honey was probably the first sweetener discovered by man, and its use dates back
to the origins of mankind itself (Havsteen, 2002); in fact, honey reportedly constituted
a component of the Paleolithic diet (Eaton and Eaton, 2000). There is evidence of
the development of beekeeping in the Neolithic, as shown in cave paintings found in
Cueva de la Araña, near Bicorp, Valencia, Spain, which depict honey being collected
by a prehistoric man using a makeshift beehive. Records of its use have been found
in Sumerian clay tablets dated 2100-2000 years B.C. (Yaghoobi et al, 2008). In
Egypt, beekeeping underwent remarkable development, and representative products
of the apiary (e.g., beeswax, honey, pollen, propolis, and royal jelly) were used both
as medicine and ceremonial materials, and jars containing residues of honey and
related substances have been found in the tombs of several pharaohs (Havsteen,
2002), such as that of Tutankhamun (Kahn et al., 2007). In Greece and Rome,
honey was also utilized as medicine and energy food (García et al., 1986; Garret and
Grisham, 2001); in India, it has been of great relevance in Ayurvedic Medicine and
Unani Medicine for centuries (Aparna and Rajalakshmj, 1999; Agrawal et al, 2007).
4
The therapeutic effect of honey was also known in Persia, as mentioned by the
scientist, philosopher and physician Av-icenna approximately 1000 years ago in his
remarkable book, Canon of Medicine (Avicenna, 1999). In Medieval Europe,
beekeeping continued to develop, and later, during the Renaissance, it also inspired
artists, such as the Florentine painter Piero di Cosimo, author of "The Discovery of
Honey" (Thomas and Mathews, 1963; Garret and Grisham, 2001). Later, in the XVII
century, the Tratado Breve sobre la Cultivación de las Colmenas was transcribed in
Spain (de Jesús María, 1653) and is one of the earliest works on beekeeping to be
written in Spanish. Thus, honey has occupied an important role in the human diet
from the dawn of mankind to the present day.

Currently, honey is widely used for nourishment, constituting a nutritious supplement

with medicinal properties recognized all over the world (Montenegro et al, 2003); this
has led to its current use in the treatment of a number of pathologies (Molan, 2001;
Kahn et al, 2007) and justifies its nomination as a functional aliment or
'nutraceutical.' Honey is produced in almost every country of the world and is
recognized as an important energy food (Muñoz et al, 2007). Because of its high
nutritious value and unique flavor, honey has become increasingly accepted by
consumers, often being used as a substitute for other sweeteners (Montenegro et
al., 2003).

Nevertheless, it is not to be considered a whole food according to human standards

but rather as a potential dietary supplement (Muñoz et al., 2007). The world
production of honey today comprises approximately 1.2 million tons, less than 1%
the total production of sugar (Álvarez-Suárez et al, 2010). The demand for honey
varies remarkably from one country to another, and China and Argentina rank
among the main exporters; these countries, however, have low annual consumption
rates, close to 0.1 to 0.2 kg per capita (Álvarez-Suárez et al., 2010). Indeed, honey
consumption is higher in developed countries, where domestic production does not
meet the market demand (Álvarez-Suárez et al., 2010). In Chile, honey is produced
by approximately 14,000 beekeepers, and there are over 335,000 apiaries, which
produce different varieties of unifloral and polyfloral honey (Muñoz et al, 2007).

5
Considering the wide interest generated since ancient times by the medicinal and
nutritional properties associated with honey, the objective of this review article was to
summarize the main benefits attributed to the intake of natural honey, with a special
focus on the effects exerted on glycemic regulation.

The composition of honey

Honey is composed of a complex mixture of water, carbohydrates and a myriad of
other minor compounds (White, 1978; García et al, 1986). The chemical composition
of honey is variable and depends on regional and climatic conditions and on the type
of flowers visited by the bees, thus, its classification as unifloral or polyfloral (Fredes,
2004; Muñoz et al, 2007; Fredes and Montenegro, 2008). However, on average,
natural honey is composed of 17.1% water, 82.4% carbohydrates — approximately
38.5% fructose, 31°% glucose and 12.9 % other sugars— and 0.5% proteins, amino
acids, vitamins, phenolic compounds, organic acids and multiple minerals, among
other minority constituents (White, 1978; García et al, 1986; Garret and Grisham,
2001; Moreira and De Maria, 2001; Fredes, 2004; Fredes and Montenegro, 2006;
Kahn et al., 2007; Montenegro and Fredes, 2008). It has also been suggested that
the presence of variable amounts of heavy metals can be related to the geographical
and botanical origin of this product (Fredes, 2004; Fredes and Montenegro, 2006).

In natural honey, as well as in propolis and royal jelly, most of the phenolic
compounds are present in the form of flavonoids (Viuda-Martos et al., 2008), a vast
family of phytochemicals comprising chalcones, flavandiols, flavonols, antho-cyanins
and proanthocyanidins. Flavonoid biosynthesis is derived from the phenylpropanoid
pathway, one of the most widely studied secondary metabolic routes in plant
systems. Several phenolic compounds, especially flavonoids, are associated with
multiple benefits on human health, including anti-inflammatory, antioxidant,
antiallergic, antithrombotic, antidiabeto-genic, hypoglycemic, normolipidemic,
hepato-protective, antiviral and anticarcinogenic activities (Havsteen, 2002;
Middleton et al, 2000; Pérez-Trueba, 2003). Due to these properties, flavonoids have
been recognized as nutraceuti-cal compounds (Tapas et al., 2008). Regarding the
flavonoids identified in Chilean honeys, it is important to highlight specific
compounds, such as chrysin, galangin, isorhamnetin, kaempferol, myricetin,
naringenin, pinobanksin, pinocembrin, quercetin, and rutin (Muñoz et al., 2007;
6
Montenegro et al, 2009). The specific effects of these compounds on glucidic
metabolism will be described further below.

Honey has been linked to several beneficial effects on human health

As mentioned above, for millennia honey has been credited with multiple medicinal
properties (Figure 1). In the following section, some of these properties are explained
in more detail.

Enhanced antioxidant activity

It is known that free radicals and reactive oxygen species (ROS), such as
hydroperoxyl, hydroxyl, and superoxide, are associated with aging and disease
mechanisms. ROS can produce oxidative damage in biomolecules, such as
carbohydrates, lipids, proteins and nucleic acids, which can alter various cell
processes and cause cell death (Viuda-Martos et al., 2008). Several studies have
found that the consumption of honey can improve the defenses against oxidative
stress (Al-Mamary et al., 2002; Schramm et al., 2003; Beretta et al., 2007; van der
Berg et al., 2008). This function has been attributed to the natural phenolic
compounds (e.g., flavo -noids) in honey (Pérez-Trueba, 2003; Schramm et al., 2003;
van der Berg et al., 2008). These phytochemicals appear to exert their antioxidant
capacities mainly through the decrease and removal of ROS, thus diminishing the
risk of pathologies and damage produced by free radicals (Beretta et al., 2007). The
exact molecular mechanisms of antioxidant activity of the phenolic compounds
present in honey and related beehive products are not yet fully understood.
However, the most probable ones include free radical scavenging, hydrogen

7
donation, the interference with propagation reactions or inhibition of enzymatic
systems involved in initiation reactions, metallic ion chelation, and acting as a
substrate for diverse free radicals, especially ROS (van Acker et al., 1996; Al-
Mamary et al., 2002; Havsteen, 2002; Middleton et al., 2000; Viuda-Martos et al.,
2008).

Effects on the immune system

It has been suggested that the consumption of honey can exert several beneficial
effects on the human immune response and on its associated mechanisms. In fact,
honey has been reported to promote the multiplication of human peripheral blood B-
and T-lymphocytes and the activation of neutrophils under conditions of cell culture
(Abuharfeil et al., 1999). In monocytic cell line culture, honey has been shown to
stimulate the release of inflammatory cytokines, such as tumor necrosis factor-alpha,
interleukin-1β and interleukin-6 (Tonks et al, 2003), which are involved in triggering a
number of functions of the immune response to infection (Molan, 2001). Moreover, in
mice, it has been found that the intake of a honey-supplemented diet stimulates the
production of antibodies during the primary and secondary immune responses
against thymus— dependent and — independent antigens (Al-Waili and Haq, 2004).
A recent study reported an immunomodulatory potential of honey in the course of
phagocytosis, mainly by modifying the oxidative burst process through the inhibition
of phagocytic myeloperoxidase activity and an inhibitory effect exerted by the major
sugar constituents of honey on exocytsis-associated ROS formation catalyzed by
my-eloperoxidase (Mesaik et al., 2008).

Antimicrobial activity
Honey and beehive-related substances have been used as antiseptic agents (e.g.,
propolis) since at least the time of Aristotle (Molan, 2001). Despite the evident
antimicrobial capacity of honey, as determined by its effective inhibition of bacterial
and fungal proliferation and growth, there does not seem to be any clear-cut cause,
suggesting that it could correspond to a combined or synergic effect of the
antioxidant compounds present (Viuda-Martos et al., 2008). The following properties
have been proposed to explain the effect of honey against bacterial growth: (i) the
presence of hydrogen peroxide, resulting from the action of the glucose-oxidase
enzyme on glucose in presence of oxygen (García et al, 1986; Wahdan, 1998;
8
Molan, 1999a, Khan et al., 2007), a compound whose activity appears to decrease
as honey remains in storage (Montenegro et al., 2009); (ii) inherent physi -cochemical
properties, such as its high sugar content (~ 80% w/w) that can produce a high
osmotic effect and its acid pH of 3 to 4.5 (Molan, 1992; Bogdanov et al, 1997); (iii)
the presence of diverse organic acids (Aparna and Rajalakshmj, 1999), including
gluconic acid (also derived from glucose catalysis), which remarkably creates an
acidic microenvironment and whose concentration varies considerably from one type
of honey to another (White et al., 1963; White, 1978); and (iv) non-peroxidic
substances (Cabrera et al., 2006), such as polyphenols, which possess antibacterial
activity. These compounds vary depending on the plant species from which the bees
gather their nectar (Cooper, 2007) and seem to remain unaltered even after long
periods of storage (Viuda-Martos et al, 2008). With regard to the antibacterial
activity, it has been recently determined that extracts of unifloral honeys from the
endemic Chilean tree, Quillay (Quillaja saponaria), which contain several natural
phenolic compounds, show antibacterial activity against Escherichia coli,
Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella typhi, Streptococcus
pneumoniae type P, and Vibrio cholerae, and antifungal activity against Candida
albicans (Montenegro et al., 2009).

Lastly, due to its antimicrobial properties, the use of natural honey has also been
recommended in medical treatments for promoting wound disinfection and healing
(Khan et al., 2007). Thus, some physicians have also advised their patients to use
honey to improve the healing of surgical scars (Molan, 1999b; Molan, 2001; Khan et
al, 2007).

Effects on glycemic regulation

The term 'glycemic regulation', also known as 'glycemic homeostasis', refers to
diverse phenomena leading to the adequate regulation of blood glucose levels (i.e.,
glycemia), which constitutes one of the mechanisms used by organisms to maintain
the properties of their internal milieu constant. For decades, there has been interest
in determining the effects of honey intake on glucose regulation disorders, and
controversial results have been obtained. On the one hand, it has been considered
that honey consumption by diabetics is pointless because it contains a considerable
proportion of sugars (White, 1978; Moreira and De Maria, 2001), while on the other
9
hand, some research has produced interesting results positioning honey as a
potential nutritional supplement for subjects with disorders of glucose homeostasis
(Bornet et al., 1985; Samanta et al., 1985; Katsilambros et al, 1988; Shambaugh et
al, 1990; Al-Waili, 2004; Agrawal et al, 2007; Ahmad et al, 2008).

Before referring to the effects of honey intake on the alterations in glycemic

regulation, it is necessary to examine such disorders in detail, as described below.

a. Disorders of glucose regulation and their associated comorbidities. There can

be as many alterations in glucose metabolism as the existing mutations in some of
the enzyme-encoding genes associated with their metabolic pathways, e.g.,
deficiency of phosphofructoki-nase-1, hepatic fructose 1,6-biphosphate aldol-ase or
ketohexokinase. These pathologies are commonly termed inborn errors of glucidic
metabolism (Hall, 2003). However, the most relevant disorders that are recognized
today as related to glucidic homeostasis are those linked to alterations in the
regulation of glycemia by insulin. Insulin is a peptide hormone produced in the
pancreas, specifically by pancreatic-beta cells; it is composed of 51 amino acids, and
the gene that encodes it is located in chromosome 11 in humans (Vincent-
Desplanques et al., 2005). Insulin has multiple functions in an organism, such as
protein and hepatic glycogen synthesis, triacylglycerol storage in adipose tissue,
and, probably the most important function, the regulation of glycemic levels, which
promote glucose uptake by its target cells, especially in muscle, the liver and
adipose tissue. To exert this function, insulin must bind to its plasma membrane
receptor and trigger a cascade of intracellular signaling, which eventually leads to
the translocation of glucose transporters, mainly GLUT4, to the plasma membrane,
resulting in glucose uptake.

When a certain amount of insulin is secreted by the pancreas, the corresponding

effector organ responds depending on its insulin sensitivity (Ferrannini and Mari,
1998). Defects in this mechanism lead to a pathophysiological state known as insulin
resistance, which has been defined as a condition in which a normal insulin
concentration produces an attenuated biological effect in terms of glucidic
homeostasis (Yalow and Berson, 1970), decreasing the ability of this hormone to
exert its functions on its aforementioned typical target tissues. When insulin cannot
10
exert its normoglycemic actions, blood glucose can increase to dangerous
concentration levels and, additionally, be accompanied by compensatory
hyperinsulinemia (i.e., excessive circulating insulin) to diminish the increased
glucose levels (Cordain et al., 2003). The latter constitutes one of the initial stages of
diabetes mellitus. Several types of insulin resistance have been reported (Vincent-
Desplanques et al., 2005), a condition also linked to the development of diverse
pathologies, such as obesity, as insulin is a fundamental regulator of virtually every
aspect of adipocyte biology (Khan and Flier, 2000). This hormone promotes the
storage of triacylglycerols in adipocytes via a number of mechanisms, which include
the differentiation from preadipocytes to adipocytes. Moreover, in mature adipocytes,
insulin stimulates the transport of glucose and the synthesis of triacylglycerols — a
phenomenon known as lipogenesis— and inhibits lipolysis (Khan and Flier, 2000). In
addition, insulin increases the uptake of fatty acids derived from circulanting
lipoproteins by stimulating the activity of the lipoprotein lipase, in adipose tissues
(Khan and Flier, 2000).

Currently, the pathology known as insulin resistance has acquired remarkable

importance because it has been proposed to be a crucial component of what is
known as 'metabolic syndrome', which consists of the combination of several
pathologies or risk factors in a single individual, increasing the susceptibility to
cardiovascular disease and diabetes. Yet, a portion of the scientific community is still
debating on whether to consider insulin resistance a component and/or diagnostic
criterion of metabolic syndrome (Reaven, 2006). In any case, metabolic diseases
have a high prevalence in society today. This is especially true for diabetes, the main
endocrine illness worldwide, with 150 million reported diabetics, and estimates
indicate this number could double by 2025 (King et al, 1998). Factors, such as
genetic predisposition, a sedentary lifestyle and stress, are implicit in the genesis of
diabetes, together with a high-calorie diet based mainly upon the intake of
excessively fatty or sweet food; indeed, it is known that the consumption of food with
a high-sugar content often constitutes one the central causes of the origin of several
endocrine-metabolic disorders (Cor-dain et al., 2003). In this respect, the prominent
French physiologist and physician, Claude Bernard, suggested in the XIX century
that the sensitivity to carbohydrates could be modulated by dietary intake
(Shambaugh et al, 1990). Thus, increasing the level of sucrose would lead to a
11
deterioration of glucose tolerance and trigger harmful health effects (Shambaugh et
al., 1990).

There is also an existing link between alterations in glucose and insulin levels and
several reproductive problems in humans (Zitzmann, 2009). Insulin resistance is
considered an important factor linked to ovulatory dysfunction in women (del Río et
al., 2006; Vigil et al., 2007a) and to hypogonadism and associated disorders in men
(Contreras et al., 2006; del Río et al., 2007; Zitzmann, 2009). Additionally, impaired
glucose tolerance and obesity, among other factors related to insulin resistance in
women, also have a negative impact on fertility (del Río et al., 2006; Vigil et al.,
2007a; Vigil et al., 2007b). As to the latter, several studies have reported that such
endocrine-metabolic pathologies and their comorbidities are associated with
polycystic ovary syndrome, a disorder defined as an ovulatory dysfunction caused by
hyperandrogenism, which is highly prevalent worldwide among reproductive-aged
women (del Río et al., 2006; Vigil et al., 2007a; Vigil et al., 2007b).

b. Effects of honey intake on glycemic regulation. A number of studies have

focused on this topic, and among them, Samantha et al. (1985) have shown that the
intake of honey has a lower hyperglycemic response, as compared to glucose and
sucrose, in healthy or type 1 diabetic individuals. Later, Bornet et al. (1985) have
studied subjects suffering from diabetes mellitus type 2, and found that honey,
compared to an isoglucidic amount of bread, presented no additional hyperglycemic
effect in the diabetic individuals when consumed for breakfast (Bornet et al., 1985).
In relation to this, yet another study has reported that, rather than producing a higher
postprandial hyperglycemic effect, honey causes a hyperglycemia similar to that
produced by consuming bread in individuals with type 2 diabetes (Katsilambros et
al., 1988). Shambaugh et al. (1990) have studied non-diabetic subjects and reported
that honey has a lower effect on increasing the levels of sugar in the blood,
compared to sucrose; in addition, these authors have suggested that honey would
cause fewer long-term health problems than fructose or sucrose, in part because it
contains nutrients other than carbohydrates (Shambaugh et al., 1990; Shambaugh et
al, 1991). Moreover, honey is sweeter that sucrose, thus, a smaller amount is
required. Considering these advantages, the above authors have suggested that it
should be favored as sweetener instead of sucrose (Shambaugh et al., 1990).
12
Another study found that honey intake, when compared to glucose and sucrose,
resulted in reduced glucose levels, blood lipids and C reactive protein (C RP) — a
marker of inflammation and oxidative damage— in healthy, diabetic and
hyperlipidemic subjects (Al-Waili, 2004). Agrawal et al. (2007) have reported that
individuals with reduced glucose tolerance or mild diabetes, who were subjected to
an oral glucose tolerance test one day and an oral honey tolerance test the next day,
showed a higher tolerance to honey, indicating that honey could be a valuable
substitute for sugar for people suffering from these metabolic pathologies (Agrawal
et al., 2007). More recent studies support the findings of the latter and have reported
that physiological glycemic responses were significantly lower in subjects who
consumed natural honey, compared to those who consumed glucose or artificial
honey (Ahmad et al, 2008). Moreover, another recent study has shown that a
regimen of a 30-day honey intake seems to slightly reduce fasting blood glucose
levels in humans (Yaghoobi et al., 2008).

c. How could honey be exerting regulatory effects on glycemic responses? The

modulation of glycemic responses (normoglycemic and hypo-glycemic effects)
observed after natural honey intake could be based on diverse mechanisms of action
that have not yet been completely elucidated. Honey contains many trace elements,
such as antioxidants, copper, zinc, and unidentified components (White, 1978;
Fredes, 2004; Fredes and Montenegro, 2006; Montenegro and Fredes, 2008); in
addition, its fructose and glucose content can play an important role in such effects
(Yaghoobi et al., 2008). The various putative underlying explanations are the
following. 1) A slow decrease in saccharide absorption in the intestine is caused by
the presence of glyce-mic carbohydrates in natural honey (Southgate 1995; Vosloo,
2005; Ahmad et al, 2008); in addition, fermentable and non-fermentable
carbohydrates from natural honey could be linked to the modulation of intermediary
metabolism in the intestinal lumen (Wang and Gibson, 1993; Kok et al, 1998;
Shamala et al, 2000; Chow, 2002; Ahmad et al., 2008). It has been argued that the
glucose component in honey is poorly absorbed by the gut epithelium (Agrawal et
al., 2007). Furthermore, the presence of certain sugars, such as palatinose
(isomaltulose), would interfere with glucose absorption (Oizumi et al., 2007). Thus,
possible differences in carbohydrate absorption could also result in differences in
glycemic control (Chepulis, 2007). 2) The effect is due to the hydrogen peroxide
13
present in honey, which has been reported as an agent that can effectively mimic the
function of insulin (Hayes and Lockwood, 1987), even though there is no evidence
yet to prove that hydrogen peroxide is absorbed in the gut or that the levels
produced are sufficient to activate insulin receptors (Chepulis, 2007). 3) Some
compounds, which may also possess insulin-like activity, from the hypopharyngeal
glands of honeybees are added to honey (Münstedt et al, 2009a). 4) The influence of
honey on glycemic control is through its effects in decreasing prostaglandin and
increasing nitric oxide (NO) levels (Yaghoobi et al., 2008). This mechanism may
participate in glycemic modulation, as it has been shown that prostaglandin E2 is
one of the main physiological inhibitors of insulin (Cheng et al, 2003), and higher
levels of NO stimulate the increase of insulin secretion (Smukler et al., 2002). 5)
There is an antioxidant activity exerted by some non-sugar components of honey,
specifically, natural phenolic compounds, such as flavonoids. Regarding the
antioxidant effects of flavonoids, it has recently been reported (Sharma et al., 2008)
that rats with streptozotocin-induced diabetes showed a decrease in their
postprandial glyce-mic responses after the administration of extracts of E. jambolana
seeds, which have been attributed with antidiabetogenic, hypoglycemic and
hypolipidemic effects (Sharma et al., 2008). Interestingly, extracts from this medicinal
Hindu plant possess the compounds, rutin, myric-etin, quercetin and kaempferol
(Sharma et al., 2008), and, as mentioned above, these are some of the compounds
identified in natural honey (Muñoz et al, 2007; Viuda-Martos et al, 2008; Montenegro
et al., 2009). Various studies using mainly mice and rats as experimental models
have shown that such flavonoids exert diverse normoglycemic effects and lead to a
lower incidence of complications associated with diabetes (Lee et al., 2005; Fang et
al., 2008; Zanatta et al., 2008; Fernandes et al., 2009; Kobori et al., 2009). In
particular, it has been shown that chrysin and chrysin-derived compounds have
hypoglycemic effects in diabetic mice (Shin et al, 1999). The polyhydroxylated
flavonol, myricetin, has also been associated with the stimulation of lipogenesis and
glucose transport in rat adipocytes (Ong and Khoo, 1996); it has been speculated
that such a compound may exert an influence on the treatment of non-insulin-
dependent diabetes mellitus (Ong and Khoo, 1996; Ong and Khoo, 2000).
Kaempferol could act on multiple molecular targets to ameliorate hyperglycemia,
including acting as a partial agonist of peroxisome proliferator-activated receptor
gamma (Fang et al., 2008), whereas its derivative, kaempferol 3-neohesperidoside,
14
has shown to possess an insulinomimetic effect in rat muscle (Zanatta et al., 2008).
In addition, quercetin has also been linked to an improvement in glucose uptake
(Fang et al., 2008) and diabetes-related symptoms in rats (Kobori et al., 2009), with
similar results having been found in rutin-administered rats (Fernandes et al., 2009).
In addition, isorhamnetin-3-O-beta-D-gluco-side, a compound derived from flavonol
isorh-amnetin, also reportedly found in Chilean natural honeys (Montenegro et al.,
2009), has proven to be effective in the prevention or treatment of diabetes-
associated complications in various rat tissues (Lee et al., 2005). Apigenin, another
flavonoid found in honey and related substances (Viuda-Martos et al., 2008), has
shown to decrease hyperglycemia, disease-provoked thyroid dysfunction and lipid
peroxidation in allox-an-treated diabetic mice (Panda and Kar, 2007). Lastly,
naringenin has been shown to prevent dyslipidemia and hyperinsulinemia in low-
density lipoprotein (LDL) receptor-null mice with diet-induced insulin resistance
(Mulvihill et al., 2009). The aforementioned evidence leads to the idea that such
flavonoids, which are present in natural honey, could be exerting their antidia-
betogenic, normoglycemic and normolipidemic properties at a molecular signaling
level (Middleton et al., 2000; Havsteen, 2002; Sharma et al., 2008), mainly by
decreasing the alterations caused by oxidative stress. The latter can be understood
in light of the increasing acceptance by the scientific community that an imbalance in
the oxidative state, such as that induced by abnormal ROS levels, is a phenomenon
linked to cellular insulin resistance, dysglycemias and related pathologies (Evans et
al., 2005; Eriksson, 2007; Martínez-Hervas et al., 2008; Choi et al., 2008). ROS
accumulation can lead to the inadequate activation of stress kinases, damage in
cellular membranes, dysfunction in organ-elles, such as the endoplasmic reticulum
and mitochondria, and in the genome (Muoio and Newgard, 2004; Eriksson, 2007;
Choi et al., 2008). In addition, inadequate oxidative modification of cell
carbohydrates, lipids and proteins can have functional consequences contributing to
the development and progression of insulin resistance (Evans et al., 2005).
Regarding the above, the flavonoids or other phenolic compounds present in the
various t ypes of natural honeys could be exerting their effects on glyce-mic control
at an intracellular level by decreasing the oxidative alterations linked to insulin
resistance, hyperglycemia and other associated pathophysiological states (Figure 2).
6) It is pos -sible that flavonoids could directly stimulate an otherwise weak insulin
effect in various ways, for example, by directly influencing phospho-kinase proteins
15
(Havsteen, 2002). 7) Lastly, in a similar way as mentioned above for carbohydrates,
the flavonoids present in honey could also be directly blocking carbohydrate
transport at the intestine level. This is remarkably interesting regarding the treatment
of diabetes from a pharmacological point of view. By measuring saccharide transport
in Xenopus laevis oocytes (Kwon et al., 2007), myricetin, fisetin, and quercetin, and
their glycoside precursor, isoquercitrin, compounds which are all present in beehive
products (Viuda-Martos et al., 2008), have been reported to initiate a strong inhibition
of the fructose and glucose transport mediated by GLUT2 (Kwon et al, 2007).

Figure 2. One of the proposed hypothetical mechanisms through which several

antioxidants (mainly flavonoids and other phenolic compounds), which are present in
natural honey, may act against the development of glycemic regulation disorders by
decreasing the oxidative stress caused by metabolic alterations, such as
hyperglycemia, hyperinsulinemia and dyslipidemia.
Nevertheless, the aforementioned explanations do not exclude the possible
mediation of the beneficial effects of honey intake on glucose homeostasis disorders
by other mechanisms not yet described.

Effects on lipid homeostasis

A few studies have focused on the influence of oral honey consumption on the
regulation of human lipid values (Al-Waili, 2004; Yaghoobi et al, 2008; Münstedt et

16
al, 2009b). It has been reported that, even though a single dose of glucose or
artificial honey (consisting of 40 g fructose + 35 g glucose in 250 mL water) leads to
an increase in cholesterol and triacylglycerols 1 to 3 h later, this effect is not
observed with natural honey (Al-Waili, 2004). Furthermore, a 15-day daily intake of
75 g of honey by hyperglycemic and hyperlipidemic individuals has resulted in a
decrease of plasma glucose, lipid levels and CRP (Al-Waili, 2004). Another study
using honey-dew honey with a high antioxidant content has indicated that HDL
cholesterol increased significantly in rats fed the honey, compared to that of the
group fed on a sugar-free diet (Chepulis, 2007; Chepulis and Starkey, 2008).
However, it has been reported that a 30-day natural honey intake in overweight or
obese human subjects caused a non-significant decrease in cholesterol (Yaghoobi et
al, 2008). Lastly, a recent study of male and female subjects who randomly received
a 75-g honey solution or a sugar solution similar to honey for 14 days has shown that
the male LDL-cholesterol values were not significanly reduced by the honey
supplementation; however, in women, these values increased in the group that
received the sugar solution but not in that fed honey (Münstedt et al, 2009b).
Therefore, female LDL-cholesterol values may be slightly reduced by substituting
sugar with honey in the daily diet, evidencing an antihy-percholesterolemic effect as
a result of honey consumption (Münstedt et al., 2009b).

The mechanisms through which honey exerts this modulation on lipid values are not
yet fully understood. However, it is worth considering that the mechanisms inherent
to lipid homeo-stasis are intimately linked to those of glyce-mic homeostasis; in fact,
both are occasionally referred to as 'energy homeostasis'. Thus, the explanations
regarding the effects exerted by honey consumption on lipid values are closely
related to those mentioned above for the action of honey intake on glycemic
regulation. Considering the high current worldwide prevalence of lipid profile
alterations, highly associated with the development of cardiovascular pathologies
and metabolic disturbances, the aforementioned evidence would suggest that honey
could be used as a nutritional supplement to enhance the lipid values of those
individuals suffering from these pathologies.
Concluding remarks
The aim of this review was to summarize the main benefits attributed to the intake of
natural honey, with special emphasis on the effects exerted on glycemic regulation.
17
The endocrine-metabolic pathologies mentioned here (e.g., impaired glucose
tolerance, insulin resistance, diabetes, and obesity) have been shown to be currently
increasing in prevalence and incidence all over the world (Braguinsky, 2002; Cordain
et al, 2003). This increase may reflect, in part, a rather sedentary lifestyle and the
effects generated by changes in the nutritional pattern experienced by world's
population in the past few decades. It is known that diet exerts a significant role in
plasma glucose modulation and insulin levels (Marsh and Brand-Miller, 2005);
however, regardless of the significance of this fact, there has been a lack of
knowledge with regard to dietary management for subjects suffering from such
disorders, and studies have been focused on promoting energy-restricted diets
rather than on modifying the diet compositionper se (Marsh and Brand-Miller, 2005).
It has been argued that individuals suffering from problems affecting glycemic
regulation cannot base their diet on the same nutritional pattern as the healthy
population because such patterns include foodstuffs that promote or aggravate those
pathologies. Avoiding the intake of sugars and sweets has been found to be
particularly advisable to maintain an adequate plasma glucose level. However, this
seems somewhat pointless, considering that carbohydrates constitute an important
component of the diet, as glucose is the main source of energy for the central
nervous system (Agrawal et al, 2007). Regarding the latter, it should be of great
interest for agricultural, food, nutritional and health sciences to be able to implement
nutritional alternatives to provide these individuals with functional food supplements
with medicinal properties, especially as related to glycemic regulation. Natural
honey, with therapeutic qualities widely recognized worldwide, should be among
these supplements.

Despite the interesting evidence presented here, the topic merits further research,
particularly with regard to understanding the specific mechanisms of action through
which natural honey intake may be modulating glycemic responses. Further studies
should determine and investigate those underlying mechanisms based on the impact
their understanding may have in medical and nutritional approaches for individuals
with glucose regulation disorders. Our research group is currently working towards
the elucidation of this topic.

18
M. E. Cortés thanks Comisión Nacional de Investigación Científica y Tecnológica
(CONICYT, Chile) and Facultad de Agronomía e Ingeniería Forestal, Pontificia
Universidad Católica de Chile, for the scholarships granted for Ph.D. studies in
Agricultural Sciences. The authors also wish to thank the Fondo Nacional de
Desarrollo Científico y Tecnológico (FONDECYT-REGULAR 2011), for funding
within the scope of the project: "Bioindicators of botanical and geographical origin of
Chilean endemic honeys", Project 1110808 to G. Montenegro.

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2) Schencke C, Vásquez B, Sandoval C, del Sol M. El Rol de la Miel en los Procesos

Morfofisiológicos de Reparación de Heridas. Int. J. Morphol. . 2016 Mar [citado 13
Jun 2018 ] ; 34(1): 385-395. Disponible en:
https://scielo.conicyt.cl/scielo.php?script=sci_arttext&pid=S07179502201600010005
6&lng=es.

International Journal of Morphology

versión On-line ISSN 0717-9502
Int. J. Morphol. vol.34 no.1 Temuco mar. 2016
http://dx.doi.org/10.4067/S0717-95022016000100056

Int. J. Morphol., 34(1):385-395, 2016.

El Rol de la Miel en los Procesos Morfofisiológicos de Reparación de Heridas
Rol of the Miel in the Morphophysiologic Process of the Reparation Wounds
Carolina Schencke*,**; Bélgica Vásquez***; Cristian Sandoval*,****,***** & Mariano
del Sol*,******,*******

30
* Doctorado en Ciencias Morfológicas, Facultad de Medicina, Universidad de La
Frontera, Temuco, Chile.

** CONICYT-PCHA/Doctorado Nacional/2014-21141130.

*** Universidad de Tarapacá, Arica, Chile.

**** Centro de Investigación CIMA, Facultad de Odontología, Universidad de La

Frontera, Temuco, Chile.

***** CONICYT-PCHA/Doctorado Nacional/2015-21150991

****** Centro de Excelencia en Ciencias Morfológicas y Quirúrgicas (CEMyQ),

Universidad de La Frontera, Temuco, Chile.

*******Centro de Investigación en Ciencias Biomédicas, Universidad Autónoma de

Chile, Chile.

Correspondencia a:

RESUMEN: Los beneficios de la miel de abeja (Apis mellifera) se conocen desde

hace miles de años y ha sido utilizada en la antigüedad por su valor nutritivo y
medicinal siendo "redescubierta" por la medicina moderna debido a sus importantes
propiedades anti-bacterianas en heridas infectadas. Nuevos estudios han
argumentado a favor de la capacidad de la miel para interactuar con la compleja
maquinaria celular y llevar a cabo la reparación de los tejidos. Por este motivo, se
realizó una revisión de los contenidos actuales de las propiedades de la miel y su rol
en los procesos morfofisiológicos de reparación de heridas. De esta manera se
abarcó la acción anti-bacteriana, anti-oxidante y anti-inflamatoria de sus
componentes. Así mismo, se revisaron las propiedades físicas y de desbridamiento,
la importancia del origen floral y ubicación geográfica en el valor medicinal de los
diferentes tipos de miel. Los estudios sugieren que los efectos de la miel son el
resultado de una actividad combinada, donde sus componentes interactúan de
manera sinérgica para lograr su función terapéutica. Su acción la realiza en todas
31
las etapas del proceso morfofisiológico de reparación logrando acelerar la
cicatrización de heridas. El origen florar y ubicación geográfica de la miel son
factores importantes a considerar, ya que ésta varía en su composición y, por lo
tanto, también su valor medicinal.

PALABRAS CLAVE: Heridas; Quemaduras; Cicatrización; Miel.

SUMMARY: The benefits of honey bee honey (Apis mellifera) have been known for
thousands of years and it has been used since ancient times for its nutritional and
medicinal values. It was "rediscovered" by modern medicine as a result of its
important anti-bacterial properties in infected wounds. New studies have argued for
the ability of honey to interact with the complex cellular machinery and achieve
tissue repair. Therefore, a review was carried out of current contents of the
properties of honey and their role in the morphophysiological processes of wound
repair. Hence, antibacterial action, anti-oxidant and anti-inflammatory components of
its properties were evaluated. At the same time, we reviewed physical and wound
debridement benefits, the importance of floral origin and geographical location in the
medicinal value of different types of honey. The studies suggest that the effects of
honey are the result of a combined activity, where its components interact
synergistically to achieve therapeutic function. Its action is realized in all stages of
the morphophysiological repair process, accomplishing accelerated wound healing.
The floral origin and geographical location of the honey are important factors to
consider since the composition of honey is variable, as is its medicinal value.

KEY WORDS: Wounds; Burns; Wound repair; Honey.

INTRODUCCIÓN
La miel es definida como una sustancia dulce, no fermentada, producida por las
abejas (Apis mellifera) que recogen y procesan el néctar de las flores o de las
secreciones de ciertas especies de plantas. Las abejas, transforman y combinan
esta sustancia con otras específicas propias que finalmente almacenan y maduran
en panales.

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Los beneficios de la miel se conocen desde hace miles de años y ha sido utilizada
en la antigüedad por su valor nutritivo y medicinal. Las primeras evidencias del
consumo de la miel aparecen en pinturas rupestres del Mesolítico, unos 6.000 años
A.C. y su uso como medicamento unos 2.500 años A.C. por los sumerios en
Mesopotamia. Entre los usos médicos, desde la antigüedad la miel ha servido en el
cuidado de heridas. Los antiguos egipcios, los asirios, los chinos, los griegos y los
romanos utilizaban la miel para tratar heridas. En los papiros de Eberts y Smith, que
datan de 1500 A.C. ya se aconsejaba tratar con miel las heridas. Hipócrates, en su
obra "Consideraciones sobre el tratamiento de las heridas", recomienda curarlas con
miel (Al-Waili et al., 2011; Tan et al., 2012; Eteraf-Oskouei & Najafi, 2013; Zbuchea,
2014; Jull et al., 2015).

Después de haber cumplido un papel importante en la tradición médica de muchos

pueblos, la miel fue "redescubierta" por la medicina moderna debido a sus
importantes propiedades bactericidas en heridas infectadas con bacterias
multiresistentes a los antibióticos (Godebo et al., 2013; Melake et al., 2015). Desde
entonces, numerosos estudios han centrado su interés en demostrar que las
propiedades biológicas y físicas de la miel le confieren una gran eficacia en el
tratamiento de heridas de diversas etiologías (Al-Waili et al.; Jull et al.) y que su uso
ofrece un tratamiento natural alternativo en la población mundial que reducen el
costo de los tratamientos modernos (Gupta et al., 2011; Schencke et al., 2013;
Mujalde et al., 2014).

La miel presenta un conjunto de propiedades que contribuyen significativamente en

el proceso de cicatrización de heridas. Muestra un efecto anti-bacteriano en heridas
susceptibles a infecciones o infectadas, actividad anti-oxidante que reduce la alta
concentración de radicales libres y especies reactivas de oxígeno (ROS) producidas
en la etapa inflamatoria, actividad anti-inflamatoria, anti-edematosa y exudativa que
reduce rápidamente el dolor, edema y exudado de las heridas, desbridamiento del
tejido necrótico estimulando la formación de tejido de granulación sano, estimula la
contracción de la herida favoreciendo el cierre de la misma y muestra propiedades
cicatrizantes que reducen al mínimo su apariencia (Suguna et al., 1993; Velnar et
al., 2009; Molan, 2011; Yaghoobi et al., 2013; Oryan et al., 2016).

33
En acuerdo con lo reportado, este estudio tuvo como objetivo realizar una revisión
general sobre los contenidos actuales de las propiedades curativas y cicatrizantes
de la miel en heridas, con énfasis en lesiones por quemadura. Además, se discutió
el rol de la miel en los procesos fisiológicos de reparación de heridas y se revisó la
importancia del origen floral y ubicación geográfica, en el valor medicinal de
diferentes tipos de miel.

Propiedades anti-bacterianas de la miel

En quemaduras, sus propiedades anti-bacterianas hacen que sea un agente natural
adecuado para facilitar el control microbiano de heridas infectadas. Para ello, cuenta
con un conjunto de factores que afectan directamente a los microorganismos
patógenos, como bacterias gram positivas y negativas, aerobias y anaerobias,
incluyendo a los tipos de bacterias multiresistentes a los antibióticos (Estrada et al.,
2005; Lay-flurrie, 2008; Nishio et al., 2016). Estos factores comprenden la acción del
peróxido de hidrógeno, la alta osmolaridad, la acidez y factores no basados en
peróxido, tales como metilglioxal (MGO) (Adams et al., 2008), el péptido
antimicrobiano de abeja defensina-1 (Kwakman et al., 2010), hidroximetifurfural
(HMF) (Nafea et al., 2011) y compuestos fenólicos, tales como flavonoides (Cushnie
& Lamb, 2005). Las acciones antimicrobianas indirectas incluyen aumento en la
producción de linfocitos, anticuerpos, citoquinas y el fortalecimiento del propio
sistema inmunológico (Molan, 2001; Subrahmanyam et al., 2007; Khoo et al., 2010;
Al-Waili et al.).

Actualmente, pocos antibióticos son eficaces frente a bacterias multiresistentes. Así,

varios estudios han combinado la miel con fármacos antimicrobianos comerci ales
(Jenkins & Cooper, 2012; Müller et al., 2013). Éstas combinaciones son ventajosas y
comúnmente utilizadas en tratamientos, principalmente porque proporcionan un
amplio espectro de actividad debido, fundamentalmente, al efecto multidiana o por
retrasar/suprimir la aparición de una población resistente a fármacos (Eliopoulos &
Eliopoulos, 1988; Ulrich-Merzenich et al., 2010).

Asímismo, otros estudios han reportado sustancias que tienen la capacidad de

potenciar respuestas inmunes específicas y no específicas, tales como,
concanavalina A (Talebi et al., 1995) y fitohemaglutinina (Oudrhiri et al., 1988),
34
lipopolisacáridos (LPS), algunos virus (Butchko et al., 1978) y ciertas drogas
(Archambault et al., 1989). que combinados con miel pueden potenciar su capacidad
bactericida. En este sentido, Abuharfeil et al. (2010) demostraron que la miel de
abeja, suplementada con LPS, tiene un efecto significativo en la capacidad
reductora de fagocitos no estimulados.

Propiedades anti-oxidante y anti-inflamatoria de la miel

Se cree que el efecto negativo en los seres humanos de diversos factores
ambientales estaría mediada por la generación de ROS. Parte de la protección
contra ROS se proporciona por los antioxidantes endógenos o por una serie de
diferentes compuestos contenidos en la dieta. Así, la miel, como fuente de
antioxidantes, es eficaz contra el deterioro oxidativo (Blasa et al., 2006).

La actividad anti-oxidante intrínseca de la miel, incluyen la inactivación y la

supresión de ROS por los fagocitos en los tejidos inflamados y disminución del
estrés oxidativo por la injuria térmica mediante el control de los radicales libres que
se forman en la quemadura de la herida. La supresión de ROS, inhibe a los
fibroblastos y conduce a una reducción de la fibrosis y cicatrización hipertrófica.
Según Tonks et al. (2001), tanto la miel de Manuka como mieles productoras de
peróxido de hidrógeno demostraron ser inhibidores de la producción de ROS por
células monocíticas (MM6).

Numerosos estudios han demostrado que las mieles más oscuras tendrían mayor
poder anti-oxidante por ser más ricas en compuestos fenólicos como flavonoides y
taninos. Es conocido que los compuestos fenólicos contribuyen significativamente a
la capacidad anti-oxidante de la miel, pero no son los únicos responsables de esta
propiedad. Otros compuestos asociados a la actividad antioxidante de la miel son el
ácido ascórbico, vitaminas del complejo B, tocoferoles, catalasa, superóxido
dismutasa, glutatión reductasa, péptidos, aminoácidos y selenio (Meda et al., 2005;
Singh et al., 2012; Jubri et al., 2013; Pourreza, 2013; Saric et al., 2013; Vandamme
et al., 2013). Gheldof et al. (2002) nombran ácidos orgánicos, tales como glucónico,
cítrico y málico. Estos ácidos son metales quelatos y, por tanto, pueden mejorar
sinérgicamente la acción de otros anti-oxidantes, tales como, los fenoles de la miel.
También, se ha encontrado la presencia de bajas concentraciones de ácido
35
salicílico, conocido por su capacidad de neutralizar radicales libres (Venema et al.,
1996). De la misma manera, diferentes cantidades y tipos de minerales pueden
influir en la actividad anti-oxidante de las mieles. El contenido mineral puede variar
de aproximadamente 0,04% en mieles claras a 0,2% en algunas muestras de mieles
oscuras (Rodriguez-Otero et al., 1994).

Según Gheldof et al. (2002), la capacidad anti-oxidante de la suma de las fracciones

es inferior a la capacidad anti-oxidante de toda la miel. Por lo tanto, la capacidad
anti-oxidante de la miel es probablemente el resultado de las interacciones
sinérgicas entre los distintos componentes.

Junto con lo anterior, las evidencias sostienen que la miel tiene un efecto favorable
sobre la regeneración de heridas, contribuyendo de manera significativa en el
proceso de cicatrización no solo a través de su propiedad anti-oxidante, sino que
también, a través de su capacidad anti-inflamatoria y de regulación de esta etapa, lo
cual se puede evidenciar en la evaluación de la evolución local de la herida
(Zbuchea).

La cicatrización de heridas es un proceso de regeneración de tejidos que incluye la

inflamación como un primer paso. A veces, estos procesos de curación son
inhibidos por terapias con drogas que lo retrasan, en consecuencia, se podrían
utilizar nuevos agentes anti-inflamatorios que no afecten estos procesos. Por otro
lado, aunque la inflamación es parte del proceso normal de la cicatrización, puede
hacer inconfortable la herida y de difícil manejo y, si se prolonga en el tiempo, puede
evitar que el tejido de reparación de la herida continúe los procesos de curación
(Hadagali & Chua, 2014). En acuerdo con lo anterior, un producto natural como la
miel es una buena alternativa para este fin, ya que no produce los efectos
secundarios de algunas drogas y propicia la cicatrización (Molan & Rhodes, 2015).
Un buen número de ensayos clínicos apoyan esta propiedad de la miel, informando
la reducción de los síntomas de la inflamación después de la aplicación tópica de la
miel en las heridas, con disminución del edema y exudado (Subrahmanyam et al.,
2001; Yaghoobi et al.; Zbuchea; Calderón et al., 2015).

36
Cabe destacar, que la miel tiene una actividad anti-inflamatoria directa, ya que la
disminución de la inflamación no solo se debe a un efecto secundario de la actividad
anti-bacteriana de la miel en la eliminación de bacterias que causan la inflamación.
Esta actividad anti-inflamatoria está bien documentada, incluye varios mecanismos,
entre los cuales se encuentran la inhibición del complemento, la infiltración de
leucocitos, la producción de citoquinas inflamatorias e inhibición de la producción de
óxido nítrico y fagocitosis por los macrófagos (Velnar et al.; Molan & Rhodes). Los
componentes fenólicos de la miel también pueden estar involucrados en la actividad
anti-inflamatoria, ya que se ha demostrado que puede inhibir la producción de la
citoquina inflamatoria factor de necrosis tumoral alfa (TNF-a). Además, se ha
descrito, en la miel de Manuka, la presencia de una proteína llamada Apalbúmina 1
(Apa-1), un potente inhibidor de la fagocitosis en macrófagos. Su mecanismo de
acción se realiza mediante el bloqueo del receptor de manosa en los fagocitos, que
es el detonador para la fagocitosis (Bean et al., 2012).

Propiedades físicas y de desbridamiento de la miel

Además de sus propias acciones anti-bacterianas, anti-oxidantes y anti-
inflamatorias, la miel crea una barrera física y un medio ambiente local húmedo,
debido a su alta viscosidad por concentraciones elevadas de azúcar y al drenaje
constante de los fluidos por osmosis desde el lecho de la herida (Molan, 2009).
Esto, favorece la cicatrización de las heridas por quemaduras debido a que ellas se
curan más rápido en un ambiente húmedo en lugar de un ambiente seco y con
formación de costra (Winter, 1962; Kandil et al., 1987; Molan, 2011). Un ambiente
húmedo asegura el crecimiento de células epiteliales, promueve el acercamiento de
los fibroblastos a los márgenes de la herida, así como la falta de adherencia de los
apósitos a la herida, dando lugar a cambios fácil y sin dolor, sin el riesgo de romper
epitelio recién formado (Molan, 2011). Además, las características de este entorno
local permiten el desbridamiento autolítico eliminando el tejido necrótico y la escara.
La miel tiene una acción estimulante sobre el plasminógeno en el lecho de la herida,
aumentando la actividad de la enzima plasmina que digiere la fibrina que se une a
restos en la superficie de la herida, pero no digiere la matriz extracelular de
colágeno, que es necesaria para la reparación de los tejidos (Molan, 2001).

37
Propiedades cicatrizantes de la miel
Nuevas pruebas han argumentado a favor de la capacidad de la miel para
interactuar con la compleja maquinaria celular y llevar a cabo la reparación de los
tejidos. Diferentes estudios han demostrado que la miel es capaz de promover la
angiogénesis, granulación y epitelización, estimular linfocitos y fagocitos, inducir la
expresión de marcadores moleculares de reparación de tejidos y la activación de
queratinocitos (Burlando & Cornara, 2013).

Junto con lo anterior, la producción de IL-6 y TNF-a por macrófagos y otros tipos
celulares en la herida son esenciales para el proceso de cicatrización y resolución
de la infección. Estudios in vitro han obtenido pruebas acerca de los mecanismos de
acción de varios tipos de miel de abejas en células de piel, logrando estimular
células monocíticas humanas al activar la producción de citoquinas. Un estudio
realizado por Majtán et al. (2010), sobre los queratinocitos y fragmentos de piel
demostró que la miel de Acacia indujo la expresión de citocinas (TNF-a, IL1-ß y
TGF-ß) logrando efectos inmunomoduladores y activadores de la metaloproteinasa
de matriz 9 (MMP-9). Esta última enzima es capaz de degradar el colágeno tipo IV y
está implicada en la desorganización de la membrana basal durante el proceso de
reepitelización. De esta manera la miel activa queratinocitos y modula la MMP-9
logrando acelerar el proceso de cicatrización de heridas.

Una de las teorías por las cuales la fase inflamatoria logra avanzar a otra fase de
cicatrización se explica por la acción del peróxido de hidrógeno, el cual es
proporcionado en forma continua por la enzima peroxidasa presente en la miel. De
esta manera, logra ser anti-bacteriano y fisiológicamente no tóxico, ya que puede
ser perjudicial cuando se añade en altas concentraciones. Los niveles producidos
por la miel diluida son aproximadamente 1000 veces menor que en soluciones de
enjuague. A esta concentración el peróxido de hidrógeno puede actuar a nivel
intracelular como "mensajero", capaz de promover respuestas y estimular la
expresión de genes tempranos de crecimiento importantes en la cicatrización de
heridas. Es probable que de esta manera logre contribuir a la modulación de células
no inflamatorias adyacentes, tales como los fibroblastos. Éste podría ser uno de los
principales mecanismos de la miel para estimular la cicatrización de heridas; sin
embargo, se necesita más investigación para confirmarla (Lusby et al., 2002).
38
Para evaluar parámetros de curación dérmica, se ha estudiado el efecto de la miel
en la resistencia a la tracción, el contenido de hidroxiprolina para reflejar la síntesis
de colágeno, el contenido de ADN para reflejar la fibroplasia, el contenido de ácido
urónico y hexosamina que constituyen los glicosaminoglicanos necesarios para la
cicatrización de heridas, entre otros.

Bajo este contexto, Suguna et al. (1992) demostraron que se produce un aumento
significativo en el contenido total de colágeno en los tejidos de granulación de las
heridas cuando son tratados con miel vía tópica o sistémica. Estos autores
señalaron que los resultados podrían deberse a que los aminoácidos arginina y el
ácido glutámico presentes en la miel podrían suministrar el precursor, prolina, para
la síntesis de colágeno y su maduración, acelerando la cicatrización de heridas y
mejorando la resistencia a la tracción. Posteriormente, Suguna et al. (1993)
observaron en este mismo modelo, que el tratamiento de heridas con miel produce
un marcado incremento en el contenido de ADN de los tejidos de granulación
reflejando la hiperplasia de las células y un incremento concomitante en proteínas y
colágeno debido a que los fibroblastos sintetizan activamente sustancia
fundamental, el substrato sobre el que se establece el colágeno. De esta manera,
estos resultados se correlacionan positivamente con lo señalado por Aljady et al.
(2000), al demostrar que la aplicación tópica y oral de miel en heridas estimula la
función de los fibroblastos, con un nivel máximo del contenido de ADN para el día 8
post herida; estimula el depósito de colágeno en el tejido granular, mostrando
niveles de hidroxiprolina significativamente mayores al grupo control entre los días
12 y 16 post herida y, mejorar la síntesis de glicosaminoglicanos al demostrar que
los niveles más altos de ácido urónico y hexosamina fueron observados en los
animales tratados con miel tópica y oral. Estos son los primeros componentes de la
matriz extracelular para ser sintetizados durante la cicatrización de heridas y formar
la plantilla para el colágeno y la deposición de elastina.

Rol de la miel en los procesos fisiológicos de reparación de heridas

Los procesos fisiológicos de reparación de heridas pueden ser divididos en tres
etapas o fases superpuestas: inflamatoria, proliferativa y de remodelación. En la
etapa inflamatoria, la miel estimula los monocitos para liberar citoquinas
39
inflamatorias incluyendo TNF-a IL-6, IL-1ß y óxido nítrico que pueden inducir la
síntesis de colágeno por los fibroblastos (Raynaud et al., 2013) e iniciar y amplificar
los procesos inflamatorios (Hussein et al., 2012). Varios estudios sugieren que
existen componentes dentro de algunos tipos de miel que pueden estimular células
monocíticas. Esto se puede explicar por el tipo de proteínas presentes, la cuales son
altamente glicosiladas (Brownlee, 1995; Tonks et al., 2001). Estudios realizados por
Majtán et al. (2006), demostraron que la glicoproteína Apa-1 es un componente
regular de la miel y del polen de abeja y estimula a macrófagos para liberar el TNF.
La fracción proteica de la glicoproteína sería la responsable de la estimulación de
este factor por macrófagos peritoneales murinos. Además, encontraron que la miel
nativa fue capaz de estimular la secreción de TNF-a de los macrófagos murinos,
mientras que la miel desproteinizada no tuvo ningún efecto. Por otro lado, Tonks et
al. (2007) aislaron una proteína de 58 kDa de la miel de Manuka, el cual es un
componente responsable de la inducción de citokinas monocíticas humanas, distinta
a la ya aislada Apa1. Estos resultados sugieren que el efecto inmunoestimulador de
la miel se basa en su contenido proteico, específicamente, de glicoproteinas. Sin
embargo, en su conjunto, la miel tiene un papel modulador en la fase inflamatoria de
la cicatrización de la herida para que inicie una inflamación activa, pero controlada,
evitando que la inflamación se desarrolle en un estado crónico o exagerado. Junto
con lo anterior, la miel actúa eliminando bacterias y residuos de la herida debido a
sus propiedades anti-bacteriana, anti-inflamatoria, anti-oxidante y de debridación
durante la fase inflamatoria (Hussein et al.; Raynaud et al.)

La etapa proliferativa o de granulación, presenta angiogénesis y fibroplasia dérmica,

junto con el inicio de la reepitelización y la contracción de la herida. La estimulación
de la angiogénesis por la miel suministra el oxígeno necesario en el proceso de
curación de las herida (Molan, 2002; Rossiter et al., 2010). La alta presión osmótica
y el peróxido de hidrógeno contenido en niveles bajos en la miel estimula el
desarrollo de nuevos capilares (Molan, 2002; Nakajima et al., 2013), el crecimiento y
la proliferación de los fibroblastos y miofibroblastos y promueve la síntesis de
colágeno y la reepitelización (Rossiter et al.; Boekema et al., 2013; Al-Jadi et al.,
2014).

40
En la etapa de remodelación, el colágeno es remodelado y realineado a lo largo de
líneas de tensión y las células que ya no son necesarias se eliminan por apoptosis.
Subrahmanyam et al., han informado que la miel puede reducir las cicatrices y
contracturas en los pacientes con quemaduras y además mejora la remode-lación
de las heridas cutáneas. Tan et al., observaron que el uso de miel en el tratamiento
de heridas reduce la costra y produce formaciones cicatriciales delgadas.

Importancia del origen floral y geográfico en las propiedades de la miel

Hay que tener en consideración que debido a que las abejas tienen diferente
comportamiento nutricional y recogen las sustancias nutritivas de diversas plantas y
lugares, las mieles producidas tendrán distintas composiciones. Por lo tanto,
diversos tipos de miel tienen diferente valor medicinal dando lugar a distintos efectos
sobre la cicatrización de heridas (Oryan et al.). Para la determinación del origen
floral es necesario analizar el polen o realizar estudios melisopalinológico, (Anklam,
1998).

Como fue mencionado anteriormente, hay numerosas investigaciones que señalan

que la miel tiene una actividad antibacteriana de amplio espectro, sin embargo,
existen variaciones en la potencia debido a las diferencias en su origen floral,
ubicación geográfica, condiciones climáticas, entre otros factores (Al-Waili et al.; Lu
et al., 2014). Algunos ejemplos de lo señalado, son las investigaciones realizadas
por Molan & Rhodes, quienes demostraron que la miel de Manuka de Nueva
Zelanda, que proviene del arbusto Leptospermum scoparium, tiene una gran
actividad anti-bacteriana que no solo se debe al peróxido de hidrógeno presente,
sino que además, al componente llamado metilglioxal, un potente inhibidor del
crecimiento bacteriano (Lu et al., 2013). Por su parte, la miel de Tualang de Malasia
presenta mejores resultados que su control (hidrofibra e hidrofibra de plata) con
respecto a la reducción del crecimiento bacteriano de Pseudomonas aeruginosa en
herida de quemadura de espesor completo en ratas (Khoo et al.). Por otra parte,
Ahmed & Othman (2013) compararon algunas propiedades y características
bioquímicas con la miel de Manuka y observaron que sus diferencias incluyen
compuestos fenólicos, flavonoides y HMF más altos, lo que le confiere mayor
eficacia que la miel de Manuka contra algunas cepas de bacterias gram negativas
en las heridas por quemaduras.
41
Por su parte, la miel monofloral de Ulmo (Eucryphia cordifolia) proveniente de Chile,
también ha demostrado tener gran poder bactericida y eficacia en el tratamiento de
heridas. Sherlock et al. (2010), sostienen que esta miel tiene un efecto
antimicrobiano más potente frente a Staphylococcus aureus, Escherichia coli y
Pseudomona aeroginosa, cuando es comparada con miel de Manuka. En modelos
animales, el tratamiento con esta miel en heridas por quemaduras mostró ser eficaz
en el control bacteriano y en la disminución de la inflamación y edema, favoreciendo
una rápida cicatrización al ser comparada con el control. Así mismo, estudios
clínicos en pacientes con úlceras venosas han reportado gran efectividad en el
tratamiento del uso tópico de miel de Ulmo asociado a la administración oral de
ácido ascórbico (Calderón et al.).

Dadas sus particulares propiedades, en Chile se ha creado una patente para el uso
de un extracto de miel monofloral de Ulmo, rico en compuestos fenólicos, capaz de
inhibir el crecimiento in vitro de bacterias patógenas humanas como Staphylococcus
aureus, Pseudomona aeruginosa, Escherichia coli, entre otras, y poseer actividad
fungicida y fungistática sobre hongos de ambientes de los géneros Mucor,
Rhizopus, Aspergillus, Candida y Penicillium (Montenegro & Ortega, 2011). Los
usos están orientados a la desinfección de superficies mediante un producto de
limpieza de uso doméstico, así como también, a la aplicación tópica o sistémica
como bactericida y fungicida en seres vivos, tales como animales y el hombre, con
un fin terapéutico.

El origen botánico y geográfico de la miel es un factor que también influye en su

actividad anti-oxidante (Frankel et al., 1998). La miel de Manuka de New Zealand
presenta un gran contenido de compuestos fenólicos existiendo una fuerte
correlación entre la actividad anti-oxidante y el contenido de fenoles totales
(Alzahrani et al., 2012). Resultados similares fueron observados con cuatro tipos de
mieles monoflorales recogidas en la región oriental de Rumania (Dobre et al., 2010)
y otros lugares como la miel de Acacia recolectada en Croacia (Krpan et al., 2009).
Por su parte, Pontis et al. (2014) encontraron una correlación positiva entre el color
y contenido de flavonoides con la capacidad antioxidante de diez muestras de miel
multifloral del estado de Roraima, Brasil. Chua et al. (2013), estudiaron la propiedad
42
anti-oxidante comparativa de tres mieles de uso común en Malasia (Tualang, Gelam
y Acacia) en relación con sus componentes bioquímicos. Observaron que no
existían diferencias significativas en el contenido de fenoles totales entre las mieles,
sin embargo, los resultados encontrados presentaron valores más altos que los
reportados en mieles provenientes de la India, Argentina y Burkina Faso de África
occidental. El contenido de flavonoides totales tampoco presentó diferencias
significativas y mostraron valores más altos a los reportados en Portugal y España.

La resistencia a la tracción comúnmente se ha asociado con la organización, el

contenido y las propiedades físicas de la red de fibras de colágeno (Dombi et al.,
1993). Bajo este contexto, estudios han demostrado que la resistencia a la tracción
en heridas también difiere según el tipo de miel utilizada ya que su acción sobre el
colágeno en el proceso de cicatrización muestra diferencias. Por otra parte, Rozaini
et al. (2004), observaron que la miel de Manuka, Durio Zibethinus (Durian) y Ananas
comosus (Nenas) presentaban una mayor resistencia a la tracción en comparación
con heridas tratadas con otras dos mieles, Melaleuca (Gelam) y Cocos nucifera
(Kelapa), infiriendo que esto es posible gracias a que el primer grupo es capaz de
aumentar el contenido de colágeno y acelerar la maduración del mismo. Nisbet et al.
(2010), demostraron que el nivel de colágeno y de hidroxiprolina en los grupos
tratados con miel monofloral de castaño (Castanea sativa), rododendro
(Rhododendron lúteo) y miel multifloral, provenientes de la región del Mar Negro de
Turquía, eran significativamente más altos que en el grupo control no tratado. En
este estudio, no se detectaron diferencias significativas entre los distintos tipos de
miel, pero se observaron menos zonas sin cicatrizar en las heridas del grupo de miel
multifloral en los días 7 y 14 post lesión. Por su parte, Schencke et al. (2015)
observaron que el tratamiento de heridas por quemaduras con miel monofloral de
Ulmo (Eucryphia cordifolia) suplementada con ácido ascóbico, promueve la
producción de fibras colágenas y rápido proceso de cicatrización. A través del
método Sirius Red (Montes & Junqueira, 1991) observaron que las fibras colágenas
se distribuían como haces paralelos al tejido epitelial recién formado, logrando una
alta densidad. En relación al tipo de colágeno, Velnar et al. indicaron que la dermis
no herida contiene un 80% de colágeno tipo I y 25% de colágeno tipo III, mientras
que en las heridas el tejido de granulación expresa un 40% de colágeno tipo III.
Schencke et al. (2015), demostraron la presencia de colágeno tipo III en toda la
43
zona cicatrizal de la dermis de heridas tratados con miel de Ulmo y suplementada
con ácido ascóbico, correlacionándose con lo descrito por Benavides (2008), quién
señaló que este colágeno se secreta sólo en estadios tempranos de la reparación,
siendo máximo entre los días cinco a siete. El colágeno tipo I también estaba
presente en la dermis cicatrizal, tornándose más denso y con una distribución
tridimensional hacia la hipodermis.

Desventajas (alergias o efectos nocivos)

Debido a los beneficios de la miel en el tratamiento de heridas y quemaduras, su
uso clínico como un agente tópico continua validándose. Se ha evaluado su
toxicidad en queratinocitos y fibroblastos, mostrando que la miel puede ser
clasificada como una sustancia no tóxica, y que puede ser utilizada con seguridad
no sólo para aplicaciones externas sobre la piel sana, sino también, como un
vendaje sobre heridas (Ranzato et al., 2012).

Sin embargo, es importante considerar que la miel podría producir intoxicaciones

sistémicas debido a la probable presencia de endosporas latentes de Clostridium
botulinum. Por este motivo, la miel de uso terapéutico se esteriliza a través de la
radiación gamma, que destruye las esporas bacterianas conservando la actividad
biológica y enzimática. Es interesante señalar que las desventajas de su uso tópico
son relativamente menores, sin informes de alergias o alteración de la glicemia en
pacientes diabéticos. Aunque la alergia a la miel es poco común, se señala que las
proteínas del polen en productos cosméticos, a base de miel, podrían funcionar
como sensibilizadores en personas alérgicas (Meda et al., 2004; Burlando &
Cornara, 2013).

CONCLUSIONES
En esta revisión se destacan las investigaciones que evidencian las propiedades
terapéuticas de la miel y sus posibles mecanismos de acción, demostrando la
eficacia de la miel en el tratamiento de heridas y quemaduras. La miel es un agente
terapéutico tópico ideal, ya que no se adhiere a la superficie de la herida. Además
de presentar una acción anti-bacteriana natural contra la mayoría de las heridas
infectadas, tiene actividad anti-oxidante, anti-inflamatoria, y de desbridamiento. Al
parecer cada uno de sus componentes actúan en conjunto participando de manera
44
sinérgica para lograr la cicatrización total de la herida. Por otra parte, las
propiedades físicas de la miel crean una barrera y un medio ambiente local húmedo
que permite el desbridamiento eliminando el tejido necrótico y la escara,
favoreciendo la cicatrización de heridas. Las propiedades cicatrizantes de la miel le
permiten promover la angiogénesis, granulación y epitelización, estimular linfocitos,
fagocitos, fibroblastos y queratinocitos y, modular la síntesis de colágeno y su
maduración. Su acción la realiza en todas las etapas del proceso fisiológico de
reparación logrando acelerar la cicatrización de heridas y mejorar la resistencia a la
tracción. Es importante considerar que la elección de la miel para su uso terapéutico
en heridas de distintas etiologías dependerá de su origen floral y ubicación
geográfica, ya que las mieles producidas tendrán diferentes composiciones y, por
tanto, diferente valor medicinal. Finalmente, en acuerdo a lo señalado en la literatura
consultada, concluimos que el uso clínico de la miel como agente tópico ofrece una
buena alternativa, ya que no produce efectos secundarios significativos, es efectivo
y de bajo costo.

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