Insulin metabolism and the risk of Alzheimer disease The Rotterdam Study

Department of Epidemiology, Erasmus MC University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
Neurology (Impact Factor: 8.29). 11/2010; 75(22):1982-7. DOI: 10.1212/WNL.0b013e3181ffe4f6
Source: PubMed


Diabetes mellitus has been associated with an increased risk of Alzheimer disease (AD), but how it exerts its effect remains controversial. Possible pathophysiologic mechanisms are glucose toxicity and a direct effect of insulin on amyloid metabolism. Most studies had short follow-up, and longer-term effects of diabetes on AD risk are unknown. We investigated whether fasting glucose and insulin levels and insulin resistance are associated with the risk of AD and whether this risk is constant over time.
The study was based on 3,139 participants of the Rotterdam Study, a population-based cohort study. All subjects were free from dementia, did not have a history of diabetes, and had fasting levels of glucose and insulin measured at baseline. Insulin resistance was estimated with the homeostasis model assessment. We investigated how fasting glucose, insulin, and insulin resistance are related to the risk of AD in 3 different strata according to time-to-event, using Cox proportional hazards models.
During follow-up, 211 participants developed AD, 71 of them within 3 years of baseline. Levels of insulin and insulin resistance were associated with a higher risk of AD within 3 years of baseline. After 3 years, the risk was no longer increased. Glucose was not associated with a higher risk of AD. There was no interaction of APOE ε4 carriership and insulin metabolism on the risk of AD.
Our findings suggest that insulin metabolism influences the clinical manifestation of AD only within 3 years.

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Available from: Monique MB Breteler, Aug 20, 2014
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    • "In recent years, a growing body of evidence suggests a link between type 2 diabetes and Alzheimer's disease (AD) (Schrijvers et al. 2010). It has been demonstrated that insulin receptors in the brain are desensitized, and the insulin signal to stimulate cell metabolism and cell repair seems to be impaired in AD patients. "
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    ABSTRACT: Recent studies suggest a possible link between type 2 diabetes and Alzheimer’ s disease (AD). Glucogan-like peptide 1 (GLP-1) facilitates insulin release from pancreas under hyperglycemic conditions. In addition to its metabolic effects, GLP-1 and its long-lasting analogs, including exenatide can stimulate neurogenesis and improve cognition in rodent AD model. The aim of the present study was to investigate the effects of exenatide on hippocampal cellularity, cognitive performance and inflammation response in a rat model of AD. Fourteen rats were used to create AD model using intracerebroventricular (ICV) streptozotocin (STZ) infusion while 7 rats were administered 0.9% NaCl only (sham-operated group). Following stereotaxic surgery, STZ received rats were randomly distributed into two groups, and treated with either saline or exenatide 20 µgr/kg/day through intraperitoneally for two weeks. Then, cognitive performance (passive avoidance learning), brain tumor necrosis factor alpha (TNF-α) levels, choline acetyltransferase (ChAT) activity and hippocampal neuronal count were determined. While the brain TNF-α levels were significantly high in the saline-treated STZ group, exenatide treatment suppressed the increase in TNF-α levels. Saline-treated STZ group showed reduced ChAT activity compared to sham group. However, exenatide significantly preserved brain ChAT activity. The cognitive performance was also impaired in saline group while exenatide improved memory in rats. Moreover, exenatide treatment significantly prevented the decrease in hippocampal neurons. Overall, the results of the present study clearly indicated exenatide might have beneficial effects on impaired cognitive performance and hippocampal neuronal viability in AD by suppressing the inflammation response and increasing cholinergic activity.
    Full-text · Article · Sep 2015 · European Journal of Pharmacology
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    • "Type 2 diabetes (T2DM) is a risk factor for AD and the two diseases share several biochemical features of metabolic dysfunction, in particular pertaining to insufficient central and peripheral insulin function. Accordingly, molecular signatures of impaired insulin function has been consistent findings in AD which pertains to brain insulin deficiency, central insulin resistance, as well as elevated fasting plasma insulin levels and impaired peripheral insulin responses [4] [5] [6] [7] [8]. Furthermore, a recent proof-of-concept clinical trial in AD has demonstrated memory-improving effects of increased central insulin exposure obtained by intranasal insulin administration [9], which further emphasizes the emerging importance of counteracting deficient insulin-associated neurotransmission in the treatment of AD neuropathology and cognitive deficits. "
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    ABSTRACT: Recent studies indicate that glucagon-like peptide 1 (GLP-1) receptor agonists, currently used in the management of type 2 diabetes, exhibit neurotrophic and neuroprotective effects in amyloid-β (Aβ) toxicity models of Alzheimer's disease (AD). We investigated the potential pro-cognitive and neuroprotective effects of the once-daily GLP-1 receptor agonist liraglutide in senescence-accelerated mouse prone 8 (SAMP8) mice, a model of age-related sporadic AD not dominated by Aβ plaques. Six-month-old SAMP8 mice received liraglutide (100 or 500 μg/kg/day, s.c.) or vehicle once daily for 4 months. Vehicle-dosed age-matched 50% back-crossed as well as untreated young (4-month-old) SAMP8 mice were used as control groups for normal memory function. Vehicle-dosed 10-month-old SAMP8 mice showed significant learning and memory retention deficits in an active-avoidance T-maze, as compared to both control groups. Also, 10-month-old SAMP8 mice displayed no immunohistological signatures of Aβ plaques or hyperphosphorylated tau, indicating the onset of cognitive deficits prior to deposition of amyloid plaques and neurofibrillary tangles in this AD model. Liraglutide significantly increased memory retention and total hippocampal CA1 pyramidal neuron numbers in SAMP8 mice, as compared to age-matched vehicle-dosed SAMP8 mice. In conclusion, liraglutide delayed or partially halted the progressive decline in memory function associated with hippocampal neuronal loss in a mouse model of pathological aging with characteristics of neurobehavioral and neuropathological impairments observed in early-stage sporadic AD.
    Preview · Article · Apr 2015 · Journal of Alzheimer's disease: JAD
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    • "Hyperglycemia may also impact amyloid burden independent of IR. Given that type 2 diabetes increases AD risk [7], larger studies of amyloid binding in patients with frank diabetes, both treated and untreated, will be needed to further examine these associations. "
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    ABSTRACT: Background Insulin resistance (IR) increases Alzheimer's disease (AD) risk. IR is related to greater amyloid burden post-mortem and increased deposition within areas affected by early AD. No studies have examined if IR is associated with an in vivo index of amyloid in the human brain in late middle-aged participants at risk for AD. Methods Asymptomatic, late middle-aged adults (N = 186) from the Wisconsin Registry for Alzheimer's Prevention underwent [C-11]Pittsburgh compound B (PiB) positron emission tomography. The cross-sectional design tested the interaction between insulin resistance and glycemic status on PiB distribution volume ratio in three regions of interest (frontal, parietal, and temporal). Results In participants with normoglycemia but not hyperglycemia, higher insulin resistance corresponded to higher PiB uptake in frontal and temporal areas, reflecting increased amyloid deposition. Conclusions This is the first human study to demonstrate that insulin resistance may contribute to amyloid deposition in brain regions affected by AD.
    Full-text · Article · Jul 2014 · Alzheimer's and Dementia
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