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High-sugar diets, type 2 diabetes and Alzheimer’s disease
Paula I. Moreira
Laboratory of Physiology, Faculty of Medicine, University of Coimbra, 3000-354
Coimbra Portugal & Center for Neuroscience and Cell Biology, University of Coimbra,
3004-517 Coimbra, Portugal
Correspondence to: Paula I. Moreira, Laboratory of Physiology - Faculty of Medicine,
University of Coimbra, 3000-354 Coimbra, Portugal
Tel: 351-239480012
Fax: 351-239480034
Email: venta@ci.uc.pt / pimoreira@fmed.uc.pt
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Purpose of review: Recent findings suggest that high-sugar diets can lead to cognitive
impairment predisposing to neurodegenerative disorders such as Alzheimer’s disease
(AD). This paper discusses metabolic derangements induced by high-fructose/sucrose
diets and presents evidence for the involvement of insulin resistance in sporadic AD
pathogenesis.
Recent findings: There has been much concern regarding the role of dietary sugars
(fructose/sucrose) in the development of type 2 diabetes (T2D). Accumulating evidence
has also demonstrated a connection between T2D and AD. The risk for developing
T2D and AD increases exponentially with age and having T2D increases the risk of
developing AD.
Summary: The incidence of T2D increased dramatically over the last decades mainly
due to western lifestyle factors such as lack of exercise and high calorie diets. In fact,
high-sugar diets are thought to promote weight gain and insulin resistance
predisposing to T2D. To aggravate this scenario, it has been consistently shown that
T2D is a risk factor for AD and both disorders share similar demographic profiles, risk
factors, and clinical and biochemical features (e.g. insulin resistance). Therefore,
dietary changes can significantly reduce the risk of T2D and AD and thereby increase
the quality of life and improve longevity.
Keywords: Alzheimer’s disease, high-sugar diets, insulin resistance, type 2 diabetes
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Introduction
Type 2 diabetes (T2D) accounts for about 90% of all cases of diabetes mellitus
and is characterized by a reduction in the ability of insulin to stimulate glucose
utilization (insulin resistance) and inadequate pancreatic -cell insulin secretion in
response to hyperglycemia [1]. The prevalence and incidence of T2D augmented
dramatically over the last decades along with increased population obesity owing to
western lifestyle factors such as lack of exercise and high calorie diets. In fact, the
increase in sugar consumption has paralleled the increasing prevalence of obesity, and
high-sugar diets are thought to promote weight gain and insulin resistance
predisposing to T2D. As diabetes progresses without appropriate treatment, many
complications occur, which leads to increased risk of mortality. Among other
complications, T2D is related with a greater rate of cognitive deficits in comparison with
the general population. Studies of cerebral structure demonstrated a pronounced
cortical, subcortical, and hippocampal atrophy in T2D patients. Accumulating evidence
also shows that T2D is a risk factor for dementia, particularly vascular dementia and
Alzheimer’s disease (AD). Interestingly, both T2D and AD share similar demographic
profiles, risk factors and, clinical and biochemical features [2].
AD, the most common cause of dementia among older people, typically begins
with a subtle decline in memory and progresses to global deterioration in cognitive and
adaptive functioning. The neuropathological features associated with the disease
include the presence of extracellular senile plaques (SPs), intracellular neurofibrillary
tangles (NFTs) and the loss of basal forebrain cholinergic neurons that innervate the
hippocampus and the cortex. SPs are formed mostly from the deposition of amyloid
(A), a peptide generated through the proteolytic cleavage of amyloid precursor protein
(APP) by the - and -secretases. NFTs are mainly composed of neurofilaments and
hyperphosphorylated tau protein. A history of stroke can increase the prevalence of the
disease among elderly patients. The risk is highest when stroke is concomitant with
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atherosclerotic vascular risk. Hypoxia is a direct consequence of hypoperfusion, a
common vascular component among the AD risk factors, and may play an important
role in the pathogenesis of this disorder. The great majority of all AD cases are
sporadic in origin, with old age and T2D considered main risk factors [3].
This review focus on the effects of high-sugar diets in the development of T2D
(and obesity), and how T2D, specifically insulin resistance, increases the risk of AD.
Type 2 diabetes: the influence of high-sugar diets
Unhealthy lifestyle, characterized by caloric overconsumption and physical
inactivity, is a risk factor for insulin resistance and T2D, often associated with obesity.
Foods containing simple sugars are prototypes of high-glycemic index foods that are
consumed in significant amounts worldwide. In fact, fructose found in sucrose and
high-fructose corn syrup has been the subject of intense debate. Products containing
fructose are preferred by consumers and cooks over those containing only glucose,
due to the intrinsically greater sweetness of fructose and its ability to improve the
texture and appearance of baked goods. As a result, fructose and high-fructose corn
syrup are present in several beverages (e.g. soda, sport and energy drinks) and food
(e.g. snacks, sauces, processed meats) that are highly consumed in developed and
developing countries.
An elevated consumption of sugar-enriched foods promotes insulin resistance
for two main reasons: induction of weight gain due to their high energy content and lack
of satiating effect, and higher postprandial blood glucose and insulin levels [4]. In fact,
high fructose intake and subsequent metabolism increase the synthesis of triglycerides,
which are assembled into very low-density lipoproteins (VLDL), and glucose that is
released into circulation culminating in increased plasma glucose. This increase
stimulates the secretion of insulin by the pancreatic cells. Insulin is an anabolic
hormone and, in an organism in positive energy balance, determines an increase in the
deposition of fat in adipose tissue and other organs.
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Fructose-enriched diets promote an increase in plasma triglycerides mainly by
the stimulation of hepatic de novo lipogenesis, and decrease in VLDL-triglyceride
clearance [5]. The increase in plasma triglyceride induced by fructose is significantly
attenuated in women supporting the idea that estrogen/progesterone may exert a
protective effect [6,7]. It was reported that 1 week of a high-fructose, hypercaloric diet
led to ectopic fat deposition in liver and skeletal muscle [8], and a high-fructose diet
maintained during 10 weeks impaired glucose homeostasis in overweight individuals
[9]. A recent randomized controlled trial [10●●] showed that even moderate amounts of
fructose and sucrose during a period of 3 weeks significantly alter hepatic insulin
sensitivity and lipid metabolism in healthy normal-weight male volunteers, compared
with similar amounts of glucose. High fructose intake has been shown to increase
energy intake via an increase in orexigenic signaling peptides levels in the
hypothalamus [11]. Recently, Page and collaborators [12●●], using arterial spin labeling,
a magnetic resonance imaging technique, quantified regional cerebral blood flow as a
surrogate for brain activity in 20 healthy, young, normal-weighed subjects before and
after drinking a 75g solution of pure glucose or fructose. The authors observed that the
hypothalamic brain signal generated after fructose ingestion was statistically different
from that generated by glucose ingestion. This difference was accompanied by a
sensation of satiety and fullness after glucose, but not fructose, ingestion [12●●]. A
previous study based on blood oxygenation level dependent functional brain magnetic
resonance imaging (BOLD fMRI) also showed that in normal weight humans, cortical
responses to infused glucose are opposite to those of fructose [13]. These findings
support the idea that glucose and fructose modulate different neurobiological
pathways, and, in the case of fructose, it stimulates pathways involved in food intake.
In rodents there is overwhelming evidence that high-sugar diets decrease both
liver and muscle insulin sensitivity predisposing to obesity, diabetes, and dyslipidemia
[14]. Similarly, young adult male baboons exposed to a high-sugar/high-fat diet
presented increased body fat and triglyceride levels, altered adipokine levels, and
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impaired glucose metabolism [15]. The adverse effects of fructose on glucose
metabolism are closely linked to alterations in lipid metabolism. In rats, 6 weeks of
high-fructose diet promoted an increase in plasma VLDL-triglycerides levels and
intrahepatic fat content, while intramuscular fat content increased after 3 months of
high-fructose diet [14]. Interestingly, hepatic insulin resistance was observed early after
the introduction of high-fructose diet, while the muscle insulin resistance appeared
latter [14]. These results suggest that fructose-induced insulin resistance is closely
linked to ectopic lipid deposition and tissue-specific lipotoxicity. Moreover, mice fed a
20% sucrose solution during 7 months presented hyperglycemia, glucose intolerance,
hyperinsulinemia, hypertriglyceridemia, and increased glycated hemoglobin and body
weight [16].
Altogether these studies show that high-sugar diets promote several metabolic
derangements predisposing to T2D and/or obesity.
Insulin resistance – A link between type 2 diabetes and Alzheimer’s
disease
Insulin, long known as an important regulator of blood glucose levels, plays key
roles in the brain. This hormone contributes to several neurobiological processes, in
particular energy homeostasis and cognition.
Accumulating evidence supports the involvement of impaired insulin signaling in AD
etiopathogenesis: 1) reduced insulin levels and insulin receptor (IR) expression were
observed in AD brains, 2) increasing AD Braak stage was associated with
progressively reduced expression levels of insulin, insulin growth factor (IGF) 1 and 2
and respective receptors, 3) AD patients show increased fasting plasma insulin levels,
decreased cerebrospinal fluid (CSF) insulin levels, and/or decreased CSF/plasma
insulin ratio, besides increased A levels, which suggest a decrease in insulin
clearance that may provoke an elevation of plasma A levels, 4) disruption of brain
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insulin signaling by the intracerebroventricular administration of the diabetogenic drug
streptozotocin (STZ) leads to the development of numerous behavioral, neurochemical
and structural features that resemble those found in human sporadic AD, and 5)
administration of insulin and glucose enhances memory of AD patients [for review see
1●,2●].
Evidence from animal studies
Animal studies show that high-fructose diets induce rapid insulin resistance,
compensatory hyperinsulinemia and memory impairment. Rats exposed to a high-
fat/high-sucrose diet presented impaired memory due to an alteration in the signaling
pathways involved in hippocampal neuronal plasticity [17]. A subsequent study
demonstrated that sucrose- and fat-enriched diets promoted a weight gain and
deposition of visceral fat in rats, but only animals fed with the sucrose diet displayed
deficits in long-term spatial memory [18]. It was also shown that rats fed diets
supplemented with high-fructose corn syrup were more insulin resistant and cognitively
impaired, due to a reduction in dendritic spine density and hippocampal levels of brain
derived neurotrophic factor [19]. Hamsters fed with 60% fructose presented a decrease
in neuronal insulin signaling in the cerebral cortex and hippocampus, and a subsequent
impairment of synaptic function [20]. Overall, this evidence suggests that high-fructose
diets-induced insulin resistance is linked to cognitive decline and predisposes to
neurodegeneration. In fact, the intake of sucrose-sweetened water was shown to in-
duce insulin resistance and exacerbate memory deficits and amyloidosis in a mouse
model of AD [21]. In the same line, a previous study from our laboratory showed that
3xTg-AD and sucrose-induced diabetic mice presented a similar profile of behavioral
and cognitive alterations, vascular anomalies, oxidative imbalance and mitochondrial
abnormalities [16●●,22●●]. Interestingly, sucrose-induced diabetic mice, showed a
significant increase in the levels of A in brain cortex and hippocampus [16●●,22●●],
supporting the idea that metabolic alterations induced by sucrose intake increase the
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risk of AD. AD mice exposed to a dietary regimen that induced insulin resistance and a
hyperinsulinemic state induced a significant accumulation of A and reduction in the
levels of insulin-degrading enzyme (IDE; ubiquitously expressed zinc-metalloprotease
involved in the clearance of insulin and A) [23]. Conversely, treatment with
rosiglitazone, an insulin sensitizer, was shown to reduce A levels and improve
learning and memory deficits [24] suggesting that insulin sensitizers might increase
insulin signaling and decrease the levels of insulin available to compete with A for
degradation by IDE.
The regulation of tau protein phosphorylation is another potential mechanism by
which insulin links T2D to AD. Both chronic peripheral hyperinsulinemia and central
insulin resistance can modulate tau protein phosphorylation. In IRS2-disrupted mice, a
model of T2D, an accumulation of NFTs was detected in the hippocampus [25] and the
neuronal/brain-specific deletion of IR in mice (NIRKO mice) led to tau protein
hyperphosphorylation [26]. Meanwhile, the pattern of tau protein phosphorylation
differed between NIRKO and IRS-2 knockout mice, suggesting that not only insulin
resistance, but also hyperinsulinemia could mediate site-specific, differential tau protein
phosphorylation. In fact, Freude and collaborators [27] found that peripherally injected
insulin directly targets the brain and causes rapid cerebral IR signal transduction and
site-specific tau protein phosphorylation. Of note, in insulin-stimulated NIRKO mice,
cerebral IR signaling and tau protein phosphorylation were completely abolished [27].
These results indicate that tau protein modification caused by insulin dysfunction and
hyperglycemia may contribute to the increased incidence of AD in diabetic subjects.
Loss of insulin-mediated activation of phosphatidylinositol 3-kinase (PI3-K) and
subsequent reduction of phosphorylation of Akt and glycogen synthase kinase (GSK)-
3 are reported to result in a substantial increase in the levels of phosphorylated tau
protein in the brains of neuron specific IR knockout mice [26]. Insulin also regulated
soluble APP release via PI3-K-mediated pathway, suggesting that PI3-K involvement in
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APP metabolism may occur at vesicular trafficking level [28]. It was also shown that
GSK-3 inhibition attenuated APP processing and inhibited hyperphosphorylated tau
protein-associated neurodegeneration [28].
Evidence from human studies
Evidence shows that individuals with T2D have nearly a twofold higher risk of
AD, independent of the risk for vascular dementia, than non-diabetic individuals [29].
Prospective and cross-sectional analyses suggest that diabetes may accelerate the
onset of AD, rather than increasing the long-term risk [30]. In fact, cross-sectional
studies report more frequent structural brain lesions, greater cortical atrophy and more
white matter hyperintensities in people with diabetes compared with non-diabetic
controls [31-33]. These studies have found relationships between these structural
abnormalities and underlying hypertension and vascular disease [31], but also
diabetes-specific parameters such as diabetes duration and fasting glucose levels [33].
These findings support the idea that diabetic subjects are more prone to develop
dementia, particularly AD.
The impairment of insulin signaling was demonstrated by postmortem studies
that revealed that mitogen-activated protein kinase (MAPK) activation occurs at very
early stages (Braak stages IV-V) [34]. A correlation between Akt activity/protein levels
and Braak staging has also been documented in human AD postmortem analyses,
which indicates a time-dependent and insulin-stimulated PI3-K signaling-dependent
pattern of changes [35].
Altogether, animal and human studies clearly show that central insulin resistance
contributes to the pathogenesis of AD.
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Conclusion
There is no doubt that high-sugar diets provoke drastic metabolic derangements
predisposing to obesity, dyslipidemia and T2D; conditions that have reached epidemic
proportions. T2D increases the incidence of life-threatening complications including an
enhanced risk of cognitive decline and dementia. In fact, accumulating evidence shows
that T2D is a main risk factor for AD, with insulin signaling abnormalities playing a key
role. Similarly to T2D, also AD is growing exponentially in our aging society. Because
many metabolic disorders arise from unhealthy diets and sedentary lifestyles, we have
in our hands (or mouth and feet!) the opportunity to reverse this dark scenario.
Key points
1. High-sugar (fructose/sucrose) diets lead to metabolic derangements predisposing to
T2D, normally associated with obesity.
2. T2D is associated with an increased risk of cognitive impairment and dementia,
particularly AD.
3. Insulin resistance is a common feature between T2D and sporadic AD.
Acknowledgements
The authors’ work is supported by the Fundação para a Ciência e a Tecnologia (FCT)
and Fundo Europeu de Desenvolvimento Regional (FEDER) (PTDC/SAU-
NEU/103325/2008) and Quadro de Referência Estratégico Nacional (QREN DO-IT –
DIAMARKER Project).
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Legends
Figure 1. Insulin resistance and Alzheimer’s disease. Central insulin resistance
(impairment of brain insulin signaling) is closely associated with the two
neuropathological hallmarks of Alzheimer’s disease; senile plaques (SPs) and
neurofibrillary tangles (NFTs). Under hyperinsulinemic conditions, insulin competes
with amyloid protein (A) for insulin-degrading enzyme (IDE), leading to the
accumulation of A and deposition of SPs. Impaired insulin/insulin receptor (IR)
signaling culminates in loss of insulin-mediated activation of phosphoinositide 3-kinase
(PI3-K)/Akt pathway, and subsequent dephosphorylation of glycogen synthase kinase-
3 (GSK-3), which potentiates tau protein hyperphosphorylation and formation of
NFTs. Overall, the impairment of brain insulin signaling is a contributing factor in AD
pathogenesis. IRS – insulin receptor substrates.
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