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The cardiometabolic benefits of glycine: Is glycine an ‘antidote’ to dietary fructose?

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The cardiometabolic benefits of glycine: Is glycine an ‘antidote’ to dietary fructose?

The cardiometabolic benets of glycine:
Is glycine an antidoteto dietary
fructose?
Mark F McCarty,
1
James J DiNicolantonio
2
To cite: McCarty MF,
DiNicolantonio JJ. The
cardiometabolic benefits
of glycine: Is glycine an
antidoteto dietary
fructose?. Open Heart
2014;1:e000103.
doi:10.1136/openhrt-2014-
000103
Accepted 26 April 2014
1
NutriGuard Research, Inc,
Encinitas, California, USA
2
Department of Preventive
Cardiology, Saint Lukes Mid
America Heart Institute,
Kansas City, Missouri, USA
Correspondence to
Dr James J DiNicolantonio;
jjdinicol@gmail.com
VASCULAR PROTECTIVE PROPERTIES OF
SUPPLEMENTAL GLYCINE
Supplemental glycine, via activation of
glycine-gated chloride channels that are
expressed on a number of types of cells,
including Kupffer cells, macrophages, lym-
phocytes, platelets, cardiomyocytes and endo-
thelial cells, has been found to exert
anti-inammatory, immunomodulatory, cyto-
protective, platelet-stabilising and antiangio-
genic effects in rodent studies that may be of
clinical relevance.
117
The plasma concentra-
tion of glycine in normally nourished indivi-
dualsaround 200 µMis near the K
m
for
activation of these channels, implying that
the severalfold increases in plasma glycine
achievable with practical supplementation
can be expected to further activate these
channels in vivo.
18 19
The impact on mem-
brane polarisation of such activation will
hinge on the intracellular chloride content;
cells which actively concentrate chloride
against a gradient will be depolarised by
channel activation, whereas other cells will
experience hyperpolarisation. In cells that
fail to concentrate chloride and that express
voltage-activated calcium channels, glycine
tends to suppress calcium inux; this effect is
thought to mediate much of the protection
afforded by glycine.
1
The role of chloride
channel activation in the mediation of gly-
cines physiological effects is commonly
assessed by the concurrent application of the
chloride channel inhibitor strychnine; if this
abolishes glycines effect, this effect is most
likely mediated by chloride channels.
From the standpoint of vascular health, a
recent report that glycine can stabilise platelets is
of evident interest.
7
When rats were fed diets
containing 2.55% glycine, bleeding time
approximately doubled, and the amplitude of
platelet aggregation in whole blood triggered by
ADP or collagen was halved. This effect was
blocked by strychnine, and the investigators were
able to conrm that platelets express glycine-
gated chloride channels. They also demon-
strated that human platelets likewise were glycine
responsive and expressed such channels. Studies
evaluating the interaction of glycine with aspirin
or other pharmaceutical platelet-stabilising
agents would clearly be appropriate, as would a
clinical study examining the impact of supple-
mental glycine on platelet function.
Another recent study has established that car-
diomyocytes express chloride channels.
17
This
may rationalise evidence that preadministration
of glycine (500 mg/kg intraperitoneal) reduces
the infarct size by 21% when rats are subse-
quently subjected to cardiac ischaemia-
reperfusion injury; this effect was associated
with increases in ventricular ejection fraction
and fractional shortening in the glycine pre-
treated animals as compared with the controls.
17
This protection was associated with a reduction
in cardiomyocyte apoptosis, blunted activation
of p38 MAP kinase and JNK and decreased Fas
ligand expression. A previous study had
reported that 3 mM glycine promoted increased
survival of cardiomyocytes in vitro subjected to
1 h of ischaemia and then reoxygenated, and
was also protective in an ex vivo model of
cardiac ischaemia reperfusion.
20
Vascular endothelial cells express glycine-
gated chloride channels, and it has been sug-
gested that glycine might exert an antiathero-
sclerotic effect by hyperpolarising the
vascular endothelium.
19
Since such cells do
not express voltage-gated calcium channels,
the impact of endothelial hyperpolarisation is
to increase calcium inux, as calcium follows
the charge gradient.
21
This in turn would be
expected to promote the calcium-mediated
activation of endothelial nitric oxide synthase.
Moreover, endothelial polarisation inuences
nicotinamide adenine dinucleotide phos-
phate (NADPH) oxidase activity; this is
boosted by depolarisation and conversely
inhibited by hyperpolarisation.
2224
The
vascular-protective impact of potassium-rich
diets is suspected to be mediated in part by
McCarty MF, DiNicolantonio JJ. Open Heart 2014;1:e000103. doi:10.1136/openhrt-2014-000103 1
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the endothelial hyperpolarisation that results from
modest physiological increases in the plasma potassium
level (reecting increased activity of the electrogenic
sodium pump).
25 26
Other factors being equal, an
increase in endothelial nitric oxide generation coupled
with a decrease in superoxide production could be
expected to have an antiatherogenic and antihyperten-
sive effect. Also speaking in favour of the antiathero-
sclerotic potential for glycine is a study demonstrating
that glycine exerts an anti-inammatory effect on human
coronary arterial cells exposed to tumour necrosis factor
(TNF) αin vitro; activation of NF-κB was suppressed, as
was the expression of E-selectin and interleukin-6.
27
So
far, there are no published studies evaluating the impact
of dietary glycine on atherogenesis in rodent models.
Evidence that glycine has an antihypertensive effect in
sucrose-fed rats is discussed below.
Glycine is a biosynthetic precursor for creatine,
haeme, nucleic acids and the key intracellular antioxi-
dant glutathione. Measures which raise or conserve
intracellular glutathione levels may be of benetfrom
the standpoint of oxidant-mediated mechanisms that
impair vascular health. A recent clinical study reports
that concurrent supplementation of elderly participants
with glycine and cysteine (100 mg/kg/day of each, cyst-
eine administered as its N-acetyl derivative) reverses the
marked age-related reduction in erythrocyte glutathione
levels while lowering the serum markers of oxidative
stress
28
; the authors, however, did not prove that the sup-
plemental glycine was crucial for this effect.
With respect to diabetes, it is of interest that high
intakes of glycine have the potential to oppose the for-
mation of Amadori products, precursors to the advanced
glycation endproducts (AGEs) that mediate diabetic
complications.
29 30
Indeed, supplementation of human
diabetics with glycine5 g, 3-4 times dailyis reported
to decrease haemoglobin glycation.
31 32
A similar effect
has been reported in streptozotocin-treated diabetic
rats.
33
These studies did not measure AGEs per se, so
their ndings should be interpreted cautiously.
Nonetheless, glycine supplementation has delayed the
progression of cataract, inhibited microaneurysm forma-
tion, normalised the proliferative response of blood
mononuclear cells and aided the humoral immune
response in diabetic rats, effects which suggest that
glycine may have potential for prevention of some dia-
betic complications.
3436
In a recent controlled but
unblinded study, patients with diabetes experiencing
auditory neuropathy achieved improvements in hearing
acuity and auditory nerve conduction while ingesting
20 g glycine daily for 6 months.
37
GLYCINE AFFORDS PROTECTION FROM
SUCROSE-INDUCED METABOLIC SYNDROME
Of particular interest are studies showing that high
glycine intakes can counteract many of the adverse
effects of a high-sucrose diet on the liver, adipose mass
and vascular function in rats.
38 39
Glycine decreased the
elevated non-esteried fatty acid content of the liver of
sucrose-fed rats, increased the state IV oxidation rate of
hepatic mitochondria, corrected an elevation of blood
pressure, normalised the serum triglycerides and insulin,
prevented an increase in abdominal fat mass and, in the
vasculature, boosted glutathione, decreased oxidative
stress and normalised endothelium-dependent vasodila-
tion. Of likely relevance to these ndings is a recent clin-
ical report that supplemental glycine (15 g daily in three
divided doses) administered to patients with metabolic
syndrome lessened indices of oxidative stress in erythro-
cytes and leucocytes, while lowering systolic blood pres-
sure.
40
These ndings are of considerable interest,
particularly in the light of evidence that high dietary
fructose intakes can promote metabolic syndrome and
non-alcoholic fatty liver disease in humans and increase
LDL cholesterol.
4143
The protective effects of glycine in sucrose-fed rats,
and in humans with metabolic syndrome, are not
readily explained on the basis of the known metabolic
effects of glycine. Fructose is known to exert its adverse
effects primarily via its impact on liver metabolism; it is
catabolised almost exclusively in the liver, and its oxida-
tion, unlike that of glucose, is not regulated by meta-
bolic need.
41 44
As a result, a high intake of fructose
oods the liver with substrate and suppresses hepatic
fatty acid oxidation, while promoting de novo lipogen-
esis and triglyceride synthesis; increased generation of
malonyl-coenzyme A is responsible for the rst two
effects, whereas an increase in glycerol-3-phosphate
contributes importantly to fructoses stimulatory impact
on triglyceride synthesis. These effects also increase
hepatic production of diacylglycerols, which impair
hepatic insulin sensitivity via activation of protein kinase
C-ε.
45 46
The increased triglyceride content of
fructose-exposed hepatocytes can be expected to stabil-
ise apoB100 and accelerate secretion of very-low-density
lipoprotein (VLDL) particles
47 48
; this phenomenon
may explain the elevation of LDL cholesterol induced
by high-fructose intakes.
42
The increased hepatic secre-
tion of VLDL triglyceride presumably is responsible for
the increase in visceral fat observed in rodents and
humans fed high-fructose diets.
41
This in turn can
induce metabolic syndrome, including an increase in
blood pressure driven in part by hyperinsulinaemia
49
(gure 1).
There is recent evidence that fructose can also act
indirectly to boost hepatic gluconeogenesis. Fructose,
but not glucose, can activate AMP kinase (AMPK) in
certain regions of the hypothalamus, resulting in
increased adrenocortical production of corticosteroids
that promote hepatic transcription of phosphoenolpyru-
vate carboxykinase, rate-limiting for gluconeogenesis.
50
How does glycine intervene in this process? We
propose that glycine-stimulated secretion of glucagon-
like peptide-1 (GLP-1) and of glucagon itself plays a key
role in this regard.
2McCarty MF, DiNicolantonio JJ. Open Heart 2014;1:e000103. doi:10.1136/openhrt-2014-000103
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GLYCINE MAY STIMULATE GLP-1 AND GLUCAGON
RELEASE
Gameiro et al,
51
working with the GLUTag cell line
derived from intestinal L-cellsthe cell type specialised
for GLP-1 production in the intestinal mucosa,have
found that glycine provokes an increase of GLP-1 secre-
tion in these cells. This reects an activation of glycine-
gated chloride channels that triggers a reduction in
membrane polarisation, leading to an increase in cyto-
plasmic free calcium and a consequent release of GLP-1.
The ability of these chloride channels to decrease mem-
brane polarisation in these cells reects the fact that
they concentrate chloride via a Na
+
-K
+
-2Cl
transporter.
Drugs which inhibit either the glycine-gated channels or
the chloride uptake mechanism prevent glycine from
stimulating GLP-1 release in GLUTag cells. Since the
apical microvilli of L-cells face the intestinal lumen, they
are ideally positioned to detect an increase in glycine in
the luminal contents. Hence, glycine supplementation
could be expected to boost GLP-1 production. Although
there do not appear to be any studies that have exam-
ined the GLP-1 response to orally administered glycine
per se, there are two clinical studies demonstrating that
plasma GLP-1 levels rise following ingestion of gelatin, a
protein extraordinarily rich in glycine (constituting 30%
of its amino acids).
52 53
This may explain why, when
glucose was fed to patients with type 2 diabetes in con-
junction with seven different proteins, gelatin was
second only to cottage cheese in potentiating the post-
prandial insulin response.
54
Oral administration of glycine in humans (75 mg
glycine/kg lean mass) has also been reported to stimulate
an increase in glucagon secretion by pancreatic α-cells.
55
This response is negated if glucose is ingested simultan-
eously, most likely reecting the impact of glucose-evoked
secretion of somatostatin from islet δ-cells.
56
The conten-
tion that oral glycine stimulates GLP-1 production is dif-
cult to square with glycines impact on glucagon, as GLP-1
is known to inhibit α-cell glucagon secretion, either dir-
ectly or by provoking δ-cell secretion of somatostatin.
57
However, there is recent evidence that glycine may act dir-
ectly on α-cells as a glucagon secretagogueand perhaps
this effect overrides that of GLP-1 (the impact of GLP-1 on
somatostatin secretion might be minor when glucose is at
basal levels, and that of GLP-1 receptor expression on
α-cells is very low
57
). Li et al
58
have shown that α-cells
express glycine-gated chloride channels that, when acti-
vated, trigger an inux of calcium and glucagon release.
This suggests that α-cells, like L-cells, have a mechanism
for concentrating chloride intracellularly, such that a
receptor-mediated increase in membrane permeability
triggers chloride efux and membrane depolarisation.
Since the afnity of glycine-gated channels for glycine is
close to the fasting concentration of glycine in plasma,
51
it
can be anticipated that a rise in plasma glycine induced
via supplementation will cause an increase in glucagon
secretion. One rather old study failed to observe an
increase in glucagon secretion when glycine was infused
intravenously, until the glycine reached supraphysiological
levels
59
; it is not clear why the results of this study appear
discordant with those of the two studies previously cited.
It is notable that GLP-1 and glucagon work in comple-
mentary ways to promote fatty acid oxidation and
oppose lipogenesis in the liver.
6065
The effects of
Figure 1 Hepatic effects of
fructose.
McCarty MF, DiNicolantonio JJ. Open Heart 2014;1:e000103. doi:10.1136/openhrt-2014-000103 3
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glucagon appear to be mediated primarily by cAMP,
whereas GLP-1 triggers activation of AMPK in hepato-
cytes. Joint action of GLP-1 and glucagon on the liver
could readily account for the ability of supplemental
glycine to counteract the excessive hepatic triglyceride
synthesis promoted by sucrose or fructose feeding (see
gure 2). Indeed, GLP-1 agonists have been shown to
protect against hepatic steatosis in sucrose-fed rats, and
to have clinical utility in non-alcoholic fatty liver
disease.
6670
Fortuitously, although glucagon could be
expected to promote hepatic gluconeogenesis, GLP-1
mediated AMPK activation would tend to offset this
effect.
71
Indeed, AMPK suppresses the transcription of
phosphoenolpyruvate carboxykinase in the liver, poten-
tially offsetting the stimulatory impact of fructose-evoked
cortisol in this regard.
7274
Intriguingly, peptide drugs with dual agonism for
GLP-1 and glucagon receptors have been developed
recently, and these agents have shown markedly bene-
cial effects in mice with diet-induced obesity.
7577
They
can induce a weight loss of 1520%, modestly decrease
calorie intake while boosting thermogenesis, decrease
hepatic triglyceride levels and serum levels of triglycer-
ides and LDL cholesterol, improve insulin sensitivity and
glucose tolerance and counteract leptin resistance.
These benecial metabolic effects are only partially
attributable to the associated weight loss and are consid-
erably greater than the benets seen with GLP-1 agonists
alone. These agents provide continual stimulation of
their target receptors, and hence understandably
achieve more potent effects than dietary glycine, which
at best could only boost GLP-1 and glucagon levels epi-
sodically. Nonetheless, while glycine does not induce
weight loss or suppress calorie intake in sucrose-fed
mice, it reduces visceral fat stores by over 50%, increases
the thermogenic potential of hepatic mitochondria by
increasing state 4 respiration, alleviates hepatic steatosis
and improves insulin sensitivity and serum lipids. Hence,
its effects are homologous to, if not as dramatic, as those
seen with the coagonist drugs.
FURTHER IMPLICATIONS OF GLP-1 UPREGULATION
If supplemental glycine does indeed boost secretion of
GLP-1, this may have interesting implications for the pre-
vention and treatment of diabetes, and for the preserva-
tion of vascular health. As is well known, GLP-1
functions to potentiate glucose-stimulated insulin secre-
tion, and this is the basis for the therapeutic utility in
diabetes of analogues of GLP-1 such as liraglutide and
exenatide which activate the GLP-1 receptor but have a
vastly longer half-life owing to their resistance to degrad-
ation by dipeptidyl protease-4 (DDP-4).
78
Endogenously
produced GLP-1 has a half-life of only several minutes in
plasma owing to its rapid degradation by DDP-4; hence,
drugs which can safely inhibit DDP-4, such as sitagliptin,
are currently employed to prolong the efcacy of
endogenously produced GLP-1 in patients with
diabetes.
79
If supplemental glycine does indeed boost
GLP-1 production, it presumably could be used as an
adjuvant to DDP-4 therapy, and, as a stand-alone
measure, might have some potential for the primary pre-
vention of diabetes.
Moreover, if supplemental glycine can promote a
physiologically meaningful increase in GLP-1 produc-
tion, it may have broader protective potential than is
currently appreciated, reecting the diverse and largely
protective physiological effects of GLP-1.
80
With respect
to vascular health, GLP-1 agonist drugs exert cardiopro-
tective effects in rodent models of myocardial infarction
and congestive failure.
8184
Clinically, they promote
modest weight loss in patients with diabetes and obese
non- diabeties, and exert favourable effects on systolic
blood pressure, serum lipids, inammatory markers and
endothelial function.
85 86
Readers interested in the
vascular-protective properties of GLP-1 agonism can be
referred to a recent review by Lorber.
86
Assessing the
impact of supplemental glycine on GLP-1 production
should be a high clinical priority.
AN IMPACT ON KUPFFER CELL ACTIVATION
The marked utility of dietary glycine in rodent models
of alcohol-induced steatosis has been traced to its ability
to suppress Kupffer cell activation.
987
Ethanol feeding,
by promoting intestinal permeability, enables portal
inux of bacterial endotoxins. The resulting activation
of Kupffer cells exposes hepatocytes to proinammatory
cytokines such as TNF-αthat play a key role in induction
of steatohepatitis. Glycine antagonises Kupffer cell acti-
vation via glycine-gated channels, as previously
discussed.
There is some recent evidence that high-fructose diets
in rats likewise impair the intestinal barrier function,
leading to an activation of Kupffer cells that exacerbates
fructose-induced steatosis.
8890
It is reasonable to suspect
that a high-glycine diet would be protective in this
regard, as it is in rodent models of alcohol-induced stea-
tosis. Whether Kupffer cell activation plays a role in the
hepatic steatosis evoked by high-fructose diets in
humans remains to be established.
Fortunately, glycine powder is inexpensive, highly
soluble and has a pleasant sweet avor; indeed, its name
is derived from the Greek work for sweet.
16
Clinically
useful effects have been observed in patients with meta-
bolic syndrome or diabetes with glycine intakes of 5 g,
34 times daily, without discernible side effects.
32 40
Glycine is readily administered by blending into a uid
of choice, and it should lend itself well to incorporation
into functional foods. Glycine intake can also be
boosted by ingestion of gelatin.
IS URIC ACID A MEDIATING RISK FACTOR?
The proposal that glycine might function as an anti-
doteto the adverse metabolic impact of fructose must
contend with the fact that fructose can markedly amplify
4McCarty MF, DiNicolantonio JJ. Open Heart 2014;1:e000103. doi:10.1136/openhrt-2014-000103
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production of uric acid in the liver. Administration of a
bolus of fructose leads to the rapid hepatic generation
of ADP owing to the unregulated activity of fructokinase;
this in turn can lead to accelerated production of AMP,
adenosine and purine catabolitesincluding the ultim-
ate catabolite (in humans) uric acid. The ability of
fructose-rich diets to boost serum urate levels is well
known, and there is no reason to suppose that glycine
would prevent this effect. This urate does not pose a
problem in fructose-fed rodents, as their uricase activity
converts urate to non-toxic allantoinbut humans do
not express uricase. Human physiological levels of urate
are clearly toxic to the tissues of rodents, as they
promote oxidative stress via NADPH oxidase activa-
tion.
9193
Increased urate levels in humans, in addition to
posing a risk for gout or gouty nephropathy, constitute a
well-established risk factor for coronary disease, hyper-
tension, type 2 diabetes and heart failure, as conrmed
by meta-analyses
9498
although its impact often appears
weak when other risk factors associated with metabolic
syndrome are corrected for. Whether uric acid is a medi-
ating risk factor in these disorders is very much in
dispute. Speaking in favour of this view are studies dem-
onstrating that xanthine oxidase inhibition with allopur-
inol often favourably inuences endothelial
dysfunction
99101
; however, a counterargument is that
xanthine oxidase activity generates superoxide, so allo-
purinol may simply be functioning as an antioxidant in
these circumstances.
102
Moreover, several studies in which urate levels have
been modulated acutely by measures other than xan-
thine oxidase inhibitionraising it with an intravenous
infusion, lowering it with an infusion of urate oxidase
have failed to observe any adverse impact of urate on
endothelial function or other cardiovascular
indices.
103 104
Indeed, urate infusion was found to
improve endothelial function in patients with type 1 dia-
betes, possibly reecting the utility of urate as a peroxy-
nitrite scavenger.
105
The long-term marked elevation of
urate with supplemental inosinebeing studied in
patients with multiple sclerosis as an antioxidant strategy
failed to inuence blood pressure.
106
Perhaps most
compellingly, a number of recent Mendelian randomisa-
tion analyses, focusing on polymorphisms of renal
tubular transport proteins for urate that inuence
serum urate levels, have failed to observe any impact of
these polymorphisms on risk for heart disease, subclin-
ical atherosclerosis, diabetes, hypertension, metabolic
syndrome or diabetes
107111
with the exception of one
small study targeting an Amish population which saw an
association with blood pressure.
112
The overall conclu-
sion of these studies is that obesity and metabolic syn-
drome raise the serum urate level, and that the former,
rather than urate per se, mediates the increased risk
associated with elevated urate levels. The hyperinsulinae-
mia associated with metabolic syndrome promotes renal
retention of urate, explaining at least in part the hyper-
uricaemia that is a feature of this syndrome.
113
It
appears that primates have evolved resistance to the
pro-oxidant effects of urate demonstrated in rodents,
such that losing their uricase activity did not comprom-
ise their Darwinian viability.
Hence, the failure of glycine to address the
fructose-mediated elevation of serum urate levels, while
unfortunate from the standpoint of gout risk, may not be
disadvantageous from the standpoint of vascular health.
Elevated urate levels appear likely to provide some protec-
tion from Parkinsonsdiseaseanding conrmed by a
Mendelian randomisation analysis.
114 115
Contributors MFM and JJD came up with the idea for the manuscript. MFM
wrote the first draft. JJD reviewed, edited and contributed to concepts in the
manuscript.
Competing interests None.
Provenance and peer review Not commissioned; internally peer reviewed.
Open Access This is an Open Access article distributed in accordance with
the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license,
which permits others to distribute, remix, adapt, build upon this work non-
commercially, and license their derivative works on different terms, provided
the original work is properly cited and the use is non-commercial. See: http://
creativecommons.org/licenses/by-nc/3.0/
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Mark F McCarty and James J DiNicolantonio
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The cardiometabolic benefits of glycine: Is
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... 40 Conceivably, this phenomenon reflects in part an upregulation of enteral production of glucagon-like peptide- 1 (GLP-1). 41 The L-cells that secrete GLP-1 express glycine- gated chloride channels; because L-cells accumulate chloride, activation of these channels exerts a depolarizing effect that promotes calcium influx and GLP-1 secretion. 28 Although the impact of supplemental glycine on GLP-1 production has not been assessed in vivo, oral gelatin, notably rich in glycine, has been shown to boost GLP-1 levels. ...
... 44 Because both GLP-1 and glucagon boost hepatic fatty acid oxidation, these hor- mones might collaborate in mediating the protective impact of supplemental glycine on fructose-fed rats. 41 Díaz-Flores et al administered 15-g glycine daily (5 g, 3 times daily) to patients with metabolic syndrome. Despite fasting glucose rising significantly from 101 mg/dL to 114 mg/dL (P¼0.001), ...
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To investigate the expression of F4/80, NF-kappaB, p-AKT, AKT in the liver of nonalcoholic fatty liver disease (NAFLD) mice. To determine the role of Kupffer cells (KCs) in the development of NASH (non-alcoholic steatohepatitis), and understand the pathogenic mechanism of NASH. Five C3H/HeN mice fed with normal diet were served as controls, while fifteen fed with high fat, high fructose, high fat combined fructose diet respectively for 16 weeks were as NAFLD mice models. The liver inflammation and hepatic damage were examined, and the expression of F4/80, NF-Kb, p-AKT, AKT and the content of lipid in the liver were also detected. Chronic intake of high fat and 30% fructose solution caused a significant increase in hepatic steatosis in animals in comparison to water controls. Liver F4/80 and NF-kappaB were significantly higher in high fat and high fat combined fructose diet fed mice than that in controls (P < 0.01, P < 0.01), F4/80 protein were higher in high fat diet treated mice than those in fructose and high fat combined fructose groups (P < 0.01, P < 0.01). Markers of insulin resistance (e. g, hepatic phospho-AKT, AKT) were only altered in fructose-fed or high fat combined fructose animals (P < 0.01, P < 0.01). High fat and fructose diet may induce NAFLD in C3H/HeN mice. Kupffer cells and signal pathway proteins were activated, and they may play key roles in the initiation and progression of NASH.
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Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum that ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) and to cirrhosis. The recommended treatment for this disease includes measures that target obesity and insulin resistance. The present review summarizes the role of newer anti-diabetic agents in treatment of NAFLD. PubMed, MEDLINE and Ovid databases were searched to identify human studies between January 1990 and January 2013 using specified key words. Original studies that enrolled patients with a diagnosis of NAFLD or NASH and involved use of newer classes of anti-diabetic agents for a duration of at least 3 months were included. Out of the screened articles, four met eligibility criteria and were included in our review. The classes of newer anti-diabetic medications described were dipeptidyl peptidase IV inhibitors and glucagon-like peptide-1 analogues. Liraglutide and Exenatide showed improvement in transaminases as well as histology in patients with NASH. Sitagliptin showed improvement in transaminases but limited studies are there to access its effect on histology. Further studies are needed to support use of newer anti-diabetic medications in patients with NAFLD.
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