The objective of this study was to evaluate the possible association between metabolic syndrome, insulin resistance and dementia, all of them precursors of type 2 diabetes and cognitive dysfunction.
Data from the Prospective Epidemiological Risk Factor (N = 2103), a prospective study of old women in Denmark were used.There it was found that the alteration of fasting blood glucose was associated with the 44% more likely to suffer cognitive dysfunction.
In addition, women with homa-ri greater than the threshold value (Homa-Ir & GT; 2,6) had 47% more likely to suffer cognitive dysfunction.These associations could indicate that a significant proportion of cases of dementia in women could be prevented with effective prevention and normalization of insulin homeostasis.
► Introduction
The sedentary western lifestyle generated an epidemic increase in obesity closely linked to type 2 diabetes (1,2).Likewise, the prevalence of cognitive dysfunction and dementia is on the increase and epidemiological studies suggest an association between type 2 diabetes and the increased risk of dementia and cognitive dysfunction (3).
Metabolic syndrome (SMET) is considered a precursor to type 2 diabetes (4);Central obesity and insulin resistance (RI) are recognized as important causal factors in the pathogenesis of the SMET (5), so that over several years a precursor state of dementia could be developed.
The prolonged prodromic phases that characterize dementia and type 2 diabetes hinder the study of possible risk factors and their temporal relationship (6.7) and in studies with brief follow -up the alleged relationships may not be reliable.In this way, publications on the association between type 2 diabetes, SMET and cognitive dysfunction are something contradictory.
Until recently, the brain was considered an insulin insensitive organ;However, it was currently accepted that insulin, part of peripheral origin, acts through its own receptors in the brain and controls cognitive functions and memory (8).Thus it could be that the RI is a disorder that affects peripheral and central receptors and the brain IR is part of a preclinical state of Alzheimer's disease (EA) (9).The temporal relationship between the SMET, the RI and the cognitive dysfunction and the dementia has recently been questioned (10,11).
This prompted the authors to carry out this work, in which data obtained as part of The Prospective Epidemiological Risk Factor (perf), a prospective study of Danish postmenopausal women (12), were evaluated in order to analyze the hypothesis about existenceof a temporal relationship between the SMET, the IR and the cognitive dysfunction.PER -study data were used to determine if there is an association between the SMET or the IR and the cognitive deficiency in a follow -up 15 years later, carried out only with subjects without signs of cognitive dysfunction in the initial exam (n = 1759).
► Methods
♦ Studio Prospective Epidemiological Risk Factor
The Prospective Epidemiological Risk Study Factor (perf) an observation study, prospective, was designed in order to obtain information about age -related diseases in postmenopausal women.The initial exam (Perf I) was made between 1999 and 2001 (n = 5855).Since 2013 and for 14 months the follow -up of 2103 participants (PERF II) (12) was carried out.
♦ Study population
This study was based on all the patients who finished the follow -up exam, PERF II (N = 2103) and the sample to analyze was identified.All women were included with valid tests at the beginning and monitoring.The qualified women for the analysis were 1759.
♦Cognitive dysfunction
The cognitive function at the beginning and the monitoring was evaluated with two brief cognitive investigation tests.The Short Blessed Test (SBT) is a test of six elements that evaluate orientation, concentration and memory.The score is from 0 to 28 and the lowest scores indicate better results.A threshold ≥10 was identified as cognitive dementia deficiency (13).The category fluency test (CFT) measures normal verbal fluidity.The subjects examined should name as many animals as possible in 60 seconds.The highest scores indicate better results and the recommended threshold for dementia is ≤14 (14).
♦ Metabolic syndrome.Initial values
The SMET was defined using a modified version of that recommended by the International Diabetes Federation (15).In addition to the criterion of incorporation of central obesity, the subjects had to have two or more of the following risk factors:
Increase in triglycerides (& GT; 1.7 mmol/L)
Decrease in HDL cholesterol (& lt; 1.29mmol/L)
Increase in fasting blood glucose (& GT; 5.6 mmol/l) or previous diabetes 2 diagnosis
Hypertension (systolic pressure & GT; 130 mmHg or diastolic & GT; 85 mmHg or HTA in treatment)
The criterion of incorporation of central obesity was only defined by a body mass index (BMI) & GT; 30 kg/m2 and as the treatment of hyperlipidemia was not part of the questionnaire at the beginning, it was not possible.
People without SMET were divided into three groups: i) people with BMI & GT; 30kg/m2, and a single more risk factor;ii) People with BMIG/m2, but with 1-4 risk factors for SMET and III) people without any risk factor for SMET.
♦ The homeostatic model to evaluate the RI
The homeostatic model to evaluate the RI (HOMA-IR, by the acronym of English) was used to evaluate the degree of RI (16).It was calculated by the values of ease glycemia multiplied by the insulin concentration divided by the constant 22.5.
► Results
Of the 1759 women included in the study, 136 had cognitive dysfunction according to the SBT, while 326 were classified with cognitive dysfunction when determined by CFT.A total of 80 people showed signs of cognitive dysfunction in both tests.
♦ Characteristics of the study population
The average age at the beginning was 68 years.The group without cognitive insufficiency was the youngest and the group of people with cognitive problems in both tests was the oldest.
The relationship between the SBT and CFT scores was negative (Rho = -0,294 [-0.336 to -18 0.250], P&T 0.0001).
♦ Association between metabolic syndrome, insulin resistance and cognitive dysfunction
Fasting hyperglycemia was associated with CFT alteration that suggests that hyperglycemia increases the risk of cognitive dysfunction.Having one to five metabolic risk factors did not significantly alter the risk of cognitive dysfunction in follow -up in relation to people without risk factors.
In people with the worst metabolic characteristics, which had the five risk factors for SMET, the risk of cognitive dysfunction in verbal fluency was three times higher (or 3.09, 95% IC 1.09-8,69) inRelationship with subjects who had none of SMET's risk factors.However, the SMET was not associated with increasing the risk of cognitive dysfunction in follow -up.
The RI was associated with increased the risk of cognitive dysfunction, calculated as well as CFT and with the combination of the SBT and the CFT.The risk of cognitive dysfunction increased between 8 and 10% for each increase in the HOMA-IIR index.
► Discussion
Fasting blood glucose was the only strongly associated metabolic risk factorWith cognitive dysfunction.
This study evaluated the temporal relationship between biomarkers and the precursors of type 2 diabetes and cognitive dysfunction and was specifically estimated if the SMET and RI are associated with the development of cognitive dysfunction.According to data from up to 15 years, it is shown that i) patients with ease alterationcognitive.
While fasting blood glucose was specifically associated with dysfunction in the verbal fluidity test, the IR seemed to generate more global cognitive dysfunction, as determined by the combination of two brief tests of cognitive investigation.The third important data is that patients with unfavorable metabolic characteristics, reflected by the presence of several metabolic and cardiovascular risk factors, have 3 - 4 times greater chances of suffering cognitive dysfunction than those with ideal metabolic characteristics.General data suggest that the RI is more the cause than the consequence of cognitive dysfunction.
Fasting blood glucose was the only metabolic risk factor strongly associated with cognitive dysfunction.When it was evaluated with the CFT, patients with fasting glycemia alteration had 44% more probabilities of cognitive dysfunction in relation to Normaglucemic subjects.While the presence of SMET itself does not seem to cause increased risk of cognitive dysfunction, patients with unfavorable metabolic characteristics have three to four times more likely to suffer cognitive dysfunction in relation to subjects with ideal metabolic characteristics.
The Framingham cohort recently showed that women with ideal cardiovascular health, determined by a 7 -point scale proposed by the American Heart Association, are less risk of dementia, cognitive decrease and cerebral atrophy (17).Of the seven risk factors that define the ideal characteristics of cardiovascular health, four are identical or at least very similar to those that define the SMET, which suggests that cardiovascular and metabolic health are closely linked to brain health.
Peripheral insulin resistance alters insulin transport through the blood cell barrier.Insulin transport decreases due to peripheral hyperinsulinemia (18), which can contribute directly to cognitive alteration and favor EA (19,20).Recently it was pointed out that RI is a prognostic factor of worse functioning of memory due to the reduction of regional glucose cerebral metabolism (21), which endorses the IR as a risk factor for the development of cognitive dysfunction.
It is considered that the data presented in this article indicate a temporary relationship between the IR and cognitive dysfunction.However, it is not possible to rule out the possibility that dementia or cognitive dysfunction leads to a diabetic phenotype and that an alteration of insulin homeostasis, as a secondary process, can accelerate certain dementia (22).The RI can be a shared underlying pathological mechanism, since it is part of the prodromic phase of both type 2 diabetes and dementia.
The formation of amyloid substance is pathognomonic of type 2 diabetes, as well as EA: it is amyloid polypépetido in the islets of the pancreas of patients with type 2 and β-amyloid diabetes in the brain of patients with EA (23) previous studiesThey indicate an association between sleep and dementia disorders (25).
The basic mechanisms of this association are multiple and it is believed that the RI has an important function,although the causal link has not yet been clarified.The transition of menopause is associated with sleep alterations, which also increase the risk of diabetes (26,27).The link observed between the IR and cognitive dysfunction could indicate that RI is an intermediate mechanism for the causal association between sleep disorders and cognitive dysfunction.
The small, but significant relationship, between the two tests was expected and indicates that these tests are not equivalent.This was reflected in the effect of fasting blood glucose and IR on cognitive function specifically related to verbal fluidity.The functioning of verbal fluidity is linked to the areas of the frontal and temporal lobes.These areas are rich in insulin receptors and it was found that they are associated with the function of memory (28,30).There are several neuropathological disorders that affect cerebral areas related to memory, being one of them.It was found that a structural alteration of the semantic networks located in areas of the frontal and temporal lobes is characteristic of the EA even in its early stages (31,32).
The concept of precision medicine is arising in relation to the prevention and treatment of EA (33).The abundant evidence of various EA phenotypes, being one of them the metabolic phenotype, suggests that it is extremely pertinent in this field.A recent meta -analysis indicates that drugs that sensitize insulin, such as metformin and thiazoldiones, could be useful to prevent dementia in diabetic patients (34).
Evidence of studies in mice showed that the analogue of the 1 -type Liraglutide glucagon type, another insulin sensitizer, interacts directly with processes that generate amyloid plaques and neurofibrillar shells, both pathognomonic of the EA (35,36).In addition, clinical studies showed promising effects of intranasal insulin in subjects with EA and its prodrome, mild cognitive insufficiency (37,38) and also in space memory in young men.(39).
The analysis was limited to the subjects who attended the monitoring exam, therefore the selection bias can affect internal validity and question the possibility of generalizing the results, since it is known that cognitive dysfunction and dementia affect the index of the index of theabandonment.In addition, the authors based their determination of cognitive dysfunction on two brief cognitive research tests on the monitoring visit, therefore, the possibility that cognitive dysfunction in this study can be caused by reversible disorders and by theso much a wrong classification is generated.The diagnostic accuracy of the two tests in relation to dementia is excellent (40–43).
Another limitation is the lack of repeated measurements of blood glucose, insulin and cognitive functioning throughout the monitoring period.
► Conclusion
The precursors of type 2 diabetes;The alteration of fasting glycemia and the IR, are associated with increasing the risk of developing cognitive dysfunction in elderly women.In addition, patients with unfavorable metabolic characteristics are more likely to develop cognitive dysfunction than those with ideal metabolic characteristics.If the association between metabolic risk factors and cognitive dysfunction is really causal, it could suggest that a significant proportion of dementia cases in women can be prevented with the normalization of insulin homeostasis.
Summary and Comment Objective: Dr. Ricardo Ferreira
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