Curr Diab Rep (2010) 10:55–60
DOI 10.1007/s11892-009-0090-x
Cholesterol in β-cell Dysfunction: The Emerging Connection
Between HDL Cholesterol and Type 2 Diabetes
Liam R. Brunham & Janine K. Kruit &
Michael R. Hayden & C. Bruce Verchere
Published online: 28 January 2010
# Springer Science+Business Media, LLC 2010
Abstract β-cell dysfunction is a critical step in the
pathogenesis of type 2 diabetes. The mechanisms respon-
sible for β-cell death and dysfunction remain incompletely
understood, but include glucolipotoxicity, the deleterious
metabolic milieu created by high plasma concentrations of
glucose and lipid species. Recently, an important role has
emerged for cholesterol in this process. In this article, we
review recent advances in our understanding of the role of
ABCA1 and cholesterol metabolism in β-cell function,
with particular attention to insights gained from human
studies.
Keywords Islet . Beta cell . Cholesterol . HDL
Introduction
Impaired β-cell function is central to the pathogenesis of
type 2 diabetes mellitus [1, 2]. Extensive research into the
reasons for β-cell failure in type 2 diabetes has elucidated
several mechanisms leading to islet death and dysfunction
[3]. Principal among these is the concept of glucolipotox-
icity, the deleterious effect of high levels of circulating
lipids and glucose on the β cell [4]. Recently, abnormalities
of cholesterol metabolism have emerged as a novel
pathway involved in islet function [5]. Type 2 diabetes
commonly occurs in the context of low levels of plasma
high-density lipoprotein (HDL) cholesterol, elevated trigly-
cerides, and an abundance of small, dense low-density
L. R. Brunham : J. K. Kruit : M. R. Hayden : C. B. Verchere (*)
Child and Family Research Institute,
980 West 28th Avenue,
Vancouver, BC V5Z 4H4, Canada
e-mail: verchere@interchange.ubc.ca
lipoprotein (LDL) particles. Low HDL cholesterol is an
independent risk factor for the development of type 2
diabetes [6]. A major question has been whether low HDL
is merely a marker for increased metabolic risk, or whether
low HDL and impaired cholesterol efflux may actually play
a role in the pathogenesis of type 2 diabetes via their effects
on the pancreatic β cell.
Impact of ABCA1 Activity on Diabetes in Humans
ABCA1 regulates the efflux of cellular cholesterol and
phospholipids to an extracellular apolipoprotein acceptor
and controls the major pathway for cholesterol transport out
of cells. ABCA1 acts in the liver and intestine to mediate
the biogenesis of HDL particles [7, 8]. The absence of
ABCA1 in humans or animal models leads to nearly absent
HDL cholesterol, accumulation of cholesterol in peripheral
tissues, and accelerated atherosclerosis [9]. Mice lacking
Abca1 specifically in β cells (Abca1−P/−P) display profound
glucose intolerance due to impaired insulin secretion,
associated with abnormal accumulation of cholesterol in
islets [10•]. These studies established a critical role of
Abca1 in mouse islet cholesterol homeostasis and insulin
secretion [5, 10•]. However, the question of whether
ABCA1 is also important for glucose homeostasis in
humans had remained unanswered.
Initial studies assessed the association of a presumed
loss-of-function polymorphism in the ABCA1 gene, R230C,
with metabolic parameters in a Mexican population [11].
This variant was associated with low HDL cholesterol, high
body mass index, and type 2 diabetes in subjects greater
than 50 years of age, and in a separate population was
associated with early-onset diabetes with an odds ratio of
approximately 2.5 [11, 12]. This variant was initially
56 Curr Diab Rep (2010) 10:55–60

identified in the Oji-Cree [13] and to date has only been a

identified in North American aboriginal populations [11–
13], suggesting that it may be a private variant in Native
American individuals.
An important question has been whether the R230C
variant is itself functional, or whether its association with
metabolic parameters and diabetes represents linkage with
another, functional variant in close proximity. We studied
the functional effects of the R230C variant in stable cell b
lines and found that it elicits approximately 30% less
cholesterol efflux than wild-type ABCA1, indicating that
this is a loss-of-function mutation, and explaining the
deleterious phenotype observed in carriers of this variant
(Samuel Canizales-Quinteros, Personal communication).
These data indicate that reductions in ABCA1 function in
Native American populations are associated with an early-
onset form of type 2 diabetes. c
Although patients with Tangier disease have been
extensively phenotyped over the past 50 years since the
first description of this condition, to our knowledge, there
have been no detailed studies of glucose homeostasis in
these patients. Historically, these patients have not been
reported to be at high risk for diabetes. One recent study
reported the results of oral glucose tolerance tests (OGTTs)
in four patients with Tangier disease; three homozygotes Fig. 1 Comparison of plasma cholesterol (a), islet cholesterol (b), and
and one suspected compound heterozygote [14]. Compared total area under the glucose tolerance test (GTT) (c) curve in wild-type
with a group of 123 unrelated control subjects, all four mice, mice with global deletion of Abca1 (Abca1−/−), and mice
lacking Abca1 specifically in islets (Abca1−P/−P). The data are re-
patients with Tangier disease had significantly elevated
plotted from Brunham et al. [10•]. Abca1−P/−P mice with normal levels
fasting plasma glucose, glucose intolerance during the of plasma cholesterol have the highest degree of islet cholesterol
OGTT, and lower plasma insulin levels during OGTT. accumulation and correspondingly display the most significant
Because all four of these subjects had pre-existing type 2 impairment in glucose tolerance
diabetes with fasting blood sugars greater than 7 mmol/L, it
is possible that these results are skewed by a selection bias.
Comprehensive studies of patients with Tangier disease are controls [15], which may protect their islets from
required to determine if the prevalence of type 2 diabetes is cholesterol accumulation and potentially explain why
greater among these individuals than would be predicted these patients are not generally reported to be at high
based on background prevalence rates. risk for diabetes. Therefore, we hypothesize that Tangier
Data from mice lacking Abca1 suggested that not only heterozygotes would be the ideal subjects in which to
the level of ABCA1 activity but also the level of total assess β-cell function in humans, as these patients have
plasma cholesterol is important in determining the degree of significant impairment in ABCA1 function but relatively
impairment of islet function [10•]. Mice with global normal levels of total plasma cholesterol. Heterozygotes
deletion of Abca1 (Abca1−/−) have very low levels of also offer the advantage of being more common than the
circulating plasma cholesterol and do not exhibit significant extremely rare Tangier homozygotes. Because the degree
accumulation of cholesterol in islets. In turn, these mice of islet dysfunction may be relatively mild in the absence
display only slight impairment in islet function. In contrast, of one copy of ABCA1, detailed studies of β-cell
Abca1−P/−P mice, which lack Abca1 only in β cells, have function, such as using hyperglycemic clamps, will be
normal levels of circulating plasma cholesterol, display required to appropriately interrogate the impact of ABCA1
significant accumulation of cholesterol in islets, and have on islet function in these patients. The results of such
much more severe impairment in islet function (Fig. 1), studies represent a major unanswered question in the
suggesting that the degree of islet cholesterol accumulation study of ABCA1 and diabetes, but should be obtainable
is related to circulating plasma cholesterol levels. Tangier using currently available tools.
disease homozygotes have total plasma cholesterol and Is the effect of ABCA1 on the β cell a direct function of the
LDL cholesterol levels approximately 40% lower than activity of the transporter, or mediated through its influence on
Curr Diab Rep (2010) 10:55–60
cellular cholesterol levels? Most evidence points toward the
impact of ABCA1 being dependent on islet cholesterol levels.
Cholesterol is essential for normal insulin exocytosis, as
treatment of β cells with a cholesterol synthesis inhibitor
impairs insulin secretion [16]. Furthermore, depletion of
membrane cholesterol with methyl-β-cyclodextrin (which
selectively desorbs membrane cholesterol) has been shown
to impact the distribution and function of ion channels in the
plasma membrane [17] and inhibit insulin granule docking
and exocytosis [18]. Whereas low concentrations of methyl-
β-cyclodextrin inhibit insulin secretion [18], higher concen-
trations have been shown to enhance single-cell exocytotic
events [17], suggesting that an optimal concentration of
membrane cholesterol is essential for normal exocytosis of
insulin granules and appropriate nutrient-stimulated insulin
release. Although the precise mechanisms by which ABCA1
influences these processes remain to be elucidated, a model
has emerged in which impaired ABCA1 function leads to
elevated islet cholesterol, disordered β-cell membrane
cholesterol composition, and inhibition of docking and
fusion of insulin-containing granules from the readily
releasable pool, leading to the observed impairment in first-
phase insulin release [10•].
ABCG1 is another cholesterol efflux transporter and
a member of the ABC transporter family of proteins.
Unlike ABCA1, which mediates efflux of cholesterol
and phospholipid species primarily to apolipoprotein A-I
(apo A-I), the preferred efflux acceptor for ABCG1 is
HDL. The absence of Abcg1 in mice leads to dramatic
accumulation of cholesterol in various tissues [19], and
the effect of combined deletion of Abca1 and Abcg1 on
macrophage cholesterol accumulation appears to be
additive [20, 21]. In mice with targeted deletion of Abca1
from islets, Abcg1 is upregulated [10•], suggesting that
increased flux through this alternate pathway may be
compensatory for the loss of Abca1 in β cells. The
consequences of Abcg1 deletion on islet function remain
to be elucidated.
Sterol regulatory element-binding protein (SREBP)-2
overexpression is another model of cholesterol-induced
islet dysfunction. SREBP-2 is a membrane-bound tran-
scription factor critical for regulating cellular cholesterol
synthesis. In the absence of cholesterol, SREBP-2 is
transported from the endoplasmic reticulum to the Golgi
where it is proteolytically cleaved to an active transcription
factor that induces the expression of cholesterol-synthesis
genes and the LDL receptor [22]. The presence of
cholesterol in cells has the opposite effect—retaining
SREBP-2 in the endoplasmic reticulum and thereby
shutting off cholesterol synthesis. Transgenic overexpres-
sion of SREBP-2 bypasses the normal cholesterol auto-
inhibitory machinery, leading to uninhibited cholesterol
synthesis. In mice, overexpression of SREBP-2 in liver and
57
adipose leads to increased expression of cholesterol
biosynthetic enzymes and significantly increases hepatic
cholesterol content [23]. Overexpression of SREBP-2 in
islets would be predicted to have a similar effect, leading to
increased islet cholesterol and impaired islet function.
Ishikawa et al. [24•] studied mice with transgenic
overexpression of SREBP-2 in β cells under the control
of the rat insulin promoter. As predicted, these mice had
significantly elevated levels of esterified and total choles-
terol in islets, whereas plasma cholesterol levels were
normal. This was associated with a significant impairment
in glucose- and potassium-stimulated insulin secretion and
marked impairment in glucose tolerance. Interestingly,
ABCA1 expression was slightly reduced in these mice.
One might expect ABCA1 expression to be increased under
these conditions as a compensatory response to limit
cholesterol accumulation. However, SREBP-2 has previ-
ously been shown to inhibit ABCA1 expression [25], which
could exacerbate the cholesterol overload phenotype under
conditions of increased SREBP-2. These findings provide
an additional model of cholesterol-induced islet dysfunction
and suggest that β-cell dysfunction can be induced by
either decreasing cholesterol efflux from cells (as in the
absence of ABCA1), or increasing cholesterol synthesis or
uptake (as in the overexpression of SREBP-2). Both
pathways support the concept of cholesterol accumulation
in islets contributing to decreased insulin secretion and
propensity to diabetes.
Based on this model, strategies that aim to limit excess
cholesterol accumulation in islets—by enhancing ABCA1
expression, increasing HDL levels, or lowering plasma
cholesterol levels—would be hypothesized to have benefi-
cial effects on islet function.
Role of HDL on Islet Function
Previous studies have documented a beneficial role of
HDLs on measures of islet function in cell culture models
[26]. LDL inhibits insulin secretion and induces β-cell
apoptosis [27–29]. In contrast, HDL protects against
apoptosis induced by interleukin-1β or by glucose [29]. A
recent study shed important new light on the potential for
HDL to impact beneficially on glucose metabolism in
humans [30••]. The authors infused 80 mg/kg of recon-
stituted HDL (rHDL) or placebo into 13 human subjects
with type 2 diabetes in a double-blind, placebo-controlled,
crossover design study. Within 4 h, plasma glucose levels
decreased in the placebo and rHDL group, with a
significantly greater decrease in patients receiving rHDL
(P<0.05). Plasma insulin levels were significantly higher
by more than 15 pmol/L in the rHDL group at the end of
the 4-hour infusion. β-cell function, as assessed by the
58
homeostasis model assessment, was increased by more than
15% in the group receiving rHDL, whereas insulin
sensitivity was unchanged. Collectively, these data indicate
that acutely raising HDL leads to reduced plasma glucose,
increased plasma insulin, and enhanced β-cell function.
Using human skeletal muscle biopsies, they further
found that incubation with HDL activated AMP kinase
and increased glucose uptake. Using an ABCA1-inhibitory
antibody, the effect of HDL or apo A-I on glucose uptake
was entirely abrogated, suggesting that HDL and apo A-I
may also exert a beneficial effect on peripheral glucose
uptake in an ABCA1-dependent manner. Thus, the authors
argue that part of the beneficial effect of rHDL on plasma
glucose is mediated by enhancing glucose uptake and part
by improved β-cell function. These data provide the first
evidence that HDL-based therapy has direct beneficial
effects on β-cell function and glucose metabolism in vivo.
Other Strategies to Improve β-cell Function
As discussed above, infusion of HDL appears to be a
potential strategy to improve β-cell function in humans.
The same may be true of infusion of recombinant apo A-I,
the major protein component of HDL. In vitro, lipid-free
apo A-I protects against glucose-induced and interleukin-
1β-induced apoptosis in cultured mouse islets, similar to
HDL [29]. In humans, infusion of a recombinant apo A-I
reduces carotid atheroma volume [31], in agreement with
animal studies showing that infusion of HDL or apo A-I
reduces atherosclerosis [32, 33]. However, the effects of
apo A-I infusion on glucose and insulin parameters have
not been reported.
Statin therapy lowers levels of plasma LDL cholesterol
and, therefore, may be predicted to have beneficial effects
on islet function and glucose metabolism. In the
WOSCOPS (West of Scotland Coronary Prevention Study)
trial, patients randomized to pravastatin had a 30%
reduction in developing diabetes over the length of the trial
[34, 35]. However, this effect is not universal. In the
JUPITER (Justification for the Use of Statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin) trial, rosu-
vastatin was associated with a statistically significant 0.6%
excess of physician-reported diabetes [36]. In addition, a
meta-analysis of statin trials suggests a slight increased risk
of diabetes in patients receiving statins when data from
WOSCOPS are excluded [37].
Statins upregulate the expression of cell-surface LDL
receptors by activating the SREBP pathway. In the liver, the
increased expression of LDL receptors leads to increased
clearance of plasma cholesterol, as the cholesterol taken up
by the liver can be excreted in bile. However, in peripheral
tissues that do not degrade cholesterol, enhanced LDL
Curr Diab Rep (2010) 10:55–60
receptor expression could lead to increased cellular choles-
terol levels (Fig. 2). The LDL receptor is expressed in islets
[26], suggesting that cholesterol uptake by β cells is LDL
receptor dependent. Therefore, statin therapy may lead to a
reduction in plasma cholesterol and an increase in β-cell
cholesterol, which may explain why statin therapy is not
more consistently associated with beneficial effects on
glucose metabolism. Both pravastatin and rosuvastatin are
hydrophilic molecules, and both have been reported to
increase adiponectin levels [38, 39], which would be
anticipated to reduce diabetes risk [40]. The reasons for
their discordant effects on diabetes are not known.
Thiazolidinediones such as rosiglitazone act as agonists
of the nuclear hormone receptor peroxisome proliferator-
activated receptor (PPAR)-γ and upregulate ABCA1 via the
PPAR-liver X receptor pathway [41]. In addition to their
actions as insulin sensitizers, thiazolidinediones have
beneficial effects on β-cell function and mass, and studies
in mice suggest that part of this effect appears attributable
Fig. 2 Hypothetical model of the impact of various strategies on β-
cell function. Cholesterol loading of islets results in reduced insulin
secretion. Statins decrease the endogenous synthesis of cholesterol
from acetyl-coenzyme A by inhibiting 3-hydroxy-3-methylglutaryl-
coenzyme A reductase (Hmgcr) but also upregulate the low-density
lipoprotein receptor (LDLR), which may lead to enhanced uptake of
cholesterol by islets, and may thereby worsen insulin release. Infusion
of high-density lipoprotein (HDL) has beneficial effects on islet
function, possibly by promoting clearance of excess islet cholesterol.
The effect of infusion of apolipoprotein (apo) A-I on islet function has
not been studied but may have similar beneficial effects. Rosiglitazone
upregulates ABCA1, and this effect is important in its beneficial
impact on islets. The impact of other cholesterol transporters such as
ABCG1 remains unknown
Curr Diab Rep (2010) 10:55–60
to upregulation of ABCA1 [10•]. The ABCA1 genotype
may also influence response to rosiglitazone therapy in
humans [42, 43], offering further support to the concept that
rosiglitazone may act in part through an effect on ABCA1
activity.
Conclusions
Compelling evidence now exists that cholesterol is an
important component of lipotoxicity of islets and may
contribute to β-cell dysfunction in type 2 diabetes. The role
of ABCA1 in β-cell function, initially established in mice
and in vitro, has now been extended to humans. Further
studies of glucose metabolism in patients with Tangier
disease will provide significant new information in this
regard. Disordered cholesterol metabolism can now be seen
as a link between the pathogenesis of type 2 diabetes and its
major macrovascular complication, atherosclerotic cardio-
vascular disease. The available data point to β-cell ABCA1
as a potential therapeutic target in type 2 diabetes. As our
understanding of the precise mechanisms regulating islet
cholesterol metabolism increases, new opportunities may
arise for the treatment of β-cell dysfunction in diabetes.
Disclosure This work was supported by grants from the Canadian
Institutes of Health Research to Drs. Verchere and Hayden. Dr.
Verchere is an Michael Smith Foundation for Health Research Senior
Scholar. Dr. Hayden holds a Canada Research Chair in Human
Genetics and is a University Killam Professor. No other potential
conflicts of interest relevant to this article were reported.
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