Diabetes and dyslipidemia: characterizing lipoprotein metabolism

Abstract

Premature atherosclerosis in diabetes accounts for much of the decreased life span. New treatments have reduced this risk considerably. This review explores the relationship among the disturbances in glucose, lipid, and bile salt metabolic pathways that occur in diabetes. In particular, excess nutrient intake and starvation have major metabolic effects, which have allowed us new insights into the disturbance that occurs in diabetes. Metabolic regulators such as the forkhead transcription factors, the farnesyl X transcription factors, and the fibroblast growth factors have become important players in our understanding of the dysregulation of metabolism in diabetes and overnutrition. The disturbed regulation of lipoprotein metabolism in both the intestine and the liver has been more clearly defined over the past few years, and the atherogenicity of the triglyceride-rich lipoproteins, and – in tandem – low levels of high-density lipoproteins, is seen now as very important. New information on the apolipoproteins that control lipoprotein lipase activity has been obtained. This is an exciting time in the battle to defeat diabetic atherosclerosis.

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open access to scientific and medical research
Open Access Full Text Article
http://dx.doi.org/10.2147/DMSO.S115855
Diabetes and dyslipidemia: characterizing
lipoprotein metabolism
GH Tomkin1,2
D Owens1,2
1Diabetes Institute of Ireland, Beacon
Hospital, 2Trinity College, University
of Dublin, Dublin, Ireland
Abstract: Premature atherosclerosis in diabetes accounts for much of the decreased life span.
New treatments have reduced this risk considerably. This review explores the relationship
among the disturbances in glucose, lipid, and bile salt metabolic pathways that occur in diabetes.
In particular, excess nutrient intake and starvation have major metabolic effects, which have
allowed us new insights into the disturbance that occurs in diabetes. Metabolic regulators such
as the forkhead transcription factors, the farnesyl X transcription factors, and the fibroblast
growth factors have become important players in our understanding of the dysregulation of
metabolism in diabetes and overnutrition. The disturbed regulation of lipoprotein metabolism
in both the intestine and the liver has been more clearly defined over the past few years, and
the atherogenicity of the triglyceride-rich lipoproteins, and – in tandem – low levels of high-
density lipoproteins, is seen now as very important. New information on the apolipoproteins
that control lipoprotein lipase activity has been obtained. This is an exciting time in the battle
to defeat diabetic atherosclerosis.
Keywords: obesity, type 2 diabetes, dyslipidemia, low-density lipoprotein, fibroblast growth
factor, forkhead transcription factor O1, farnesyl X transcription factors
Introduction
Diabetes is still often considered a sugar-related disease, but the disease might well
have been named diabetes lipidus if only lipids instead of sugar could have been tasted
in the urine, as suggested by Shafrir and Raz.1 Only in recent years has the devastat-
ing complication of the lipid-related disease atherosclerosis become more feared
than the glucose-centric small vessel disease.2–5 Whereas small vessel disease is very
much related to hyperglycemia, large vessel disease has been difficult to attribute to
dysglycemia. Many studies have failed to reduce cardiovascular disease (CVD) events
by improvement in blood sugar control.6–9
On the other hand, cholesterol-lowering
treatment, in particular, statins, have been shown to have a major impact on cardio-
vascular events from the first statin trials in diabetic patients.10–12 The pathways by
which insulin regulates fuel usage are still being discovered. It is clear that there is
a switch from glucose to fat metabolism overnight when, in the fasting state, insulin
deficiency results in not only high serum glucose but also high serum triglyceride levels.
The triglycerides are packaged in lipoprotein particles driving the cascade through
abnormal chylomicrons, very-low-density lipoprotein (VLDL), intermediate-density
lipoprotein (IDL), low-density lipoprotein (LDL), and finally high-density lipoprotein
(HDL) (Figure 1).
Correspondence: GH Tomkin
Diabetes Institute of Ireland, Beacon
Hospital, Clontra, Quinns Road, Shankill,
Dublin 18, Ireland
Email tomking@tcd.ie
Journal name: Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy
Article Designation: REVIEW
Year: 2017
Volume: 10
Running head verso: Tomkin and Owens
Running head recto: Diabetes and dyslipidemia
DOI: http://dx.doi.org/10.2147/DMSO.S115855
This article was published in the following Dove Press journal:
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy
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Tomkin and Owens
Fasting hypertriglyceridaemis is significantly associated
with cardiovascular events and death.13 A similar picture
emerges when postprandial triglycerides are examined.14–16
Starvation and bariatric surgery both have a profound effect
on serum lipids.17–19 Cholesterol is both absorbed and syn-
thesized. Insulin regulates both these pathways, and since
cholesterol synthesis is regulated through the bile acid cho-
lesterol pathway, bile acids play a major part in cholesterol
homeostasis.20
The purpose of this review is to explore the relationship
among insulin resistance, diabetes, and dyslipidemia. We
highlight areas of research that may lead to the discovery of
possible new treatments to prevent premature heart disease
in diabetes.
Insulin action
The secretion of insulin is glucose dependent. This is relevant
in the fed state to prevent postprandial hyperglycemia. In
fasting conditions, when the blood sugar is low, insulin is
still needed; otherwise, free fatty acids will rise and hepatic
glucose suppression will not occur, leading to hyperglycemia.
In the fasting state, when blood sugars are low, fatty acids,
not glucose, stimulate insulin secretion from the β cells.21
It has been shown that fatty acids acutely enhance insulin
secretion, oxygen consumption rate, and extracellular acidifi-
cation rate in human islets at fasting glucose concentrations,
with monounsaturated fatty acids (MUFAs) being more
potent than saturated fatty acids (SFAs).22
Cen et al22 sug-
gest that the high fatty acids in their study may account for
the hyperinsulinemia in patients who have raised fatty acids
but normal blood sugars. In overnutrition, insulin initially
manages to store the excess calories in the adipose tissue.
This process breaks down at some stage and fatty acids collect
in the liver and the muscle, leading to insulin resistance, and
a vicious cycle arises in which the pancreas fails to deliver
sufficient insulin to cope with the increased demands. This
leads to even more difficulty in disposal of the fatty acids, and
then the lack of inhibition of glucose release in the liver leads
to hyperglycemia against a background of raised fatty acids.
The high glucose level inhibits β-oxidation via a product of
the glycolytic pathway, malonyl coenzyme A (Co-A), and
fatty acids are directed toward formation of triglycerides.23
In the long term, the rise in free fatty acids has a detrimental
effect on the β cells, leading to apoptosis.24
Diacylglycerol and insulin resistance
Diacylglycerol (DAG) is the precursor for triglyceride bio-
synthesis. The DAG kinases (DAGKs) are a group of kinases
that regulate signal transduction via protein kinase C (PKC),
Ras and Rho family proteins, and phosphatidylinositol
5-kinases.25 Elevated DAG content is linked with the develop-
ment of insulin resistance in type 2 diabetes.26,27
DAGK delta
activity and total DAG level are reduced in skeletal muscle
from type 2 diabetic patients.28,29 Adenosine monophosphate
(AMP)-activated protein kinase (AMPK) is a central regula-
tor of energy metabolism. Metformin, the most commonly
used drug to treat type 2 diabetes, activates AMPK to suppress
gluconeogenesis.30 AMPK also suppresses gluconeogenesis
by the downregulation of FoxO1 target genes.31 Transform-
ing growth factor beta (TGF-b)/daf-16 (FoxO1) interact
Figure 1 Lipoprotein cascade.
Notes: In the circulation, VLDL is gradually delipidated, resulting in increasingly smaller lipoprotein particles, ie, IDL, LDL, and small dense LDL. The intestinally derived
chylomicron, characterized by presence of apoB48, is delipidated to form the chylomicron remnant, which is taken up by the liver.
Abbreviations: HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein.
Chylomicron
B48
Chylomicron
remnant
B48
VLDL
IDL
B100
LDL
B100
HDL
LDL
Small
dense LD
L
Liver
B100

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Diabetes and dyslipidemia
with AMPK to regulate metabolic and nutrient sensory path-
ways and glucose metabolism.32,33 Yadav et al33 have shown
that that TGF-b1 signaling suppressed the liver kinase B1
(LKB1)–AMPK axis, thereby facilitating the nuclear trans-
location of FoxO1 and activation of key glucogenic genes
regulating glucose-6 phosphatase and phosphoenolpyruvate
carboxykinase both in the fasting state and in type 2 diabetes.
PKC blocks AMPK activation.34 Nutrient excess in type 2
diabetes or obesity elevates DAG levels and PKC activity,
in addition to impairing insulin sensitivity.35
AMPK activity
is reduced in insulin-resistant and obese animal models.36
AMPK is involved in lipid metabolism through acetyl-CoA
carboxylase and malonyl-CoA decarboxylase.37,38
Jiang et
al39 have shown that DAGK delta deficiency impairs AMPK
and lipid metabolism, as well as influencing skeletal muscle
energetics. It seems that DAGK delta is a major player in the
reduction in lipid oxidation and the insulin resistance found
in type 2 diabetes (Figure 2).
Bile acids
There is a third player in this process, namely, the bile
acids. The two primary bile acids are chenodeoxycholic and
cholic acids. They are synthesized in the liver, conjugated
with taurine or glycine, and excreted in the bile.20 They aid
fat absorption through their ability to form micelles, thus
solubilizing fat and cholesterol.40 An increase in dietary
cholesterol suppresses cholesterol synthesis and a decrease
in dietary intake increases de novo synthesis in the liver. The
bile acid-activated receptors play an important regulatory
part in not only maintaining lipid, but also glucose, homeo-
stasis.41–43 Chenodeoxycholic acid, which is an important
farnesoid X receptor (FXR) agonist, lowers the biliary secre-
tion of cholesterol, and reduces the cholesterol saturation of
LDL through reduced clearance of plasma apolipoprotein B
(apoB).44 Hepatic microsomal cholesterol 7 alpha hydroxy-
lase (CYP7A1) and 3-hydroxy-3-methylglutaryl CoA (HMG
CoA) reductase activities were reduced and specific LDL
receptor binding was also reduced.45–47 Ghosh et al48 have
shown that chenodeoxycholic acid reduces plasma clearance
of LDL, somewhat mitigated by a decrease in LDL produc-
tion. Proprotein convertase subtilisin/kexin type (PCSK9),
apoA1, apoC111, lipoprotein (a), triglycerides, and insulin
levels were reduced. This is of interest because FXR ago-
nists have been shown to prevent the development of insulin
resistance in animals.49
Glucose-dependent insulinotropic polypeptide (GIP)
stimulates insulin secretion. The action of GIP is impaired
in type 2 diabetes. GIP has been shown to lower nonesteri-
fied fatty acid (NEFA) concentration in obese type 2 diabetic
patients despite diminished insulinotropic activity. GIP has
also been shown to increase subcutaneous adipose tissue tri-
glycerides. Reduction in NEFA concentration with GIP cor-
related with a reduction in adipose tissue insulin resistance.50
Fibroblast growth factors (FGFs)
FGF 15/19 and FGF 21 play an important role in metabolic
regulation.51–53
Both molecules have demonstrated ability
to lower serum glucose, triglyceride, and cholesterol levels;
improve insulin sensitivity; and reduce body weight.54,55
FGF 19 activates FGF receptor 4 (FGFR4), the predomi-
nant receptor expressed in the liver, and regulates bile acid
homeostasis.53,56–57 FGF 21 has recently been shown in mice
to antagonize the action of FGF 15/19.53 Zhang et al53 have
found, as expected, that overexpression of either FGF15 or
FGF 21 reduced body weight, fasting glucose level, and insulin
level, as well as decreasing plasma triglyceride and cholesterol
levels. FGF 15 lowered the bile acid pool, but unexpectedly,
the authors report that they found that FGF 21 increased the
bile acid pool size through the beta-Klotho/FGFR4 complex.
CYP7A1 catalyzes the first and rate-limiting step in the classic
bile acid pathway.58
Cyp7A1 is tightly regulated by a negative
feedback loop mediated by FGF 15/19.59,60 Overexpression of
FGF15 significantly reduces Cyp7A1 mRNA.53 In contrast,
FGF 21 overexpression results in CYP7A1 upregulation, sug-
gesting that bile acid synthesis was the reason for the increased
bile acid pool size in these animals. Serum FGF 21 has been
shown to be increased in obesity.61 The authors have shown
that there was a positive correlation between adiposity, fast-
ing insulin, and triglycerides and a negative correlation with
HDL cholesterol. Logistic regression analysis demonstrates
an independent association between serum FGF 21 and the
metabolic syndrome.61 FGF 21 has been shown to be raised in
type 2 diabetic patients with nonalcoholic fatty liver disease.62
More recently, Alonge et al63 have shown that glucagon and
Figure 2 Metformin stimulates AMPK, which downregulates gluconeogenesis both
directly and through downregulation of FoxO.
Abbreviation: AMPK, adenosine monophosphate-activated protein kinase.
Metformin
AMPK
FoxO
Gluconeogenesis

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insulin cooperatively stimulate FGF 21 gene transcription by
increasing the expression of activating transcription factor 4.
It has also been shown that FGF 21 is a superior biomarker to
other adipokines.64 The authors suggested that serum FGF 21
might be considered an alternative to the oral glucose tolerance
test.64
An FGF 21 analog has been shown to be superior to
glargine insulin and a glucagon-like peptide-1 (GLP1) agonist
liraglutide in reducing hemoglobin A1c (HbA1c) and improv-
ing glycemic control, insulin resistance, serum lipids, and
liver function states in type 2 diabetic db/db mice (Figure 3).65
The FGF 21 analog LY2405319 has shown, in a 28-day
proof-of-concept study66 in type 2 obese diabetic patients, sig-
nificant improvement in lipids, with favorable effects on body
weight, fasting insulin, and adiponectin. There was a trend
toward glucose lowering.66 Another analog, PF-05231023, has
been shown – in type 2 diabetes – to decrease body weight,
improve lipoprotein profile, and increase adiponectin levels.
The drug had no effect on glycemic control. The drug had
effects on multiple markers of bone formation and resorp-
tion, and it increased insulin-like growth factor-1 (IGF-1).
In adults, FGF 21 has been shown to be raised.64 In Chinese
children aged between 6 and 18 years, the opposite has
been described, with deficiency – rather than resistance –
being found.67 The authors suggest that in children, FGF 21
deficiency – rather than resistance – contributes to insulin
resistance and hypoadiponectinemia. Interestingly, leptin has
recently been shown to increase FGF 21 levels in Wistar rats
and in human-derived hepatoma HepG2 cells.68 Thus, the
pathways between bile, cholesterol, glucose, and fat meta-
bolic processes are linked, but there are still many discover-
ies yet to be made. Looking at the problem the other way, a
deficiency of insulin leads to hyperglycemia, hypertriglyc-
eridemia, and hypercholesterolemia, apart from abnormal
bile acid metabolism, which affects the apoB-containing
lipoproteins, and an interconnected decrease in HDL.
Serine/threonine protein kinase
(STK25)
The networks controlling fat deposition and insulin respon-
siveness are very complex and attract much attention. The
enzyme STK25 has been shown to influence intramyocellular
lipid accumulation, impair skeletal muscle mitochondrial
function and sarcomeric ultrastructure, and induce perimysial
and endomysial fibrosis, thereby reducing endurance exercise
capacity and muscle insulin sensitivity.69
The same group had
previously shown that STK25 regulates lipid partitioning in
human liver cells by controlling triglyceride synthesis as well
as lipolytic activity and, thereby, NEFA release from lipid
droplets for β-oxidation and triglyceride secretion.70
Forkhead transcription factors
FoxO1 plays an important role in orchestrating fuel metabo-
lism and influences glucose, fat, and bile metabolic pathways
through its effect on mitochondrial function and adipocyte
differentiation.71–75 FoxO1 alters mitochondrial biogenesis,
morphology, and function in the liver of insulin-resistant
mice, while genetic ablation of FoxO1 significantly normal-
izes mitochondria and metabolism.73,76 In the adipocyte,
silencing of FoxO1 inhibits cell differentiation and lipid
accumulation, with changes in expression of mitochondrial
respiration chain proteins.71,73,74 FoxO1 has been shown to
control lipid droplet growth and adipose autophagy.77–81
Inhibition of autophagy leads to browning of white adipose
tissue, which is characteristic of increased expression of
uncoupling protein 1 (UCP1).78–81 UCP1 uncouples mito-
chondrial respiration from adenosine triphosphate (ATP)
production/oxidative phosphorylation, dissipating energy
as heat.82,83 Liu et al84 have recently shown that FoxO1 inter-
acts with transcription factor EB (Tfeb), a key regulator of
autophagosomes and lysosomes, and mediates the expression
of UCP1, UCP2, and UCP3. However, the study84 showed
that inhibition of FoxO1 suppressed Tfeb and autophagy,
attenuated UCP2 and UCP3, but increased UCP1 expression
(Figure 4). The enzyme protein deglycase (DJ-1) is involved
in multiple physiological processes. Wu et al85 have recently
shown that this protein is involved in maintaining energy
balance and glucose homeostasis, regulating brown adipose
tissue (BAT) activity. They showed that DJ-1-deficient mice
had reduced body mass, increased energy expenditure, and
improved insulin sensitivity. DJ-1 has been shown to inhibit
FoxO1-dependent UCP1 expression in BAT. FoxO1 has also
been shown to downregulate apoA1 gene activity in HepG2
cells under oxidative stress induced by hydrogen peroxide.86
ApoA1 forms HDL particles and has an antioxidant function.
Figure 3 FGF 15/19 and FGF 21 have opposing effects on bile acid synthesis through
their effect on Cyp7A1.
Note: Glucagon, leptin, and insulin increase FGF 21, which increases adipose tissue
UCP1. Cyp7A1 is also termed cholesterol 7a-hydroxylase.
Abbreviation: FGF, broblast growth factor.
FGF 15/19
Glucagon
Leptin
Insulin
Cyp7A1 RNA
Cyp7A1 RNA
FGF 21
Adipose
tissue UPC1

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Diabetes and dyslipidemia
Leptin is an important metabolic regulator. Leptin injec-
tions have been shown to increase plasma FGF21 in vivo in
Wistar rats and in vitro using human-derived hepatocarci-
noma HepG2 cells, mediated by STAT 3 activation.68 FoxO1,
FoxO3, and FoxO4 have been shown to be involved in muscle
proteasomal and autophagy–lysosomal degradation. Diabetes
strongly affects protein metabolism, muscle wasting being
a very significant finding in uncontrolled diabetes. Insulin
and IGF-1 enhance muscle protein synthesis through their
receptors.87 O’Neill et al88 have shown that both IGF-1 and
the insulin receptor are involved in muscle proteostasis, the
insulin receptor being more important than IGF-1. They
found that muscle-specific deletion of FoxO1, FoxO3, and
FoxO4 in double knockout of both insulin receptor and IGF-1
in mice completely rescued the muscle mass without chang-
ing the proteasomal activity.
FoxO1, rapamycin, and perilipin
(PLIN)
Muscle is an important tissue for whole-body glucose
homeostasis.89,90
Target of rapamycin (TOR) C2 is found in
the insulin signaling pathway and is responsible for regu-
lating muscle glucose metabolism.91–93 Acute inhibition of
mTOR complexes increases lipid utilization, probably due
to the effect of mTOR C2.91 PLIN 3 is a regulator of lipid
storage.94–96 Knockdown of PLIN 3 in the liver of high-fat-
diet-fed mice improves hepatic steatosis along with glucose
homeostasis.97 PLIN 3 overexpression has been shown
to increase muscle triglyceride.98 FoxO1 is a regulator of
PLIN 1. AMPK modulates FoxO1 transcriptional activity.99
A FoxO1 antagonist has been shown to suppress autophagy
and lipid droplet growth in adipocytes.77
Fibroblast activation protein (FAP)
FAP is a serine protease, and it has been shown to regulate
the degradation of FGF 21100 Sánchez-Garrido et al101 have
shown that inhibition of FAP using a known FAP inhibitor,
talabostat, enhances levels of FGF21 in obese mice, reduc-
ing body weight, food consumption, and adiposity while
increasing energy expenditure, glucose tolerance, and insu-
lin sensitivity, as well as lowering cholesterol levels. The
metabolic effect of FAP inhibition was markedly reduced
in lean animals.101
Peroxisome proliferator-activated
receptor (PPAR)
Insulin resistance in skeletal muscle plays a major role in
obesity and type 2 diabetes.27 The PPAR superfamily of tran-
scription factors includes the isoforms PPAR-alpha, which
modifies insulin resistance in the liver; PPAR-γ, which regu-
lates genes involved in fatty acid metabolism, inflammation,
and macrophage homeostasis;102 and PPAR delta, which has
been implicated in obesity-associated insulin resistance.103
It is highly expressed in muscle compared to PPAR alpha
and gamma. A high-fructose diet-induced obesity results
in insulin resistance in mice with hyperinsulinemia, hyper-
leptinemia, hyperlipidemia, and hypoadiponectinemia. The
diet has been shown to impair insulin and AMPK signaling
pathways and reduce glucose transporter type 4(GLUT-4)
and GLUT-5 expressions. The study showed that a PPAR
delta agonist GW0742 had no effect on control mice, but in
the high-fructose-diet animals, it increased the expression of
PPAR delta and significantly attenuated all the effects of the
diet on the phosphorylation of insulin receptor substrate-1
(IRS-1), protein kinase B (PKB) or AKT, and glycogen syn-
thase kinase 3 beta (GSK-3B). The agonist reduced skeletal
muscle triglyceride and increased muscle glucose uptake. The
drug increased phosphorylation of both AMPK and acetyl
Co-A carboxylase (ACC) and increased protein expression
of carnitine palmitoyl transferase-1 (CPT-1), all suggesting
an increase in fatty acid oxidation. There was a dramatic
increase of FGF-21 production in the muscle.104
DAG transferase
Hypertriglyceridemia is a major finding in uncontrolled
diabetes. Indeed, many years ago,105 Shafrir and Gutman105
showed that as glucose intolerance increased from normal to
diabetes through prediabetes, free fatty acids became much
more markedly abnormal and preceded the glucose shift from
normal to diabetes. Free fatty acids are converted to DAG
through diglyceride acyltransferase (DGAT)-1 and then to
triacylglycerol through DGAT2. The other major pathway of
triglyceride synthesis is the glycerol phosphate pathway. In
both pathways, fatty acyl-CoA and DAG are converted jointly
to form triglyceride, catalyzed by DGAT. A novel DGAT1
Figure 4 Effect of FoxO1 on adipocyte differentiation and mitochondrial function.
Notes: FoxO is a regulator of glucose metabolism, lipid accumulation, and
adipocyte differentiation. It also increases adipocyte browning and interacts with
Tfeb to regulate UCPs 1, 2, and 3.
Abbreviation: Tfeb, transcription factor EB.
Adipocyte browning
FOXO1 Lipid
accumulation
Adipocyte
differentiation
UPC1
UPC2
UPC3
EB
Glucose

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Tomkin and Owens
inhibitor has been shown in mice to improve insulin resistance
in adipose tissue, as well as systemic glucose metabolism,
through a reduction in body weight.106
Triglyceride and cholesterol
absorption in diabetes
Excess calories are first stored as triglyceride in adipose tis-
sue to be released as fuel through the fatty acid cycle when
carbohydrate is in short supply. Lipoprotein lipase (LpL) is
suppressed by insulin, and therefore in insulin deficiency
states, lipolysis increases even in a high-glucose environ-
ment. FoxA2 has been shown in the liver to regulate the
LpL gene; thus, FoxA2 may be another important regulator
of lipid and glucose metabolic pathways.107
Dietary fat is
solubilized by bile acids in the intestine and, apart from the
short-chain fatty acids, is absorbed by the lymphatic system
passing to the liver. Triglyceride absorption is unregulated, so
that fecal fat remains in very small quantities even in very-
high-fat diets. Fatty acids stimulate synthesis of apoB100,
which is edited to apoB48 in the intestine.108 ApoB48 is the
solubilizing protein by which triglycerides and cholesterol
are carried to the liver and then around in the circulation
in the postprandial state. Although triglyceride absorption
is unregulated, cholesterol absorption is tightly regulated.
NPC1L1 is the regulating transporter protein in the first step
in cholesterol absorption in the intestine. NPC1L1 mRNA is
upregulated in diabetes.109 It has been shown that in a high-
glucose environment, cholesterol absorption is increased.110
The dimer proteins ABCG 5/8 act together in the intestine
to excrete excess cholesterol back into the lumen. These
genes are downregulated in diabetes.109 Genetic variants in
ABCs G5/8 have been shown to protect against myocardial
infarction (MI) but also to increase the risk of symptom-
atic gallstone disease, demonstrating the interdependence
between bile acid and cholesterol metabolic pathways.111 The
final step in the absorption process is the attachment of the
triglyceride and cholesterol onto apoB48 through MTP. MTP
is upregulated in diabetes, and this is reflected in higher levels
of apoB48 in serum (Figure 5).112 These particles are thought
to be particularly atherogenic because of their large size and
rapid turnover, so even though their cholesterol quantity per
particle is low, the total carrying power of these particles is
large; therefore, they are inherently atherogenic since the
particles lodge in atheromatous plaques.113
The postprandial apoB48-containing particles and the
VLDL apoB100 triglyceride-rich particles gather various
apoproteins in the circulation. For example, apoC1 inhib-
its clearance of triglyceride by LpL. High levels of white
adipose tissue apoC1 secretion has been shown to delay
clearance of postprandial chylomicrons in overweight and
obese subjects.114 ApoC11 is an obligatory cofactor for LpL.
Recently, deficient cholesterol esterification has been found
to occur in an apoC11-deficient zebrafish, which mimics
the familial chylomicronemia syndrome in human patients,
with a defect in apoC2 or LpL genes.115 ApoC111 inhibits
the delipidation of triglyceride from the particle by inhibiting
the action of LpL, thus delaying the clearance of the particle
from the circulation.116
The Bruneck Study117 was designed
to examine the importance of various apolipoproteins in
the genesis of cardiovascular events over a 10-year period.
The study found that apoC11, apoC111, and apoE were the
apolipoproteins most significantly associated with incident
Figure 5 Cholesterol absorption and chylomicron assembly and breakdown.
Notes: Diacylglycerol is formed from free fatty acids under the inuence of DGAT-1. Dietary cholesterol uptake from the intestine into the lymph is regulated by NPC1L1.
ApoB48 is synthesized in the intestine. Triglyceride, cholesterol, and apoB48 are combined under the inuence of MTP to form the chylomicron. In the circulation, the
chylomicron is delipidated by LPL and cleared by the liver.
Abbreviations: DGAT, diglyceride acyltransferase; LPL, lipoprotein lipase.
Diacylglycerol
Fatty acids
DGAT-1
Triglyceride
Lymph cholesterol
Intestinal apoB48
MTP
NPC1L1
Chylomicron
LPL
Chylomicron
remnant
Dietary cholesterol

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CVD. These associations were independent of HDL and
non-HDL cholesterol and extended to stroke and MI. Interest-
ingly, these three apolipoproteins, apoC1, apoC11, and apoE,
were implicated in de novo lipogenesis, glucose metabolism,
complement activation, blood coagulation, and inflammation,
through the lipidomic and proteomic profiles determined in
the study.118 In the liver, NPC1L1 plays a part in the transport
of cholesterol to the canaliculi, wherein the VLDL particle
is assembled. The ABCs G5/8 play an important part in
regulating the amount of cholesterol diverted to the bile for
excretion. AUP1 is an endoplasmic reticulum-associated
protein. Very recently, it has been shown to be involved in
the regulation of apoB100, hepatic lipid droplet metabolism
in the liver, and intracellular lipidation of VLDL particles.119
Its role in the intestine is so far unknown.
Diabetes disturbs the synthesis and metabolism of
triglyceride-rich lipoprotein particles, increasing their ath-
erogenicity. The specific role of triglycerides in atherogenesis
has been difficult to tease out as the lipoprotein cascade is
so interdependent and changes in the chylomicron influence
VLDL assembly in the liver through the increase in delivery
of both triglyceride and cholesterol to the liver.120 The increase
in triglyceride content of the VLDL particle translates to an
LDL particle with an increase in fatty acids. LDL atheroge-
nicity is dependent at least in part on its oxidizability. The
more the number of fatty acids with more-than-one double
bond, the easier it is to oxidize, and it is the oxidized LDL
that is taken up in an unregulated way by the macrophage,
the hallmark of the atheromatous plaque.120 Small dense LDL
particles are particularly associated with atheromatous risk
and these particles arise from triglyceride-rich VLDL par-
ticles. An analysis of lipoprotein subfractions in 920 patients
with and without type 2 diabetes confirmed the increase in
concentration and size of smaller LDL particles.121
Free radical production is increased in the hyperglycemic
state, so the diabetes environment increases the oxidation of
LDL. In this context, delays in treatment intensification with
oral antidiabetic drugs have been shown to increase the risk
of major cardiovascular events.122
Diabetes dyslipidemia,
atherosclerosis, and HDL
The hallmark of diabetes dyslipidemia is high triglycerides
with low HDL.123,124 The interdependence of triglycerides and
HDL has made it very difficult to separate the risk of athero-
sclerosis from one or the other. Until recently, HDL has come
out on top and the triglyceride-rich lipoproteins have been
undervalued as risk factors for accelerated atherosclerosis.
Epidemiological studies in the 1970s established the strong
inverse relationship between low HDL levels and coronary
heart disease.125,126 More recently, the focus has been on the
quality of HDL since functionality has been shown to be
of major importance in predicting atherogenic risk.127,128
Hermans et al128 have suggested that the ratio of HDL-C/
apoA1 might be a better way to predict angiopathic risk. Sun
et al129 have shown that HDL from people with type 2 diabetes
had the ability to stimulate secretion of tumor necrosis fac-
tor (TNF)-a, an inflammatory cytokine, in incubated human
peripheral blood mononuclear cells to a greater extent as
compared to HDL from control subjects. They showed that
HDL from the patients with coronary artery disease (CAD)
had a greater capacity to stimulate TNF-a as compared to
HDL from the type 2 diabetic subjects who did not have
coronary heart disease. The proinflammatory ability of
HDL was a significant predictor for the presence of CAD
in patients with diabetes. HDL particle number, rather than
cholesterol content, may be a better predictor of atherogenic-
ity. A multiethnic study130 of atherosclerosis has examined
this in patients with the metabolic syndrome and diabetes.
Tehrani et al130 found that HDL particle number in diabetes
predicted coronary heart disease (CHD) and CVD. In those
with metabolic syndrome, only LDL particle number was
positively associated with CVD.
A retrospective study131 among >47,000 patients attending
Italian diabetic centers investigated >15,000 patients with no
evidence of renal disease. A 4-year follow up demonstrated
that low HDL and high triglyceride levels were independent
risk factors for the development of diabetic kidney disease
over 4 years.131 Poor glycemic control in type 2 diabetes
enhances functional and compositional alterations of small
dense HDL3.132 Gomez Rosso et al132 showed that defective
functionality of small dense HDL particles was present in
patients with type 2 diabetes mellitus with poor glycemic
control. The HDL had also diminished its antioxidant ability.
One of the benefits of lifestyle intervention is the increase
in HDL and, in particular, large HDL. It has recently been
shown that lifestyle intervention can offset unfavorable
genetic loading for most lipid traits, including the size of
HDL.133 The understanding of functionality of HDL may
become clearer following the description of the use of atomic
force microscopy to examine the organization of apoA1.134
Conclusion
The dysregulation of metabolism when relative or absolute
insulin deficiency appears has been more clearly defined in
the past few years. The interplay between the bile, cholesterol,

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Tomkin and Owens
and carbohydrate metabolic pathways and the genes involved
have opened up new possibilities of treatments to ameliorate
the atherogenic potential of diabetic dyslipidemia. Overfeed-
ing leads to obesity and insulin resistance. Hyperinsulinemia
progresses to a relative, and then absolute, deficiency of
insulin. It is difficult to dissect the metabolic disturbances
that occur at each stage of the disease process. Dyslipidemia
potentiates the disease process through oxidation of LDL,
which further damages the β-cell. The abnormal HDL and
the deficiency of its antioxidant functions in the defense of
the β-cell have made for exciting speculations on treatments
that might slow or stop β-cell destruction. Calorie excess,
together with inadequate exercise, remains central to type
2 diabetes and diabetic dyslipidemia. Bariatric surgery and
starvation both have shown how calorie restriction can ame-
liorate the metabolic dysfunction of type 2 diabetes, which
includes dyslipidemia.
The most obvious lipid defect in uncontrolled diabetes
is the elevated level of triglycerides. A consequence is the
lowering of HDL. The triglyceride-rich lipoproteins have
again come into fashion as important atherogenic particles.
Although these particles carry much less cholesterol than
LDL per particle, their actual load is similar to LDL if one
takes into account their rapid half-life. LDL has a half-life
of days rather than minutes in the case of chylomicrons. The
influence of insulin on regulation of the apoB48-containing
chylomicron in the intestine through a complex series of
steps has helped to understand how dysregulation occurs
in diabetes.
Disclosure
The authors report no conflicts of interest in this work.
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