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Journal ArticleDOI

A review of the putative causal mechanisms associated with lower macular pigment in diabetes mellitus.

14 Aug 2019-Nutrition Research Reviews (Cambridge University Press)-Vol. 32, Iss: 2, pp 247-264
TL;DR: In this paper, a review explores the currently available evidence to illuminate the metabolic perturbations that may possibly be involved in MP depletion, including increased oxidative stress, inflammation, hyperglycaemia, insulin resistance, overweight/obesity and dyslipidaemia; factors that may negatively affect redox status and the availability, transport and stabilisation of carotenoids in the retina.
Abstract: Macular pigment (MP) confers potent antioxidant and anti-inflammatory effects at the macula, and may therefore protect retinal tissue from the oxidative stress and inflammation associated with ocular disease and ageing. There is a body of evidence implicating oxidative damage and inflammation as underlying pathological processes in diabetic retinopathy. MP has therefore become a focus of research in diabetes, with recent evidence suggesting that individuals with diabetes, particularly type 2 diabetes, have lower MP relative to healthy controls. The present review explores the currently available evidence to illuminate the metabolic perturbations that may possibly be involved in MP’s depletion. Metabolic co-morbidities commonly associated with type 2 diabetes, such as overweight/obesity, dyslipidaemia, hyperglycaemia and insulin resistance, may have related and independent relationships with MP. Increased adiposity and dyslipidaemia may adversely affect MP by compromising the availability, transport and assimilation of these dietary carotenoids in the retina. Furthermore, carotenoid intake may be compromised by the dietary deficiencies characteristic of type 2 diabetes, thereby further compromising redox homeostasis. Candidate causal mechanisms to explain the lower MP levels reported in diabetes include increased oxidative stress, inflammation, hyperglycaemia, insulin resistance, overweight/obesity and dyslipidaemia; factors that may negatively affect redox status, and the availability, transport and stabilisation of carotenoids in the retina. Further study in diabetic populations is warranted to fully elucidate these relationships.

Summary (2 min read)

Introduction

  • The macula is an oval-shaped area at the centre of the retina which consists of a dense collection of light-sensitive cone cells responsible for central, high-resolution vision and colour perception(1).
  • In light of this evidence, the relatively recent emphasis on MP as a possible ocular-protectant in diabetes(16), a pathological condition similarly associated with inflammation, oxidative stress and progressive retinal damage, is logical and represents a natural extension of previous work in AMD(12–15).
  • Importantly, treatment with antioxidants (lutein and/or zeaxanthin) has been shown to lower oxidative stress and inflammation and increase endogenous antioxidants; findings which in some(17,18) but not all(20) studies occurred independently of any effects on hyperglycaemia.
  • A number of cross-sectional studies(16,26–29), including findings from their own study group(28), and randomised controlled trials (RCT)(30,31), have explored the relationship between type 1 and type 2 diabetes and MPOD in humans.

Literature search methods

  • The review was carried out in two stages.
  • First, the authors identified all relevant published articles from human and animal studies which reported on the relationship betweenMP (lutein and/or zeaxanthin and/ormeso-zeaxanthin) and diabetes (type 1 and type 2), up until the year 2019.
  • A total of thirteen papers on adiposity and MP (Table 3) and seven papers on MP and dyslipidaemia (Table 4) were included to help analyse the relationship between MPOD and the metabolic correlates of type 2 diabetes (adiposity and dyslipidaemia).
  • //www.cambridge.org/core, also known as Downloaded from https.

Diabetes mellitus

  • Diabetes mellitus is a group of metabolic disorders caused by the complex interaction of genetics, environmental factors and lifestyle choices(37).
  • Over the past number of decades, the number of individuals with diabetes, particularly type 2 diabetes, has increased dramatically, making it a critical and universal public health challenge(38).
  • Type 1 diabetes usually develops in normal-weight children, teenagers and younger adults, and is an autoimmune condition involving the selective destruction of pancreatic β-cells, ultimately resulting in complete deficiency of insulin(39).
  • Whilst diabetes is characterised by having higher than normal blood glucose levels, the pathogenesis and development of type 1 and type 2 diabetes differ; therefore, the relationship between MPOD and the different forms of diabetes should not be generalised.
  • These pathological mechanisms merit further exploration and will be discussed in more detail herein.

Oxidative stress and diabetes

  • Chronic hyperglycaemia induces oxidative stress in patients with diabetes(45).
  • //www.cambridge.org/core, also known as Downloaded from https.
  • Hyperglycaemia, oxidative stress and changes in redox homeostasis are fundamental events in the pathogenesis of diabetic retinopathy.
  • Dietary lutein, zeaxanthin and vitamins E and C, as well as endogenous antioxidant enzymes, therefore act in concert with one another to lower the levels of ROS (via ROS detoxification) and to recycle oxidised lipid antioxidants (via re-reduction).

Inflammation and diabetes

  • Diabetic retinopathy has traditionally been considered a disease of the retinal microvasculature, associated with oxidative stress induced by hyperglycaemia.
  • A recent novel RCT, the Diabetes Visual Function Supplement Study (31), explored the effects of a nutritional supplement (which included lutein and zeaxanthin) on patients with type 1 and type 2 diabetes, and suggested that the preparation used mitigated the damaging effects of systemic inflammation on ocular function, and that these effects may have been mediated by enhancements in MPOD.
  • //www.cambridge.org/core, also known as Downloaded from https.
  • There appears to be a theoretical basis for a relationship between the characteristic body fatness of type 2 diabetes and lower levels of MPOD.
  • Table 5 (column a) outlines the dietary factors causally associated with the metabolic correlates of type 2 diabetes, and Table 5 (column b) outlines the dietary factors associated with protection against the metabolic perturbations of type 2 diabetes.

Conclusion

  • The present review outlines their current understanding of the relationship between diabetes and MPOD.
  • Impaired defence against reactive oxidative species (ROS) at the retina may not only be attributable to lower intake of foods rich in carotenoids and other antioxidants (for example, fruit, vegetables, legumes), however, but may also arise from the increased utilisation of these antioxidants in diabetes (via chronic inflammation and oxidative stress).
  • It is important to note the significant limitations which currently prevail in the reviewed literature.
  • Small sample sizes, the merging of type 1 and type 2 diabetic patients in statistical analyses, and the complex interplay of diabetes and its accessory factors (adiposity, dyslipidaemia, oxidative stress and inflammation) with MPOD status are also challenging.

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Technological University Dublin Technological University Dublin
ARROW@TU Dublin ARROW@TU Dublin
Articles
2019
A review of the putative causal mechanisms associated with A review of the putative causal mechanisms associated with
lower macular pigment in diabetes mellitus lower macular pigment in diabetes mellitus
Grainne Scanlon
Technological University Dublin
, grainne.scanlon@tudublin.ie
James Loughman
Technological University Dublin
, james.loughman@tudublin.ie
Donal Farrell
Technological University Dublin
See next page for additional authors
Follow this and additional works at: https://arrow.tudublin.ie/otpomart
Part of the Optometry Commons
Recommended Citation Recommended Citation
Scanlon G, Loughman J, McCartney D. A review of the putative causal mechanisms associated with lower
macular pigment in diabetes mellitus. Nutrition Research Reviews. 2019 Aug 14:1-18. doi: 10.1017/
S095442241900012X
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Authors Authors
Grainne Scanlon, James Loughman, Donal Farrell, and Daniel McCartney
This article is available at ARROW@TU Dublin: https://arrow.tudublin.ie/otpomart/77

A review of the putative causal mechanisms associated with lower mac ular
pigment in diabetes mellitus
Grainne Scanlon
1
*, James Loughman
1
,
2
, Donal Farrell
3
and Daniel McCartney
3
1
Centre for Eye Research Ireland, School of Physics, Clinical & Optometric Sciences, Environmental Sustainability and Health
Institute, Technological University Dublin, Dublin, Republic of Ireland
2
African Vision Research Institute, University of KwaZulu-Natal, Durban, South Africa
3
School of Biological and Health Sciences, Technological University Dublin, City Campus, Dublin, Republic
of Ireland
Abstract
Macular pigment (MP) confers potent antioxidant and anti-inflammatory effects at the macula, and may therefore protect retinal tissue from the
oxidative stress and inflammation associated with ocular disease and ageing. There is a body of evidence implicating oxidative damage and
inflammation as underlying pathological processes in diabetic retinopathy. MP has therefore become a focus of research in diabetes, with recent
evidence suggesting that individuals with diabetes, particularly type 2 diabetes, have lower MP relative to healthy controls. The present review
explores the currently available evidence to illuminate the metabolic perturbations that may possibly be involved in MPs depletion. Metabolic
co-morbidities commonly associated with type 2 diabetes, such as overweight/obesity, dyslipidaemia, hyperglycaemia and insulin resistance,
may have related and independent relationships with MP. Increased adiposity and dyslipidaemia may adversely affect MP by compromising the
availability, transport and assimilation of these dietary carotenoids in the retina. Furthermore, carotenoid intake may be compromised by the
dietary deficiencies characteristic of type 2 diabetes, thereby further compromising redox homeostasis. Candidate causal mechanisms to explain
the lower MP levels reported in diabetes include increased oxidative stress, inflammation, hyperglycaemia, insulin resistance, overweight/
obesity and dyslipidaemia; factors that may negatively affect redox status, and the availability, transport and stabilisation of carotenoids in
the retina. Further study in diabetic populations is warranted to fully elucidate these relationships.
Key words: HDL: Macular pigment: TAG: Oxidative stress: Inflammation
Introduction
The macula is an oval-shaped area at the centre of the retina
which consists of a dense collection o f light-sensitive cone
cells responsible for central, high-resolution vision and colour
perception
(1)
. At the centre of the macula lies the fovea, where
macular pigment (MP) is located. MP is comp rised of three car-
otenoids: lutein, zeaxanthin and the retinal metabolite of
lutein, meso-zeaxanthin
(2,3)
. Lutein and zeax anthin are not
synthesised de novo in humans but are exclusively of dietary
origin, typically derived from a diet rich in coloured fruit and
vegetables
(4)
,whilemeso-zeaxanthin can be generated by
conversion from retinal lutein
(5)
ormaybeobtainedfrom
dietary sources such as trout and salmon
(6)
. The highest con-
centration of MP is found in the receptor axon layer of the
foveola, while in the parafovea, MP is located in the inner
plexiform layers
(7,8)
, an area of the retina which is primed
for the generation of reactive oxygen species (ROS) and con-
sequently, oxidative damage
(9)
. These hydroxyl-carotenoids are
selectively located in the macula to the exclusion of all other
dietary carotenoids. Fig. 1 highlights the location of MP and the
macula within the eye.
MP has a number of important functions in the eye. Evidence
suggests that MP contributes to visual performance and/or expe-
rience, as it acts as an optical filter for blue light (peak absorption
approximately 460 nm)
(3,10)
. The importance of MPs antioxidant
and anti-inflammatory properties is supported by its capacity to
protect against the cumulative damaging effects of oxidative
stress
(9)
, and inflammation
(11)
, which affect the macula in condi-
tions such as age-related macular degeneration (AMD)
(1215)
.In
light of this evidence, the relatively recent emphasis on MP as a
possible ocular-protectant in diabetes
(16)
, a pathological condi-
tion similarly associated with inflammation, oxidative stress
and progressive retinal damage, is logical and represents a natu-
ral extension of previous work in AMD
(1215)
.
The underlying molecular mechanisms associated with the
onset of diabetes and the potential protective effects of lutein
and/or zeaxanthin against retinal oxidative damage, inflamma-
tion and visual function have been explored in diabetic murine
Abbreviations: AMD, age-related macular degeneration; CAT, catalase; CRP, C-reactive protein; DiVFuSS, Diabetes Visual Function Supplement Study; GPx,
glutathione peroxidase; GSH, glutathione; MP, macular pigment; MPOD, macular pigment optical density; RCT, randomised controlled trial; RPE, retinal pigment
epithelium; ROS, reactive oxygen species; SOD, superoxide oxidase; VEGF, vascular endothelial growth factor.
* Corresponding author: Grainne Scanlon, fax þ353 1 402 4915, email grainne.scanlon@dit.ie
Nutrition Research Reviews, page 1 of 18 doi:10.1017/S095442241900012X
© The Authors 2019
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models
(1723)
. The onset of diabetes in alloxan and streptozotocin
diabetic mice and rats was accompanied by an increase in mark-
ers of oxidative stress and inflammation including: malondialde-
hyde, 8-hydroxy-2deoxyguanosine, NF-B and vascular
endothelial growth factor (VEGF), with a concomitant decrease
in local antioxidants including glutathione (GSH) and gluta-
thione peroxidase (GPx)
(1719)
. Importantly, treatment with anti-
oxidants (lutein and/or zeaxanthin) has been shown to lower
oxidative stress and inflammation and increase endogenous anti-
oxidants; findings which in some
(17,18)
but not all
(20)
studies
occurred independently of any effects on hyperglycaemia.
The beneficial effects of these carotenoids on retinal function
have also been observed in diabetic murine models, and these
include the preservation of electro-retinogram b-wave ampli-
tude and prevention of neurodegenerative effects on the inner
retinal layers
(1719)
. Findings from these studies provide
important insights into the potential role that MP may have in
protecting against diabetic retinal disease; however, the
observed findings need to be interpreted with caution, as higher
MP dosages have been used in animal studies compared with
those used clinically in humans, and many of these studies have
never conclusively demonstrated retinal uptake of the adminis-
tered carotenoids beyond the retinal pigment epithelium (RPE)
and choroid
(24,25)
. A summary of the experimental animal studies
examining MP optical density (MPOD) in diabetes is outlined in
Table 1.
A number of cross-sectional studies
(16,2629)
, including find-
ings from our own study group
(28)
, and randomised controlled
trials (RCT)
(30,31)
, have explored the relationship between type
1 and type 2 diabetes and MPOD in humans. MPOD is generally
found to be lower in diabetes
(16,26,28)
, with some studies sug-
gesting that oxidative stress is implicated in its depletion
(16,26)
.
Lower levels of MPOD have also been associated with raised gly-
cated Hb (HbA1c) levels and the presence of retinopathy in
patients with type 2 diabetes
(16)
. In another study, patients with
diabetes (type 1 and 2) with grade 2 diabetic maculopathy had
significantly lower MPOD compared with those with no macul-
opathy (P = 0·016)
(26)
.
Although oxidative stress is implicated as a causative factor,
the exact reasons why MP is lower in diabetes, and type 2 dia-
betes in particular
(16,28)
, are not fully understood. One study
found lower levels of MP in type 2 v. type 1 diabetes
(28)
, sug-
gesting that other coincident metabolic and pathological
abnormalities which are characteristic of type 2 diabetes (for
example, overweight/obesity, dyslipidaemia) may explain the
lower MPOD levels observed. Furthermore, lutein and zeaxan-
thin supplementation has been shown to exert positive and ben-
eficial ocular effects in those with diabetic eye disease, including
structural improvements in measures of macular oedema and
functional improvements in visual acuity and other visual func-
tion measures
(30,31)
. Table 2 outlines a summary of the cross-
sectional studies and RCT examining the relationship between
MPOD and diabetes (type 1 and 2).
Although the evidence exploring MP and diabetes is rela-
tively sparse, the findings that have been reported are sufficient
to suggest that MPOD may be adversely affected by the condi-
tion, and that there is a plausible rationale to explore the possible
benefits of lutein and/or zeaxanthin supplementation for ocular
health and visual function in diabetes, particularly type 2. The
recent generation of such evidence has prompted this literature
review, which is designed to explore and elucidate the metabolic
perturbations and candidate causal mechanisms which may
underpin the likely complex interdependency of MP and dia-
betic eye disease (references used in Tables 1 and 2
(1623,2636)
).
Literature search methods
For the purpose of the present review, partly because of the rel-
ative dearth of higher-level RCT evidence, we have appraised all
forms of published research, even lower-level evidence sources,
to ensure that the scientific and clinical implications of the avail-
able evidence might be synthesised into useful treatise, which
accurately reflects what is known about this area, and what
remains to be elucidated. The review was carried out in two
stages. First, we identified all relevant published articles from
human and animal studies which reported on the relationship
between MP (lutein and/or zeaxanthin and/or meso-zeaxanthin)
and diabetes (type 1 and type 2), up until the year 2019. The sec-
ond part of the search involved identifying publications which
investigated the relationship between the metabolic perturba-
tions typically associated with diabetes, and type 2 diabetes in
particular (for example, adiposity/dyslipidaemia) and MP. Pre-
selected keywords including lutein, zeaxanthin, macular
pigment, diabetes, diabetes AND MP, diabetes AND lutein/
zeaxanthin, BMI, body fat AND diabetes, adipose, high den-
sity lipoprotein AND diabetes, triglycerides AND diabetes,
oxidative stress, inflammation, hypertension AND MP, insulin
resistance and hyperinsulinemia were entered into academic
databases and search engines including PubMed, Google
Scholar, Mendeley, Scopus, Cochrane Library and the ISRCTN
registry to define our search of the literature relating to MP and dia-
betes up until 2019. Although many supporting publications were
retrieved, in total, only eight animal studies (Table 1) and eleven
human studies (Table 2) were included to help clarify our current
understanding of the links between diabetes and MP. A total of thir-
teen papers on adiposity and MP (Table 3) and seven papers on
MP and dyslipidaemia (Table 4) were included to help analyse
the relationship between MPOD and the metabolic correlates of
type 2 diabetes (adiposity and dyslipidaemia). The overall findings
suggest that MP is lower in diabetes, type 2 diabetes in particular,
Fig. 1. Diagram highlighting the location of macular pigment and the macula
within the eye. For a colour figure, see the online version of the paper.
2 G. Scanlon et al.
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and that supplementation with macular carotenoids and/or other
antioxidants may confer protection against diabetic eye disease. To
elucidate the causal mechanisms and metabolic perturbations
which might possibly explain the lower MP levels observed in dia-
betes, we will first explore the condition diabetes mellitus itself,
including its association with oxidative stress and inflammation;
and subsequently present the evidence linking adiposity and dys-
lipidaemia with type 2 (or poorly controlled type 1) diabetes
and MPOD.
Diabetes mellitus
Diabetes mellitus is a group of metabolic disorders caused by the
complex interaction of genetics, environmental factors and life-
style choices
(37)
. Diabetes is characterised by a deficiency of
insulin and/or systemic insulin resistance. Over the past number
of decades, the number of individuals with diabetes, particularly
type 2 diabetes, has increased dramatically, making it a critical
and universal public health challenge
(38)
. Type 1 diabetes usually
develops in normal-weight children, teenagers and younger
adults, and is an autoimmune condition involving the selective
destruction of pancreatic β-cells, ultimately resulting in complete
deficiency of insulin
(39)
. Conversely, type 2 diabetes is linked to a
sedentary lifestyle and being overweight, and is characterised by
systemic insulin resistance and subsequent pancreatic endocrine
dysfunction, which results in attenuated insulin synthesis as well
as inhibition of its cellular effects
(37)
. Whilst diabetes is character-
ised by having higher than normal blood glucose levels, the
pathogenesis and development of type 1 and type 2 diabetes
differ; therefore, the relationship between MPOD and the
different forms of diabetes should not be generalised. At presen-
tation, type 2 diabetes is most often accompanied by other co-
morbidities including overweight/obesity, insulin resistance,
hypertension and dyslipidaemia, features which are less
common in type 1 diabetes at diagnosis, but which may occur
as complications of type 1 diabetes later in the course of the
disease. Oxidative stress and inflammation are implicated in both
type 1 and type 2 diabetes; however, research has shown that
these metabolic disturbances are very pronounced in type 2
diabetes
(4044)
. The oxidative stress, inflammation, adiposity
and dyslipidaemia which characterise diabetes may have inde-
pendent relationships with MPOD, and therefore constitute
plausible causal mechanisms in diabetic eye disease. These
pathological mechanisms merit further exploration and will be
discussed in more detail herein.
Oxidative stress and diabetes
Chronic hyperglycaemia induces oxidative stress in patients with
diabetes
(45)
. Oxidative stress, defined as the excessive produc-
tion of ROS, results in oxidative injury when the redox balance
is upset; i.e. where the level of oxidative species exceeds the
capacity of the antioxidant defence system to neutralise
them
(46,47)
. ROS can include free radicals, which are partially
reduced oxygen species containing one or more unpaired elec-
trons (for example, superoxide anion or hydroxyl radical), and
species with their full complement of electrons in an unstable or
Table 1. Summary of experimental animal studies examining the relationship between lutein and/or zeaxanthin and diabetes mellitus (DM)
Study Design: animal model Lutein and/or zeaxanthin Outcome, evidence and conclusion
Muriach et al. (2006)
(18)
Albino mice (alloxan-induced
DM)
Lutein (70 % purity, 0·2 mg/kg body weight) Decrease in oxidative stress (decrease MDA and NF-κB, increase GSH and GPx);
ERG b-wave restored
Kowluru et al. (2008)
(19)
Rats (STZ-induced DM) Zeaxanthin (0·02 or 0·1 % equivalent to 8·4 mg/kg).
Placebo controlled
Decrease in oxidative stress (decrease 8-OHdG, nitrotyrosine, iNOS, VEGF and
ICAM-1 levels)
Arnal et al. (2009)
(23)
Rats (STZ-induced DM) Lutein (in combination with DHA). Placebo controlled Decrease in oxidative stress (MDA and nitrotyrosine, increase GSH and GPx).
Restored ERG b-wave amplitude and latency time
Sasaki et al. (2010)
(17)
Mice (STZ-induced DM) Lutein (0·1 mg, w/w). Placebo controlled Decrease in ROS and ERK activation and apoptosis. Protection of inner retina
from visual impairment
Tang et al. (2011)
(21)
Mice (db/db) spontaneous
diabetes
1 % (energy) Wolfberry (lutein and zeaxanthin).
Placebo controlled
Lower expression of endoplasmic reticulum stress biomarkers (BiP, PERK, ATF6,
caspase-12) and restored AMPK, thioredoxin, Mn SOD, and FOXO3α activities
Yu et al. (2013)
(22)
Mice (db/db) spontaneous
diabetes
Wolfberry diet (lutein and zeaxanthin). Placebo
controlled
Activation of AMPK in mitochondria which caused retinoprotection in the retina of
db/db mice
Kowluru et al. (2014)
(20)
Rats (STZ-induced DM) Multi-nutritional supplement (lutein 20 mg; zeaxanthin
40 mg/kg of powder diet, in addition to numerous
antioxidants). Placebo controlled
Carotenoids ameliorated capillary cell apoptosis. Improved ERG, a- and b-wave
amplitudes. Decreased oxidative damage and increased antioxidant activity.
Inflammatory markers (decrease in VEGF, IL-1β and NF-κB)
Zhou et al. (2017)
(32)
Rats (high-fat diet and low-
dose STZ-induced DM)
Zeaxanthin (50 mg/kg; 200 mg dissolved in 10 ml
maize oil). Placebo controlled
Supplementation with zeaxanthin reduced blood glucose, improved cognitive
deficits, neural cell survival and increased p-AKT levels. Inhibited cleaved
caspase-3 levels and NF-κB nuclear transcription in the hippocampus
MDA, malondialdehyde; GSH, glutathione; GPx, glutathione peroxidase; ERG, electroretinogram; STZ- streptozotocin; 8-OHdG, 8-hydroxy-2deoxyguanosin; iNOS, inducible NO synthase; VEGF, vascular endothelial growth factor; ICAM-1,
intercellular adhesion molecule; ROS, reactive oxygen species; ERK, extra-cellular receptor kinase; BiP, binding Ig protein; PERK, protein kinase RNA-like ER kinase; ATF6, activating transcription factor 6; AMPK, AMP-activated protein
kinase; Mn SOD, Mn superoxide dismutase; FOXO3α forkhead O transcription factor 3 α; p-AKT; phosphorylated serine/threonine kinase.
Lower macular pigment in diabetes mellitus 3
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Citations
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TL;DR: The role of glucose in the regulation of circulating levels of IL-6, TNF-α, and interleukin-18 (IL-18) in subjects with normal or impaired glucose tolerance (IGT), as well as the effect of the antioxidant glutathione are assessed.
Abstract: Background— Circulating levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) are elevated in diabetic patients. We assessed the role of glucose in the regulation of circulating levels of IL-6, TNF-α, and interleukin-18 (IL-18) in subjects with normal or impaired glucose tolerance (IGT), as well as the effect of the antioxidant glutathione. Methods and Results— Plasma glucose levels were acutely raised in 20 control and 15 IGT subjects and maintained at 15 mmol/L for 5 hours while endogenous insulin secretion was blocked with octreotide. In control subjects, plasma IL-6, TNF-α, and IL-18 levels rose (P<0.01) within 2 hours of the clamp and returned to basal values at 3 hours. In another study, the same subjects received 3 consecutive pulses of intravenous glucose (0.33 g/kg) separated by a 2-hour interval. Plasma cytokine levels obtained at 3, 4, and 5 hours were higher (P<0.05) than the corresponding values obtained during the clamp. The IGT subjects had fasting plasma IL-6 and TNF-α levels ...

80 citations

Journal ArticleDOI
TL;DR: Ocular carotenoids absorb light from the visible region, enabling them to protect the retina and lens from potential photochemical damage induced by light exposure and, consequently, protect the eye from oxidative stress, apoptosis, mitochondrial dysfunction, and inflammation.
Abstract: Carotenoids are natural lipid-soluble antioxidants abundantly found as colorful pigments in fruits and vegetables. At least 600 carotenoids occur naturally, although about 20 of them, including β-carotene, α-carotene, lycopene, lutein, zeaxanthin, meso-zeaxanthin, and cryptoxanthin, are detectable in the human blood. They have distinct physiological and pathophysiological functions ranging from fetal development to adult homeostasis. β-carotene is a precursor of vitamin A that essentially functions in many biological processes including vision. The human macula lutea and eye lens are rich in lutein, zeaxanthin, and meso-zeaxanthin, collectively known as macular xanthophylls, which help maintain eye health and prevent ophthalmic diseases. Ocular carotenoids absorb light from the visible region (400–500 nm wavelength), enabling them to protect the retina and lens from potential photochemical damage induced by light exposure. These natural antioxidants also aid in quenching free radicals produced by complex physiological reactions and, consequently, protect the eye from oxidative stress, apoptosis, mitochondrial dysfunction, and inflammation. This review discusses the protective mechanisms of macular xanthophylls in preventing eye diseases such as cataract, age-related macular degeneration, and diabetic retinopathy. Moreover, some preclinical animal studies and some clinical trials are discussed briefly to understand carotenoid safety and efficacy.

71 citations


Cites background from "A review of the putative causal mec..."

  • ...It has been shown that MP attenuates oxidative stress and slows down the progression of apoptosis, mitochondrial dysfunction, and inflammation in diabetes, which can be improved by increasing dietary supplementation of lutein and zeaxanthin [77]....

    [...]

  • ...It has been demonstrated that patients with type 2 diabetes have a lower level of MP as compared to healthy controls [77]....

    [...]

Journal Article
TL;DR: EPR spectroscopy was used to measure light-induced singlet oxygen generation in post-mortem human macula and retinal pigment epithelium/ choroid (RPE/choroid), and it was shown that a mixture of meso-zeaxanthin, zeaxanth in a ratio of 1:1:1 can quench more singinglet oxygen than the individual carotenoids at the same total concentration.
Abstract: It is thought that direct quenching of singlet oxygen and scavenging free radicals by macular pigment carotenoids is a major mechanism for their beneficial effects against light-induced oxidative stress. Corresponding data from human tissue remains unavailable, however. In the studies reported here, electron paramagnetic resonance (EPR) spectroscopy was used to measure light-induced singlet oxygen generation in post-mortem human macula and retinal pigment epithelium/choroid (RPE/choroid). Under white-light illumination, production of singlet oxygen was detected in RPE/choroid but not in macular tissue, and we show that exogenously added macular carotenoids can quench RPE/choroid singlet oxygen. When the singlet oxygen quenching ability of the macular carotenoids was investigated in solution, it was shown that a mixture of meso-zeaxanthin, zeaxanthin, and lutein in a ratio of 1:1:1 can quench more singlet oxygen than the individual carotenoids at the same total concentration.

18 citations

Journal ArticleDOI
TL;DR: In this paper, a comprehensive literature review of the National Library of Medicine and Web of Science databases was performed, resulting in 341 publications meeting search criteria, of which, 18 were found eligible for inclusion in this review.
Abstract: Diabetic retinopathy, which was primarily regarded as a microvascular disease, is the leading cause of irreversible blindness worldwide. With obesity at epidemic proportions, diabetes-related ocular problems are exponentially increasing in the developed world. Oxidative stress due to hyperglycemic states and its associated inflammation is one of the pathological mechanisms which leads to depletion of endogenous antioxidants in retina in a diabetic patient. This contributes to a cascade of events that finally leads to retinal neurodegeneration and irreversible vision loss. The xanthophylls lutein and zeaxanthin are known to promote retinal health, improve visual function in retinal diseases such as age-related macular degeneration that has oxidative damage central in its etiopathogenesis. Thus, it can be hypothesized that dietary supplements with xanthophylls that are potent antioxidants may regenerate the compromised antioxidant capacity as a consequence of the diabetic state, therefore ultimately promoting retinal health and visual improvement. We performed a comprehensive literature review of the National Library of Medicine and Web of Science databases, resulting in 341 publications meeting search criteria, of which, 18 were found eligible for inclusion in this review. Lutein and zeaxanthin demonstrated significant protection against capillary cell degeneration and hyperglycemia-induced changes in retinal vasculature. Observational studies indicate that depletion of xanthophyll carotenoids in the macula may represent a novel feature of DR, specifically in patients with type 2 or poorly managed type 1 diabetes. Meanwhile, early interventional trials with dietary carotenoid supplementation show promise in improving their levels in serum and macular pigments concomitant with benefits in visual performance. These findings provide a strong molecular basis and a line of evidence that suggests carotenoid vitamin therapy may offer enhanced neuroprotective effects with therapeutic potential to function as an adjunct nutraceutical strategy for management of diabetic retinopathy.

17 citations

Journal ArticleDOI
01 Sep 2021
TL;DR: Macular pigment can be augmented in glaucomatous eyes by supplementation with a formulation containing the carotenoids lutein, zeaxanthin and meso-zeaxanth in a double masked, randomized and placebo-controlled clinical trial.
Abstract: Purpose To evaluate macular pigment response to carotenoid supplementation in glaucomatous eyes. Design Double-masked, randomized, placebo-controlled clinical trial, the European Nutrition in Glaucoma Management Study ( ClinicalTrials.gov identifier, NCT04460365 ). Participants Sixty-two participants (38 men, 24 women) with a diagnosis of open-angle glaucoma were enrolled. Forty-two were randomized to receive the active supplement, 20 participants were allocated to placebo. Methods Macular pigment optical density (MPOD) was measured by autofluorescence using the Heidelberg Spectralis scanning laser ophthalmoscope. Macular pigment optical density volume within the central 6° of retinal eccentricity as well as MPOD at 0.23°, 0.51°, 0.74°, and 1.02° were recorded at baseline and at 6-month intervals over 18 months. Visual function was assessed using visual acuity, mesopic and photopic contrast sensitivity under glare conditions, photo stress recovery time, microperimetry, and Glaucoma Activities Limitation 9 questionnaire. Advanced glaucoma module scans of retinal nerve fiber layer thickness and ganglion cell complex thickness over the central 6° of retinal eccentricity also were completed at each study visit. Main Outcome Measures Change in MPOD after supplementation with 10 mg lutein, 2 mg zeaxanthin, and 10 mg meso-zeaxanthin or placebo over 18 months. Results A mixed-model repeated measures analysis of variance revealed a statistically significant increase in MPOD volume (significant time effect: F(3,111) = 89.31, mean square error (MSE) = 1656.9; P 0.05 for all). A statistically significant increase in mesopic contrast sensitivity under glare conditions was noted at 18 months in the treatment group, but not placebo. No other structural or functional changes were observed. No serious adverse events were noted during the trial. Conclusions Macular pigment can be augmented in glaucomatous eyes by supplementation with a formulation containing the carotenoids lutein, zeaxanthin, and meso-zeaxanthin. The greatest relative benefit was observed in those with the lowest baseline levels, but increases were noted across all participants and each retinal eccentricity. The potential benefits of MP augmentation for macular health in glaucoma merit further long-term evaluation.

8 citations

References
More filters
Journal ArticleDOI
13 Dec 2001-Nature
TL;DR: This integrating paradigm provides a new conceptual framework for future research and drug discovery in diabetes-specific microvascular disease and seems to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain.
Abstract: Diabetes-specific microvascular disease is a leading cause of blindness, renal failure and nerve damage, and diabetes-accelerated atherosclerosis leads to increased risk of myocardial infarction, stroke and limb amputation. Four main molecular mechanisms have been implicated in glucose-mediated vascular damage. All seem to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain. This integrating paradigm provides a new conceptual framework for future research and drug discovery.

8,289 citations


"A review of the putative causal mec..." refers background in this paper

  • ...of advanced glycation endproducts (AGE); increased expression of the receptor for AGE (RAGE) and its activating ligands; activation of protein kinase-C isoforms; and activity of the hexosamine pathway(61)....

    [...]

Journal ArticleDOI
01 Jan 2003-JAMA
TL;DR: Overweight and obesity were significantly associated with diabetes, high blood pressure, high cholesterol, asthma, arthritis, and poor health status, and increases in obesity and diabetes continue in both sexes, all ages, all races, all educational levels, and all smoking levels.
Abstract: Context Obesity and diabetes are increasing in the United States. Objective To estimate the prevalence of obesity and diabetes among US adults in 2001. Design, Setting, and Participants Random-digit telephone survey of 195 005 adults aged 18 years or older residing in all states participating in the Behavioral Risk Factor Surveillance System in 2001. Main Outcome Measures Body mass index, based on self-reported weight and height and self-reported diabetes. Results In 2001 the prevalence of obesity (BMI ≥30) was 20.9% vs 19.8% in 2000, an increase of 5.6%. The prevalence of diabetes increased to 7.9% vs 7.3% in 2000, an increase of 8.2%. The prevalence of BMI of 40 or higher in 2001 was 2.3%. Overweight and obesity were significantly associated with diabetes, high blood pressure, high cholesterol, asthma, arthritis, and poor health status. Compared with adults with normal weight, adults with a BMI of 40 or higher had an odds ratio (OR) of 7.37 (95% confidence interval [CI], 6.39-8.50) for diagnosed diabetes, 6.38 (95% CI, 5.67-7.17) for high blood pressure, 1.88 (95% CI,1.67-2.13) for high cholesterol levels, 2.72 (95% CI, 2.38-3.12) for asthma, 4.41 (95% CI, 3.91-4.97) for arthritis, and 4.19 (95% CI, 3.68-4.76) for fair or poor health. Conclusions Increases in obesity and diabetes among US adults continue in both sexes, all ages, all races, all educational levels, and all smoking levels. Obesity is strongly associated with several major health risk factors.

5,790 citations


Additional excerpts

  • ...increase the risk of type 2 diabetes(160)....

    [...]

Journal ArticleDOI
01 Jun 2005-Diabetes
TL;DR: What was learned about the pathobiology of diabetic complications starting with that 1966 Science paper and continuing through the end of the 1990s are described, including a unified mechanism that links together all of the seemingly unconnected pieces of the puzzle.
Abstract: It’s a great honor to join the exceptional club of Banting Award winners, many of whom were my role models and mentors. In addition, giving the Banting Lecture also has a very personal meaning to me, because without Frederick Banting, I would have died from type 1 diabetes when I was 8 years old. However, it was already apparent at the time I was diagnosed that for too many people like me, Banting’s discovery of insulin only allowed them to live just long enough to develop blindness, renal failure, and coronary disease. For example, when I started college, the American Diabetes Association’s Diabetes Textbook had this to say to my parents: “The person with type 1 diabetes can be reassured that it is highly likely that he will live at least into his 30s.” Not surprisingly, my parents did not find this particularly reassuring. At the same time we were reading this in 1967, however, the first basic research discovery about the pathobiology of diabetic complications had just been published in Science the previous year. In my Banting Lecture today, I am thus going to tell you a scientific story that is also profoundly personal. I’ve divided my talk into three parts. The first part is called “pieces of the puzzle,” and in it I describe what was learned about the pathobiology of diabetic complications starting with that 1966 Science paper and continuing through the end of the 1990s. In the second part, I present a unified mechanism that links together all of the seemingly unconnected pieces of the puzzle. Finally, in the third part, I focus on three examples of novel therapeutic approaches for the prevention and treatment of diabetic complications, which are all based on the new paradigm of a unifying mechanism for the pathogenesis of diabetic complications. …

4,691 citations

Journal ArticleDOI
TL;DR: The molecular and cellular underpinnings of obesity-induced inflammation and the signaling pathways at the intersection of metabolism and inflammation that contribute to diabetes are discussed.
Abstract: Over the last decade, an abundance of evidence has emerged demonstrating a close link between metabolism and immunity. It is now clear that obesity is associated with a state of chronic low-level inflammation. In this article, we discuss the molecular and cellular underpinnings of obesity-induced inflammation and the signaling pathways at the intersection of metabolism and inflammation that contribute to diabetes. We also consider mechanisms through which the inflammatory response may be initiated and discuss the reasons for the inflammatory response in obesity. We put forth for consideration some hypotheses regarding important unanswered questions in the field and suggest a model for the integration of inflammatory and metabolic pathways in metabolic disease.

3,913 citations


"A review of the putative causal mec..." refers background in this paper

  • ...The inhibition of signalling downstream of the insulin receptor is a primary mechanism through which inflammatory signalling leads to insulin resistance(79)....

    [...]

  • ...Hyperglycaemia increases the levels of pro-inflammatory proteins(79), and it is now believed that inflammatory processes...

    [...]

  • ...of diabetic complications(79), and is now also implicated in the pathogenesis of many ocular diseases including AMD(80) and diabetic retinopathy(81)....

    [...]

01 Jan 2000
TL;DR: This paper showed that hyperglycaemia increases the production of reactive oxygen species inside cultured bovine aortic endothelial cells and that this increase in reactive oxygen can be prevented by an inhibitor of electron transport chain complex II, an uncoupler of oxidative phosphorylation, by uncoupling protein-1 and by manganese superoxide dismutase.
Abstract: Diabetic hyperglycaemia causes a variety of pathological changes in small vessels, arteries and peripheral nerves. Vascular endothelial cells are an important target of hyperglycaemic damage, but the mechanisms underlying this damage are not fully understood. Three seemingly independent biochemical pathways are involved in the pathogenesis: glucose-induced activation of protein kinase C isoforms; increased formation of glucose-derived advanced glycation end-products; and increased glucose flux through the aldose reductase pathway. The relevance of each of these pathways is supported by animal studies in which pathway-specific inhibitors prevent various hyperglycaemia-induced abnormalities. Hyperglycaemia increases the production of reactive oxygen species inside cultured bovine aortic endothelial cells. Here we show that this increase in reactive oxygen species is prevented by an inhibitor of electron transport chain complex II, by an uncoupler of oxidative phosphorylation, by uncoupling protein-1 and by manganese superoxide dismutase. Normalizing levels of mitochondrial reactive oxygen species with each of these agents prevents glucose-induced activation of protein kinase C, formation of advanced glycation end-products, sorbitol accumulation and NFκB activation.

3,814 citations

Frequently Asked Questions (2)
Q1. What contributions have the authors mentioned in the paper "A review of the putative causal mechanisms associated with lower macular pigment in diabetes mellitus" ?

Candidate causal mechanisms to explain the lower MP levels reported in diabetes include increased oxidative stress, inflammation, hyperglycaemia, insulin resistance, overweight/ obesity and dyslipidaemia ; factors that may negatively affect redox status, and the availability, transport and stabilisation of carotenoids in the retina. Further study in diabetic populations is warranted to fully elucidate these relationships. 

In view of the limited evidence available, supplementation with lutein, zeaxanthin and/or meso-zeaxanthin, either with or without other antioxidants, represents a fertile area for future interventional research. Rather, their review suggests the need for a more holistic evaluation of diet and lifestyle in relation to MPOD in diabetes. In this context, inflammation and oxidative stress, the dual pathogenic driving forces of diabetes which occur independent of hyperglycaemia, may be amenable to dietary intervention and nutritional supplementation. The safety and low cost of such interventions further commend their potential value as a therapeutic adjunct in diabetic eye disease, and may come to represent an essential element of ocular care for this important and expanding patient group.