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.
    European Journal of Pharmacology 09/2015; DOI:10.1016/j.ejphar.2015.09.024 · 2.53 Impact Factor
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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.
    Alzheimer's and Dementia 07/2014; 11(5). DOI:10.1016/j.jalz.2014.03.011 · 12.41 Impact Factor
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    • "In the Rotterdam study, a non-diabetic population cohort study, it was reported that IR assessed by homeostasis model assessment ratio was associated with the onset of AD within 3 years.66 A Japanese epidemiological study, the Hisayama study, reported that IR was associated with AD pathology.67 "
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    ABSTRACT: Type 2 diabetes mellitus (T2DM) is a risk factor for cognitive dysfunction and dementia in the elderly. T2DM has been thought to be associated with vascular diseases, eventually leading to vascular dementia, but recent studies have established that T2DM is also associated with Alzheimer's disease (AD). With the increase in the number of elderly individuals with T2DM, the number of diabetic patients with cognitive dysfunction has been increasing. T2DM may accelerate AD-associated pathologies through insulin resistance. Vascular pathologies may also be associated with cognitive dysfunction and dementia in T2DM subjects. Several other mechanisms also seem to be involved in T2DM-related cognitive dysfunction. More investigations to clarify the association of T2DM with cognitive impairment are warranted. These investigations may help to increase our understanding of AD and open a new door to the development of therapeutics. Recent pharmaceutical advancement in T2DM treatment has resulted in the availability of a wide range of antidiabetics. Some evidence has suggested that antidiabetic therapies help to prevent cognitive dysfunction. At present, however, the optimal level of blood glucose control and the best combination of medications to achieve it in terms of cognitive preservation have not been established. More investigation is warranted. Cognitive dysfunction is an emerging new complication of T2DM that requires further study.
    Clinical Interventions in Aging 06/2014; 9:1011-1019. DOI:10.2147/CIA.S48926 · 2.08 Impact Factor
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