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Omega-3 Fatty Acids and Diabetic Complications

  • Interactive Research School For Health Affairs (IRSHA)
  • IRSHA, Bharati Vidyapeeth Deemed University
  • Center for Innovation in Nutrition, Health & Disease, IRSHA, BVU, Pune


All forms of diabetes are characterized by hyperglycemia and macro- and micro-angiopathy which in turn lead to several complications viz. nephropathy, cardiomyopathy, retinopathy, neuropathy, and loss of RBC deformability. Also, the fatty acid elongase and desaturase activities are known to decrease in diabetes. The present review tries to summarize the link between omega-3 fatty acids and diabetic complications. Thus, reports in the literature suggest that supplementation with omega-3 fatty acid, especially eicosapentaenoic acid (EPA, 20:5, n-3), showed beneficial effect in diabetic nephropathy by improving the renal function in human as well as in the experimental animal studies. DHA plays a major role in signaling cascades and rhodopsin regeneration, while insufficiency of DHA is associated with impairment of retinal function; supplementation with DHA improved the retinal function. While omega-3 polyunsaturated fatty acids (PUFAs) offered protection against cardiovascular diseases, omega-6 PUFAs also showed cardioprotective action. Supplementation with omega-3 fatty acids improved nerve conduction velocity (NCV) and Na+, K+-ATPase activity in diabetic neuropathy. Omega-3 fatty acids increased red blood cell (RBC) deformability and decreased plasma viscosity, thereby helping in improving cardiomyopathy associated with RBC deformability.
Omega-3 Fatty Acids and Diabetic
A.V. Mali, S.S. Bhise, and Surendra S. Katyare
Diabetes mellitus (DM)one of the most common diseases
known to mankind from the oldest time, as reported in
Egyptian manuscript about 3000 years ago, has become a
serious global problem today. However, the clear-cut dis-
tinction between type 1 and type 2 DM was made only in 1936
[1]. DM is characterized by elevated blood glucose levels in
the body due to either impaired response of cells to insulin in
type 2 diabetes or its insufcient synthesis in the body in type 1
diabetes [2]. When cells do not utilize glucose in adequate
quantities, it accumulates in the blood leading to hyper-
glycemia. Diabetes is also associated with accelerated
atherosclerotic disease affecting arteries that supply the heart,
brain, and lower extremities. All forms of diabetes are char-
acterized by hyperglycemia which in turn leads to complica-
tions viz. nephropathy, cardiomyopathy, retinopathy,
neuropathy, and loss of RBC deformability which result due to
macro- and micro-angiopathy [3].
Liver plays a central role in lipid metabolism including
that of de novo synthesis of fatty acids. The liver also
modies fatty acid structure through metabolic pathways
that include desaturation, elongation, mono-oxidation, and
peroxisomal oxidation (chain shortening). These pathways
are particularly critical for the generation of end products of
polyunsaturated fatty acid (PUFA) synthesis. Thus, starting
with alpha-linolenic acid (ALA, 18:2, n-3) liver synthesizes
two major omega-3 fatty acids viz. eicosapentaenoic acid
(EPA, 20:5, n-3) and docosahexaenoic acid (DHA, 22:6,
n-3) which are important and essential for membrane
structurefunction relationships. Arachidonic acid (20:4,
n-6) and DHA are the main C2022 PUFAs present in
membranes of all tissues including that of RBC membrane
[4]. It has been reported that in diabetes, the elongase and
desaturase activities decrease signicantly which result in
membrane lipid deformability [5]. The ensuing membrane
lipid deformability could also contribute to diabetic com-
plications [6]. It also has been widely reported that there is a
deciency in essential fatty acid metabolism in both human
and animal diabetes [7,8].
The dietary sources of omega-3 fatty acids include sh
and seafood which are rich in EPA and DHA. Oily sh such
as salmon, trout, sardines, anchovies, mackerel, and herring
are the best sources. The other omega-3 fatty acid, ALA, is
found in plant-based foods such as axseeds, ax oil, wal-
nuts, canola oil, and soybean.
The dietary n-3 polyunsaturated fatty acids (PUFAs) have
been associated with various important functions such as
anti-inammatory effects, improving endothelial function,
controlling the blood pressure, and reducing hypertriglyc-
eridemia and insulin insensitivity. According to some epi-
demiologic studies, a lower prevalence of Type 2DM was
found in populations consuming large amounts of seafood
products, which are rich in n-3 PUFAs [9].
The link between omega-3 fatty acids and diabetes and its
complications has not been clear so far. Some studies have
revealed protective effects with appropriate intakes of
omega-3 fatty acid, while others have found no association
at all; some researchers have even hinted that high omega-3
intakes might augment risk of diabetes. Numerous in vitro
and in vivo studies have been carried out in respect of
omega-3 fatty acids and diabetic complications. The present
review tries to summarize the reported effects and role of
omega-3 and omega-6 PUFAs in nutrition and metabolism
on diabetic complications viz. nephropathy, cardiomyopa-
thy, retinopathy, neuropathy, and loss of RBC deformability.
A.V. Mali S.S. Bhise S.S. Katyare (&)
Center for Innovation in Nutrition, Health and Diseases, IRSHA,
Bharati Vidyapeeth Deemed University, Medical College
Campus, Dhankawadi, Katraj, Pune, 411043, Maharashtra, India
A.V. Mali
S.S. Bhise
©Springer International Publishing Switzerland 2016
M.V. Hegde et al. (eds.), Omega-3 Fatty Acids, DOI 10.1007/978-3-319-40458-5_16
Omega-3 and Diabetic Nephropathy
Diabetes is the leading cause of end-stage renal disease. The
complex metabolic, vascular, and inammatory perturba-
tions that characterize DM often lead to progressive albu-
minuria, renal injury, and dysfunction: Diabetic renal
nephropathy (DN) and the observed complications seem to
be related to the altered membrane fatty acid composition
In type 1 diabetes, dietary n-3 LCPUFAs appear inversely
associated with the degree, but not with the incidence of
albuminuria [12]. In experimental settings and in epidemi-
ologic studies, intake of omega-6 fatty acids was associated
with reduced albuminuria. Apparently, PUFAs do not seem
to attenuate glomerular dysfunction. However, the presently
available evidence is insufcient to rule out such an effect.
The authors suggest that further research is necessary to
establish the potential of PUFA consumption and supple-
mentation in DN [13].
In double-blind placebo-controlled trial, it was found that
12 weeks of sh oil supplement had no benecial effect on
vascular endothelial function, but improved renal function.
Thus, serum creatinine level was signicantly lower in sh
oil-treated type 2 DM patients [14].
In meta-analysis, in chronic kidney disease, it was found
that the use of n-3 long-chain PUFA (LCPUFA) reduced
urinary protein excretion, but there was no decline in the
glomerular ltration rate (GFR). However, in view of small
number of participants in trials, different methods of
assessing proteinuria and GFR, the authors suggest that
large, high-quality trials are warranted for reliable clinical
outcomes [15].
In animal studies, it was found that in streptozotocin
diabetic rats, twenty four hour urinary albumin excretion
was signicantly increased compared to the non-diabetic
control; gamma linolenic acid (GLA) treatment signicantly
reduced albuminuria. Intercellular adhesion molecule-1
(ICAM-1), monocyte chemoattractant protein-1 (MCP-1),
bronectin (FN) mRNA, and protein expression levels were
signicantly higher in DM kidneys, and these increases were
signicantly lowered by GLA treatment. Under in vitro
conditions, in the presence of high glucose concentration,
GLA signicantly inhibited increases in MCP-1 mRNA
expression and protein levels in mesangial and tubular
epithelial cells; ICAM-1 and FN expression showed a pat-
tern similar to the expression of MCP-1. Thus, GLA atten-
uated inammation by two mechanisms: by inhibiting
enhanced MCP-1 and ICAM-1 expression as well as by
preventing the accumulation of extracellular matrix
(ECM) in diabetic nephropathy [16].
Eicosapentaenoic acid (EPA) has been reported to have
benecial effects on the progression of various renal diseases
including diabetic nephropathy. In KKA(y)/Ta mice, EPA
improved type 2 diabetic nephropathy possibly by attenua-
tion of metabolic abnormalities and inhibition of renal
inammation, oxidative stress, and TGF beta expression
[17]. Monocyte chemoattractant protein-1 (MCP-1) regu-
lating macrophage recruitment protein is known to be
up-regulated in patients with diabetic nephropathy. In type 2
diabetic KKA(y)/Ta mice, EPA ameliorated diabetic
nephropathy which would suggest that the observed
down-regulation of MCP-1 is critically involved in the
benecial effect of EPA, probably in concert with
improvement of other clinical parameters [18].
Omega-3 and Diabetic Retinopathy
The potential pathogenic mechanisms that may predispose to
diabetic retinopathy include the following: platelet dys-
function, altered eicosanoid production, increased blood
viscosity in association with impaired cell deformability, and
pathologic leukocyte/endothelium interaction. Omega-3
fatty acids exert several important biological effects on
these factors [19].
The vasodegenerative phase of diabetic retinopathy is
characterized by retinal vascular degeneration as also by the
inadequate vascular repair due to compromised bone
marrow-derived endothelial progenitor cells (EPCs). It is
proposed that in diabetes, n-3 PUFA deciency results in
activation of acid sphingomyelinase (ASM), the central
enzyme of sphingolipid metabolism; ASM represents a
molecular metabolic link connecting the initial damage in the
retina and the dysfunction of EPCs [20]. ASM is an important
early responder in inammatory cytokine signaling. The
endothelial caveolae-associated ASM is believed to be an
essential component in mediating inammation and vascular
pathology in in vivo and in vitro models of diabetic
retinopathy. Human retinal endothelial cells (HREC), as
against glial and epithelial cells, express the plasma mem-
brane form of ASM that overlaps with caveolin-1. Treatment
of HREC with DHA specically reduced expression of the
caveolae-associated ASM, prevented tumor necrosis factor-a
(TNFa)-induced increase in the ceramide-to-sphingomyelin
ratio in the caveolae, and inhibited cytokine-induced
inammatory signaling. ASM is expressed in both vascular
and neuroretina. Interestingly, however, only vascular ASM
is specically increased in the retinas of animal models at the
vasodegenerative phase of diabetic retinopathy [20,21].
In type 2 diabetes animal model, DHA-rich diet pre-
vented diabetes-induced increase in the number of retinal
acellular capillaries and signicantly enhanced the life span
of type 2 diabetic animals by blocking the up-regulation of
ASM and other inammatory markers in diabetic retina.
DHA-rich diet also normalized the numbers of circulating
EPCs, improved EPC colony formation, and prevented the
222 A.V. Mali et al.
increase in ASM activity in EPCs [20]. The absence of ASM
in ASM(-/-) mice or inhibition of ASM activity by DHA
prevents acellular capillary formation [21].
Oxidative stress and inammation play a signicant role in
the pathobiology of diabetic retinopathy. It is suggested that
increased consumption of PUFAs may prevent or postpone the
occurrence of diabetic retinopathy. In STZdiabetic rats with
retinopathy, changes in serum glutathione peroxidase,
brain-derived neurotrophic factor (BDNF), vascular endothelial
growth factor (VEGF), and interleukin 6 (IL-6) reverted to near
control by ALA treatment, especially in ALA + STZ
group. The observations lend support to the concept that both
oxidative stress and inammation are involved in DR, and ALA
treatment is of benet in its prevention [22].
Diabetes increases oxidative stress, nitrotyrosine con-
centrations, and apoptosis in the retina. As a consequence,
the total thickness of retinas decreases signicantly com-
pared to that in the control rats. In particular, in the diabetic
rats the thickness of the outer and inner nuclear layers was
reduced signicantly, and loss of ganglion cell layer
(GCL) is evident. Administration of insulin and DHA, and
lutein alone or in combination with insulin could prevent
these retinal changes. In the diabetic rats the electroretino-
gram showed impairment of b-wave amplitude and latency
time. DHA and lutein prevented all these changes even
under hyperglycemic conditions. Lutein and DHA were able
to normalize all the diabetes-induced biochemical, histo-
logical, and functional modications. In view of the
observed benecial effects relating to the cell death mecha-
nisms, further studies to evaluate the use of insulin and
DHA, and lutein as potential adjuvant therapies to help
prevent vision loss in diabetic patients, are desirable [23].
In db/db mice, n-3 PUFA diet signicantly preserved
retinal function to levels similar to those observed in
non-diabetic control mice on normal chow. Conversely,
retinal function gradually deteriorated on-6 PUFA-rich diet.
Also, in the n-3 PUFA-fed mice there was an enhanced
ability to respond to glucose challenge. Interestingly, the
protection of visual function was independent of cytopro-
tective or anti-inammatory effects of n-3 PUFAs.
In T2DM mice, dietary n-3 PUFA preserved retinal
function which is consistent with the notion that with dys-
lipidemia it negatively impacts retinal function. Keeping in
mind the benecial effects of dietary n-3 PUFAs on visual
function, the authors suggest that increasing n-3 PUFA
intake in diabetic patients may slow the progression of
vision loss in T2DM [24].
The n-3 LCPUFAs inuence retinal cell gene expression,
cellular differentiation, and cellular survival. DHA is a major
structural fatty acid of retinal photoreceptor outer segment
membranes and hence can inuence the function of the
photoreceptor membrane. DHA activates a number of
nuclear hormone receptors which in turn operate as
transcription factors for molecules that modulate oxidation
reduction sensitive and proinammatory processes. DHA
can also affect the retinal cell signaling mechanisms
involved in phototransduction. Thus, DHA may play a major
role in signaling cascades by enhancing activation of
membrane-bound retinal proteins and may also be involved
in rhodopsin regeneration. Evidently, insufciency of DHA
is associated with alterations in retinal function [25].
Hammes et al. maintained STZdiabetic rats on sh oil
(750 mg Maxepa, 5 times per week for six months), con-
taining 14 % eicosapentaenoic acid (EPA) and 10 %
docosahexaenoic acid. The treatment resulted in a twofold
increase of EPA in total fatty acids and a reduction in the
thromboxane 2/3 ratio from 600 (untreated diabetic rats) to
50 (treated diabetic rats). However, despite these biochem-
ical changes, diabetes-associated pericyte loss remained
unaffected, and the formation of acellular, occluded capil-
laries was increased by 75 %. Based on these observations,
the authors concluded that dietary sh oil supplementation
may be harmful for the diabetic microvasculature in the
retina. These results are in contradiction with the benecial
effects cited above [19]. However, it may be pointed out that
in the studies by Hammes et al., the doses of DHA and EPA
were several times higher and also for a longer duration
(20 weeks). It is therefore possible that the undesirable
adverse effects ensued due to over dosages and treatment for
prolonged period. As against this in the former studies, the
authors treated the STZdiabetic rats with 13.3 mg DHA/kg
body weight for a period of 12 weeks [23].
Lipid composition of retinal membranes reected the
dietary manipulation. In STZdiabetic rats, diabetes ampli-
ed some fatty acid changes consistent with reduced desat-
urase activity that was evident. Diabetes produced
signicant reduction in rod function (33 %) only in the
absence of sh oil, whereas cone responses (46 %) and
inner retinal oscillatory potentials (47 %) showed either no
effect of diet or a partial diet effect with a signicant diabetes
effect. A diet balanced in long-chain PUFAs modies retinal
lipid membranes in diabetes and prevents rod dysfunction.
Dietary modication was not found in the cone or glial
response, but a partial improvement was evident in the
oscillatory potentials (OPs), most likely secondary to the
larger photoreceptor output [6].
Omega-3 and Diabetic Cardiomyopathy
The worldwide increasing prevalence of T2DM poses an
immense public health hazard leading to a variety of com-
plications, such as cardiovascular diseases, nephropathy, and
neuropathy [11].
Omega-3 polyunsaturated fatty acids (PUFAs) offer pro-
tection against cardiovascular disease which is one of the
16 Omega-3 Fatty Acids and Diabetic Complications 223
major causes of death in patients with DM by virtue of their
antihyperlipidemic, antihypertensive, anti-inammatory, and
other properties. Omega-6 PUFAs are also cardioprotective
In type 2 diabetic patients, without or with autonomic
neuropathy and normal healthy subjects, BP and ECG were
monitored during a 24 h period and during a 2 hr hyper-
glycemic clamp. Delta QTc during the night was blunted in
diabetics and delta LF/HF was decreased in patients with
autonomic neuropathy. In hyperglycemia, QTc and LF/HF
increased signicantly in normal healthy subjects while in
patients without autonomic neuropathy only LF/HF
increased. A 6 month treatment with n-3 PUFA partially
restored delta LF/HF and delta QTc only in patients without
autonomic neuropathy [26].
Studies on heart rate variability (HRV) and n-3 PUFA
have been performed in several populations such as patients
with ischemic heart disease, diabetes mellitus, and chronic
renal failure, and in healthy subjects. These studies have
demonstrated a positive association between cellular content
of n-3 PUFA and HRV. Also, supplementation with n-3
PUFA increased HRV and thereby decreased the risk of
arrhythmic events and provided protection against sudden
cardiac death (SCD) [27].
Administration of formulation omega-3 with Fenugreek
terpenenes (Om3/terp) considerably inhibited key enzymes
related to diabetes. Thus, a-amylase activity decreased by 46
and 52 %, and maltase activity decreased by 37 and 35 %,
respectively, in pancreas and plasma. Additionally, this
supplement helped protect the b-cells of the experimental
animals from death and damage. Interestingly, the formula-
tion of Om3/terp also modulated key enzyme related to
hypertension and angiotensin-converting enzyme (ACE) by
37 % in plasma and kidney. Administration of fenugreek
essential oil to surviving diabetic rats improved starch and
glucose oral tolerance additively. Om3/terp also signicantly
decreased the levels of glucose, triglyceride (TG), total
cholesterol (TC), and LDL cholesterol (LDL-C) in the
plasma and liver of diabetic rats and increased the HDL
cholesterol (HDL-C) level, which helps in maintaining the
homeostasis of blood lipids. Taken together, the ndings
suggest that this formulation of Om3/terp exhibits attractive
properties and can, therefore, be considered for future
application in the development of anti-diabetic,
anti-hypertensive, and hypolipidemic foods [28].
It has been suggested that omega-3 FA treatment partially
blocks the development of experimental diabetic cardiomy-
opathy possibly by affecting sarcoplasmic reticulum calcium
transport activity [29]. Diabetic cardiomyopathy has also been
associated with a decrease in Na
-ATPase activity and
expression as well as alterations in membrane lipid compo-
sition. Diabetes signicantly decreased activities of alpha 1
(a1) and alpha 2 (a2) isoforms and mRNA levels of a2 and
beta 1(b1) isoforms. At the protein level, a1-isoform
increased, while both a2- and b1-isoforms decreased. Chan-
ges in fatty acid content of the membrane were consistent with
the inhibition of desaturase activity; supplementation with
sh oil produced an increase in the incorporation of EPA in
the membrane. Supplementation with sh oil also increased
the level of b1-isoforms and restored the activity of the
a2-isoenzyme without signicant changes in the level of a1-
and a2-isoforms. Based on these studies, the authors suggest
that sh oil therapy may be effective in preventing some of the
adverse consequences of diabetic cardiomyopathy [30].
In patients with type 2 DM and cardiovascular autonomic
neuropathy, combined treatment with n-3 PUFA, benfoti-
amine, and a-lipoic acid resulted in signicant positive
changes in TC, TG, and LDL and HDL cholesterol levels.
However, the efcacy of this treatment was not related to the
improved compensation of DM, but was due to the direct
inuence of pharmacological agents on the metabolic rate
studied [31].
Diets higher in sh and omega-3 LCPUFA may reduce
cardiovascular risk in diabetes by inhibiting platelet aggre-
gation, improving lipid proles, and reducing cardiovascular
mortality. Fish and omega-3 LCPUFA can be recommended
to people with diabetes and included into a diabetes man-
agement program [32].
In STZdiabetic rat model, the myocardial levels of
matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of
matrix metalloproteinase-4 (TIMP-4) changed. There was
reduction in troponin (Tnl) and alpha-actinin protein levels.
The diabetes-induced alterations in MMP-2 and TIMP-4
contribute to myocardial contractile dysfunction by targeting
TnI and alpha-actinin. Treatment with sodium selenate or
with omega-3 sh oil with vitamin E had improved these
parameters [33]. Doxycycline, a MMP-2 inhibitor, or an
antioxidant selenium treatment in vivo prevented
diabetes-induced cardiac dysfunction signicantly [34]. The
author suggests that antioxidants and MMP inhibitors both
could regulate MMP function, but may also utilize different
mechanisms of action in cardiomyocytes, particularly related
to beta-AR signaling pathway [34].
There is also evidence to suggest that besides other car-
diomyopathies the anti-inammatory action of omega-3
PUFAs may have benecial effects on chronic chagasic
cardiomyopathy due to improved control of the inamma-
tory response. The authors predict that patients will have
lower inammatory markers and an improved metabolic and
anthropometric prole [35].
224 A.V. Mali et al.
Omega-3 and Diabetic Neuropathy
Diabetic neuropathy is a degenerative complication of dia-
betes accompanied by an alteration of nerve conduction
velocity (NCV) and Na
-ATPase activity.
In STZdiabetic rats, supplementation with DHA only
partially prevented the decrease in NCV and did not affect
nerve blood ow (NBF). On the other hand, supplementation
with GLAlipoic acid (GLA-LA) conjugate was more
effective than supplementation with DHA alone in prevent-
ing experimental diabetic neuropathy. The difference could
be due in part to an antioxidant protective effect of LA on
GLA [7].
Adeciency in essential fatty acid metabolism has been
widely reported in both human and animal diabetes. Sup-
plementation with sh oil was less effective on diabetic
neuropathy than n-6 fatty acids. The partial effect of n-3 fatty
acids might be attributed to the presence of EPA which
competes with arachidonic acid and thereby amplies the
diabetes-induced decrease in this fatty acid in serum and
tissues. Fish oil supplementation changed the fatty acid
content of sciatic nerve membranes, decreasing C18:2(n-6)
fatty acids and preventing the decreases in arachidonic acids
and oleic acid C18:1(n-9) fatty acids [8].
Whether supplementation with DHA alone could prevent
neuropathy in STZ-induced diabetes was determined in
separate experiments. Eight weeks of diabetes induced sig-
nicant decreases in NCV, NBF, and sciatic nerve and
erythrocyte Na
-ATPase activities. Na
activity was signicantly lower in sciatic nerve membranes
of diabetic rats and was signicantly restored in diabetic
animals that received sh oil supplementation. Diabetes
induced a specic decrease of a1- and a3-isoform activity
and protein expression in sciatic nerve membranes. Fish oil
supplementation restored partial activity and expression to
varying degrees depending on the isoenzyme. These effects
were associated with a signicant benecial effect on NCV.
This study indicates that sh oil has benecial effects on
diabetes-induced alterations in sciatic nerve Na
activity and function [36].
Liposomes containing DHA phospholipids, at a dose of
60 mg/kg, were given daily to diabetic rats by gavage. DHA
phospholipids totally prevented the decrease in NCV and
NBF; DHA phospholipids also prevented the decrease in
-ATPase activity in the RBCs but not in the sciatic
nerve. The levels of DHA in the sciatic nerve membranes
correlated with NCV. The results demonstrate a protective
effect of daily doses of DHA in experimental diabetic neu-
ropathy. Thus, treatment with DHA phospholipids could
provide a suitable approach for evaluation in clinical trials
[34]. It is also reported that highly puried ethyl esterica-
tion product of natural EPA (EPA-E) has signicant
benecial effects on diabetic neuropathy and serum lipids as
well as other diabetic complications such as nephropathy
and macroangiopathy [37].
Omega-3 and Red Blood Cell Deformability
The content of PUFA is known to affect membrane uidity
and cell signaling. Patients with insulin resistance display a
pattern of higher proportion of long-chain saturated fatty
acids, mainly palmitic, stearic, and arachidic acids.
Decreased levels of erythrocyte membrane DHA in
end-stage renal diseases with type 2 diabetes patient group
suggest that there may be reduced endogenous synthesis of
DHA due to the decreased desaturase and elongase activities
Omega-3 fatty acids increased red blood cell (RBC) de-
formability and decreased plasma viscosity. Also, there is a
drop in red cell aggregation after treatment with omega-3
capsule. Thus, there is growing evidence to suggest that
omega-3 FA can delay atherogenesis [39]. The omega-3 FA
gets incorporated into RBC phospholipids at the expense of
C18:2 omega-6 FA. At the same time, the total unsaturation
index of phospholipids increases. This in turn brings about
increase in membrane uidity which is responsible for the
increased erythrocyte deformability. The observed changes
have been attributed to incorporation of omega-3 FA in
erythrocyte phosphatidylcholine (PC) [40,41]. Daily sup-
plementation of 3 g of n-3 FA (EPA and DHA) increased
unsaturation of PC and phosphatidylethanolamine (PE). At
the same time, there was slight decrease in PC and PE
content, but the content of sphingomyelin (SPM) increased.
This supplementation caused a 42 % decrease in plasma
triacylglycerol levels. However, the membrane uidity was
unchanged [42].
In subjects supplemented with sh oil, the levels of n-3
FA increased signicantly in erythrocytes. This was mainly
at the expense of linolenic (18:n6) and oleic acid (18:n1); the
relative amount of arachidonic acid was unchanged [43].
The total phospholipid/CHL ratio was unchanged while the
PC + SPM/PE increased which is consistent with the
observations of Popp-Snijders et al. [40].
Supplementation with functional foods which are rich in
omega-3 fatty acids (e.g., sh oils among others) may be a
novel strategy to reduce insulin insensitivity, dyslipidemia,
hypertension, retinopathy and pro-inammatory state,
improved renal function as well as improved RBC
deformability [44].
16 Omega-3 Fatty Acids and Diabetic Complications 225
The forgoing results suggest that n-3 PUFA supplemen-
tation in diet presents many benets in T2DM management
mainly in terms of diabetic complications. However, the
treatment is less effective with respect to glucose control,
inammation and oxidative stress. Nonetheless, n-3 PUFA
supplementation may be a reasonable therapeutic strategy in
individuals with T2DM to decrease the risk of complications.
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16 Omega-3 Fatty Acids and Diabetic Complications 227
... Linoleic acid and linolenic acid are essential polyunsaturated fatty acids with anti-inflammatory properties. Proper intake of these polyunsaturated fatty acids plays an active role in improving kidney function in patients with DKD (Garman et al., 2009;Mali et al., 2016;Dos Santos et al., 2018). However, it is shown that the levels of free fatty acids such as linoleic acid and arachidonic acid in the urine of patients with DKD are significantly increased (Sasaki et al., 2009). ...
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Objective: Diabetic kidney disease (DKD) leads to low high albuminuria and gradually progresses to very high albuminuria with kidney insufficiency. However, about 20-40% of DKD is normoalbuminuric DKD (NADKD), which has impaired kidney function but normal urine albumin. This study is to investigate the urine metabolomic profiles of patients with NADKD and albuminuria DKD (ADKD). Methods: In total, 95 patients were divided into a simple diabetes mellitus group (SDM group), an ADKD group, and a NADKD group. All subjects were analyzed for urine metabolites using non-targeted metabolomics based on ultra-performance liquid chromatography - tandem mass spectrometry. Results: The urine metabolomic profiles of the SDM group, NADKD group, and ADKD group were significantly different, and 65 different metabolites were identified among the three groups. Metabolic pathway analysis of these differential metabolites found that the top three significantly changed metabolic pathways were linoleic acid metabolism, citrate cycle, and, arginine and proline metabolism. There are 12 metabolites enriched in these three metabolic pathways. In detail, compared with those in the SDM group, the levels of γ-linolenic acid in the ADKD group were increased significantly, while the levels of succinic acid, cis-aconitic acid, citric acid, L-proline, L-erythro-4-hydroxyglutamate, N-methylhydantoin, N-carbamoylputrescine, spermidine, and 5-aminopentanoic acid were reduced significantly; compared with those in the NADKD group, the levels of linoleic acid, γ-linolenic acid, and L-malic acid in the ADKD group were increased significantly (P < 0.05), while the levels of L-proline, L-erythro-4-hydroxyglutamate, N-carbamoylputrescine, and spermidine were significantly reduced (P < 0.05). However, there were no significant difference between the SDM group and NADKD group (P > 0.05). Conclusion: The urine metabolomic profiles between the NADKD group and the ADKD group are significantly different. Specifically, these two groups have distinct levels of linoleic acid, γ-linolenic acid, L-malic acid, L-proline, L-erythro-4-hydroxyglutamate, N-carbamoylputrescine, and spermidine.
... Diabetes mellitus (DM) is the oldest disease known to mankind since about 3,000 years ago and is referred to in ancient Egyptian treatise. 1 The prevalence of DM is continuously increasing and recent estimate shows that DM incidence will rise from 366.2 million people to 551.8 million by 2030. 2,3 Generally, DM is classified as either Type-I or II, but Type-II DM is more prevalent form of diabetes. ...
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Loss of pancreatic β-cell function is a hallmark of Type-II diabetes mellitus (DM). It is a chronic metabolic disorder that results from defects in both insulin secretion and insulin action. Recently, United Kingdom Prospective Diabetes Study reported that Type-II DM is a progressive disorder. Although, DM can be treated initially by monotherapy with oral agent; eventually, it may require multiple drugs. Additionally, insulin therapy is needed in many patients to achieve glycemic control. Pharmacological approaches are unsatisfactory in improving the consequences of insulin resistance. Single therapeutic approach in the treatment of Type-II DM is unsuccessful and usually a combination therapy is adopted. Increased understanding of biochemical, cellular and pathological alterations in Type-II DM has provided new insight in the management of Type-II DM. Knowledge of underlying mechanisms of Type-II DM development is essential for the exploration of novel therapeutic targets. Present review provides an insight into therapeutic targets of Type-II DM and their role in the development of insulin resistance. An overview of important signaling pathways and mechanisms in Type-II DM is provided for the better understanding of disease pathology. This review includes case studies of drugs that are withdrawn from the market. The experience gathered from previous studies and knowledge of Type-II DM pathways can guide the anti-diabetic drug development toward the discovery of clinically viable drugs that are useful in Type-II DM.
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Chronic chagasic cardiomyopathy is an inflammatory disease that occurs in approximately 30 % of patients infected by the protozoan Trypanosoma cruzi, and it has a profile of high morbidity and mortality. The worst prognosis and the progression of this cardiomyopathy are associated with an exacerbated immune response and the production of proinflammatory cytokines, which also occur in other cardiomyopathies. Some nutrients, including omega-3 polyunsaturated fatty acids (PUFAs), promote the inhibition and/or stimulation of cytokine production. The objective of this trial is to study the effects of omega-3 PUFA supplementation on the inflammatory response and lipid profile in patients with chronic chagasic cardiomyopathy. This is a parallel, randomized, placebo-controlled, double-blind clinical trial with 40 patients that will be conducted at a reference unit for Chagas disease patients, where the patients will be selected. The study will include patients with chronic chagasic cardiomyopathy who are 18 years of age or older. The exclusion criteria are (a) ongoing diarrheal disease, (b) inflammatory bowel disease, (c) diabetes or other endocrine disease, (d) use of fibrates, niacin, or statins, (e) use of anti-inflammatory drugs, (f) pregnant and lactating women, (g) use of vitamin, mineral, or omega-3 supplementation during the previous 30 days, (h) hospital admission during the study, and (i) other associated cardiomyopathies. The intervention will be treatment with omega-3 PUFAs at a dose of 3 g/day for 8 weeks, compared to placebo (corn oil). The primary endpoints will be the concentrations of inflammatory markers (interleukin (IL)-1, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)alpha, interferon (IFN)gamma, and transforming growth factor (TGF)beta). Secondary endpoints will be the fasting glucose, lipid, and anthropometric profiles. For statistical analysis, we plan to run either a t test or Wilcoxon test (numerical variables) and Pearson's chi2 or Fisher's exact test (categorical data), as appropriate. Evidence suggests that the anti-inflammatory action of omega-3 PUFAs may have beneficial effects on chronic chagasic cardiomyopathy, as shown for other cardiomyopathies, due to improved control of the inflammatory response. At the end of the study, we predict that patients will have lower inflammatory markers and an improved metabolic and anthropometric profile.Trial registration: Current Controlled Trials NCT01863576.
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Clinical features similar to diabetes mellitus were described 3000 years ago by the ancient Egyptians. The term diabetes was first coined by Araetus of Cappodocia (81-133AD). Later, the word mellitus (honey sweet) was added by Thomas Willis (Britain) in 1675 after rediscovering the sweetness of urine and blood of patients (first noticed by the ancient Indians). It was only in 1776 that Dobson (Britain) firstly confirmed the presence of excess sugar in urine and blood as a cause of their sweetness. In modem time, the history of diabetes coincided with the emergence of experimental medicine. An important milestone in the history of diabetes is the establishment of the role of the liver in glycogenesis, and the concept that diabetes is due to excess glucose production Claude Bernard (France) in 1857. The role of the pancreas in pathogenesis of diabetes was discovered by Meting and Minkowski (Austria) 1889. Later, this discovery constituted the basis of insulin isolation and clinical use by Banting and B
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Objective: Diabetic retinopathy (DR) is associated with hyperglycemia-driven microvascular pathology and neuronal compromise in the retina. However, DR is also linked to dyslipidemia. As omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) are protective in proliferative retinopathy, we investigated the capacity of ω-3PUFAs to preserve retinal function in a mouse model of type 2 diabetes mellitus (T2DM). Design: Male leptin-receptor-deficient (db/db) mice were maintained for 22 weeks (4 weeks–26 weeks of life) on calorically and compositionally matched diets, except for 2% enrichment in either ω-3 or ω-6PUFAs. Visual function was assessed at 9, 14 and 26 weeks by electroretinography. Retinal capillary and neuronal integrity, as well as glucose challenge responses, were assessed on each diet. Results: The ω-3PUFA diet significantly preserved retinal function in the mouse model of T2DM to levels similar to those observed in nondiabetic control mice on normal chow. Conversely, retinal function gradually deteriorated in db/db mice on a ω-6PUFA-rich diet. There was also an enhanced ability of ω-3PUFA-fed mice to respond to glucose challenge. The protection of visual function appeared to be independent of cytoprotective or anti-inflammatory effects of ω-3PUFAs. Conclusion: This study identifies beneficial effects of dietary ω-3PUFAs on visual function in T2DM. The data are consistent with dyslipidemia negatively impacting retinal function. As ω-3PUFA lipid dietary interventions are readily available, safe and inexpensive, increasing ω-3PUFA intake in diabetic patients may slow the progression of vision loss in T2DM.
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The vasodegenerative phase of diabetic retinopathy is characterized by not only retinal vascular degeneration but also inadequate vascular repair due to compromised bone marrow derived endothelial progenitor cells (EPCs). We propose that n-3 polyunsaturated fatty acid (PUFA) deficiency in diabetes results in activation of the central enzyme of sphingolipid metabolism, acid sphingomyelinase (ASM) and that ASM represents a molecular metabolic link connecting the initial damage in the retina and the dysfunction of EPCs. Type 2 diabetic rats on control or docosahexaenoic acid (DHA)-rich diet were studied. The number of acellular capillaries in the retinas was assessed by trypsin digest. mRNA levels of interleukin (IL)-1β, IL-6, intracellular adhesion molecule (ICAM)-1 in the retinas from diabetic animals were compared to controls and ASM protein was assessed by western analysis. EPCs were isolated from blood and bone marrow and their numbers and ability to form colonies in vitro, ASM activity and lipid profiles were determined. DHA-rich diet prevented diabetes-induced increase in the number of retinal acellular capillaries and significantly enhanced the life span of type 2 diabetic animals. DHA-rich diet blocked upregulation of ASM and other inflammatory markers in diabetic retina and prevented the increase in ASM activity in EPCs, normalized the numbers of circulating EPCs and improved EPC colony formation. In a type 2 diabetes animal model, DHA-rich diet fully prevented retinal vascular pathology through inhibition of ASM in both retina and EPCs, leading to a concomitant suppression of retinal inflammation and correction of EPC number and function.
Objective: To analyze the effect of long-chain (LC) polyunsaturated w-3 fatty acids (PUFAs) on the daily arterial stiffness parameters in patients with type 2 diabetes (DM2) and cardiovascular autonomic neuropathy (CAN). Material and methods: The study involved 39 patients with DM2 and verified functional stage of CAN. Patients were divided into 2 groups: therapy group (n=21) and control group (n=18). Patients of the control group received traditional hypoglycemic therapy; patients of the therapy group additionally received 1 capsule/day of the ω-3 PUFAs for three months. Results: The use of the ω-3 PUFAs resulted in a statistically significant decrease in aortic augmentation index (AAI) and pulse wave velocity in the aorta (PWV) during the active period. There was a decrease in AAI in the aorta and the brachial artery and in PWV in the aorta during the night. Conclusion: The efficacy of ω-3-PUFAs is a result of a direct effect of the pharmacological agent on the circadian arterial stiffness parameters.
Eighty-one patients with diabetes mellitus type 2 (DM) and cardiovascular autonomic neuropathy were studied. The combined treatment with ω-3 PUFA, benfotiamine, and α-lipoic acid resulted in significant positive changes in total cholesterol, triacylglycerol, LDL and HDL cholesterol levels. The efficacy of this treatment was not associated with the improved compensation of DM but was a result of the direct influence of pharmacological agents on the metabolic rate studied.
Background In this study, we aimed to compare the serum lipid profile and fatty acid (FA) compositions of erythrocyte membrane (EM) and plasma in three different patient groups (group 1: Type 2 Diabetes Mellitus (T2DM) + End-Stage Renal Disease (ESRD), group 2: ESRD, group 4: T2DM) and healthy controls (group 3) simultaneously. Methods 40 ESRD patients treated with hemodialysis (HD) in Gulhane School of Medicine (20 with T2DM) and 32 controls (17 with T2DM, 15 healthy controls) were included in the study. Plasma and EM FA concentrations were measured by Gas Chromatography-Flame Ionisation Detector (GC-FID). Results Plasma and EM palmitic acid (PA) and stearic acid (SA) levels were significantly higher in T2DM patients compared to controls (p= 0.040 and p= 0.002 for plasma, p= 0.001 and p= 0.010 for EM, respectively). EM docosahexaenoic acid (DHA) levels were also significantly lower in patients with ESRD + T2DM and ESRD compared to controls (p= 0.004 and p= 0.037, respectively). Conclusions : Patients with insulin resistance displays a pattern of high long chain saturated FAs (PA, SA and arachidic acids). However, while there are no recognized standards for normal EM DHA content, decreased levels of EM DHA in ESRD patient groups (group 1 and 2) suggest that there may be reduced endogenous synthesis of DHA in HD subjects, due to the decreased functionality of desaturase and elongase enzymes. Because membrane PUFA content affects membrane fluidity and cell signaling, these findings are worthy of further investigation.
Both oxidative stress and inflammation play a significant role in the pathobiology of diabetic retinopathy. Increased consumption of polyunsaturated fatty acids (PUFAs) may prevent or postpone the occurrence of diabetic retinopathy. Hence, the effect of α-linolenic acid (ALA), an essential fatty acid, on oxidative stress, inflammatory indices and production of vascular endothelial growth factor (VEGF) in streptozotocin-induced diabetic retinopathy indices in vivo was studied. Serum and retina concentrations of vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), plasma and retina concentrations of lipid peroxides and antioxidant enzymes were estimated in streptozotocin (STZ)-induced diabetic animals. STZ-induced diabetic rats had significantly higher levels of VEGF in the serum and retina and IL-6 in the serum, whereas BDNF was lower in the serum, all of which reverted to near normal in ALA-treated diabetic animals. STZ treatment decreased serum glutathione peroxidase levels, which was restored to normal by both pre- and post-ALA treatment groups. STZ-induced changes in serum glutathione peroxidase, BDNF, VEGF and IL-6 that reverted to near control by ALA treatment, especially in ALA + STZ group, lending support to the concept that both oxidative stress and inflammation participate in DR and ALA treatment is of benefit in its prevention.