without diabetes. We examined prospectively relations of fasting insulin levels and insulin cretion
to cognitive decline, among healthy, community-dwelling older men without diabetes.
Methods—Fasting plasma insulin and c-peptide (insulin cretion) levels were measured in 1,353
non-diabetic men, aged 60–92 years (mean=71.3), in the Physicians’ Health Study II who participated
in cognitive testing an average of 3.3 years later. Two asssments were administered 2 years apart
(range=1.5–4.0) using telephone-bad tests (general cognition, verbal memory, and category
fluency). Primary outcomes were the Telephone interview for Cognitive Status (TICS), global
cognition (averaging all tests) and verbal memory (averaging four verbal tests). Multivariable linear
regression models were ud to estimate relations of insulin and c-peptide to cognitive decline.
Results—Higher fasting insulin was associated with wor decline on all tests, after adjustment.
Findings were statistically significant for the TICS and category fluency: e.g., the multivariable-
adjusted mean difference (95% CI) in decline for men with the highest vs. lowest insulin levels was
−0.62 (−1.15, −0.09) points on the TICS (p-trend=0.04); this difference was similar to that between
在职研究生准考证men 7 years apart in age. Similarly, there was wor decline across all tests with increasing c-peptide,evaphone
but findings were statistically significant only for global score (p-trend=0.03).
Conclusions—Higher fasting insulin and greater insulin cretion in older men may be related to
overall cognitive decline, even in the abnce of diabetes.
Keywords insulin; c-peptide; cognitive decline; dementia; diabetes BACKGROUND Type 2 diabetes – initially characterized by insulin resistance and hyperinsulinemia – has been identified as a risk factor for cognitive decline and dementia.[1] However, it is difficult to dintangle the impact of hyperinsulinemia from the effect of quelae that accompany diabetes
itlf. Thus, in prior work we addresd the relation of elevated insulin cretion and fasting
insulin levels to cognition among community-dwelling, healthy elders without diabetes. We
recently found that both elevated mid-life fasting insulin and c-peptide levels were significantly
associated with late-life cognitive decline in a large, random sample of non-diabetic women
in the Nurs’ Health Study (NHS). The relations were not affected by adjustment for
vascular factors, such as hypertension, dyslipidemia, and heart dia. However, since some
of the deleterious effects of diabetes are more rious in women than men,[2,3] our findings
comein women are not necessarily generalizable to men. Thus, in the current study, we measured
fasting plasma levels of insulin and c-peptide in a random sample of 1,353 older men without
diabetes, from the well-characterized Physicians’ Health Study II[4,5] cohort, and then related
the measures to subquent cognitive change.
METHODS
The Physicians’ Health Study
等等用英语怎么说
The Physicians’ Health Study I (PHSI) was a randomized, double-blind, placebo-controlled,
2×2 factorial trial of aspirin and beta-carotene for primary prevention of cardiovascular dia
(CVD) and cancer in men. Beginning in 1982, 22,071 U.S. male licend physicians, then aged
40–84 years, were randomized to one of four factorial groups. They were followed thereafter
annually, via mailed lf-reported questionnaires, to ascertain endpoints and lifestyle and
health-related factors.[6,7] The Physicians’ Health Study II (PHSII)[4,5] randomized trial
began in 1997 and was completed on August 31, 2007. An extension of PHSI, it examined
prevention of CVD, cancer, and age-related eye dias with vitamin supplements in 14,641
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men – of whom 7,641 were original participants of PHSI. Morbidity and mortality follow-up
in PHSII were extremely high at 95.3% and 97.7%, respectively.[4,5]
Between 1995 and 2001, blood samples were obtained from 11,133 (76%) of the 14,641 PHS II participants. Participants were nt blood collection kits containing the following: (a ) 3EDTA and 3 citrate tubes, (b ) a gel-filled freezer pack, (c ) a completed overnight courier air bill, and (d ) written instructions and other supplies needed for venipuncture. Specimens were nt to our laboratory in freezer packs within 24 hours of blood draw. Once received, samples were fractionated into plasma, red blood cells, and buffy coat, and then frozen at −170°C. The entire process was completed swiftly to ensure that samples were frozen within 30 to 36 hours after venipuncture; precautions weretaken to prevent thawing or warming of specimens during storage.[8,9]Ascertainment of Plasma Insulin and C-peptide Levels Using stored blood samples obtained after ≥8-hour fast, we measured plasma insulin, using a radioimmunoassay specific for insulin (Linco, St. Louis, MO) bad on an antirum with less than 1% cross-reactivity for proinsulin and des-31, 32-proinsulin, and plasma c-peptide, using antirum M1230 in an alcohol precipitation non-equilibrium assay[10] with reagents provided by Diagnostic Systems Laboratory (Webster, TX). The assays were conducted in a single batch.Aliquots from a pool of quality-control (QC) plasma were randomly inrted into the batch of sa
mples. Intra-assaycoefficients of variation (CVs) for insulin and c-peptide from the 57blinded QCpairs were 6.8% and 7.2%, respectively.Cognitive Function Asssment Starting in 1998, cognitive testing began among 6,773 eligible PHSII participants aged 65 years or older. There was 88% participation (5,953 men) among tho eligible. A cond wave of testing was conducted 2 years later, with 88% follow-up achieved among tho who completed baline testing.[11]
The cognitive interview consisted of five tests: (1) Telephone Interview for Cognitive Status
(TICS); (2) immediate and (3) delayed recall trials of the East Boston Memory Test (EBMT);
(4) delayed recall trial of the TICS 10-word list; and (5) category fluency. The TICS (scores
range from 0–41 points)[12] is a telephone-administered instrument similar to the Mini-Mental
State Examination[13]; it has high reliability and validity for measuring general cognition.
stationery是什么意思[12] The EBMT[14] is a verbal memory (paragraph recall) task and involves immediate and
15-to-20-minute delayed recalls (scores range from 0–12 points). The 20-minute delayed recall
of the TICS 10-word list also asss verbal memory (scores range from 0–10 points). Lastly,
in the category fluency test, subjects name as many different animals as possible in one minute.
Category fluency captures language, and becau it involves abstract conceptualization and
strategy, it also maps to the domain of executive function.[15] All tests were conducted over
初中英语教案设计the phone by trained interviewers blind to study hypothes.
Reliability and validity of this telephone method have been established.[16] Thirty-day test-
retest reliability (r=0.7) and inter-rater reliability (r ≥.95 for each test) are high. The global score
from the telephone battery correlated strongly (r=0.81) with a global score generated from 21
in-person neuropsychological tests. Furthermore, recent validation work demonstrated that low
scores on the telephone-bad global score were significantly associated with an 8-fold risk of
dementia diagnosis by blinded neurologists.
Measurement of Covariates and Potential Confounders
Information on a variety medical conditions (e.g., hypertension, diabetes), lifestyle factors
(e.g., smoking, exerci, alcohol u) and medications (e.g., elevated cholesterol treatment)
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was obtained from the annual mailed lf-report questionnaires.[17] Self-reports have proven
highly accurate among male health professional participants.[17,18]
潍坊日向友好学校
Determination of sample for Analysis We measured insulin and c-peptide in a random sample of 1,353 PHSII cognitive study participants who had provided blood samples and had no lf-reported history of diabetes as of the time of their first cognitive interview. For analys of fasting insulin, the sample included 1,314 participants, as 39 men had insulin levels below the assay limit of detection (2 μIU/mL).Informed connt was obtained from all participants. The current study and the overall PHSII study were approved by the Institutional Review Board of Brigham and Women’s Hospital (Bo
ston, MA).Statistical Analysis Study outcomes—Primary outcomes were general cognitive function and verbal memory,a strong predictor of Alzheimer dia (AD).[19,20] For asssing general cognition, we considered the TICS and the global score combining all 5 cognitive tests. This global score was calculated by averaging the z-scores from each test. Verbal memory was calculated by combining results of the verbal memory tests (immediate and delayed recalls of the EBMT and 10-word list), also using z-scores. Composite scores are regularly ud in cognitive rearch [21,22], as they integrate information from a variety of sources.We examined category fluency as a condary outcome, as executive function is related to vascular factors[23] and is of interest in considering possible cognitive effects of higher levels of insulin or c-peptide.Overall Analysis—Distributions of insulin and c-peptide were found to be verely right-skewed. Of note, we had previously identified only mild skew of c-peptide in the PHS cohort
when blood samples were taken at a mean age of 57 years.[24] Thus, distributions in the prent
study of PHS men with mean age=71.3 years (range=60–92) at blood draw were consistent
with tho of men in the Honolulu-Asia Aging Study[25], who had a mean age=77 years at
blood draw.
Given the non-normal distributions, insulin and c-peptide values were natural-log-
transformed. For analysis, we then created four categories, according to distance (log-SD) from
日语培训班机构the log-mean[25]: 1) values less than one log-SD below the log-mean, 2) values below the log-
mean but within one log-SD, 3) values above the log-mean but within one log-SD, 4) values
greater than one log-SD above the log-mean. We ud linear regression models to estimate the
age- and multivariable-adjusted mean differences in cognitive change across the four
categories. Categorical analys allowed us to examine whether an inver U-shaped relation
egyptianmay exist between insulin measures and cognitive change, which has been reported.[25] Since
no U-shaped relations were obrved, we tested for linear trends by examining insulin and c-
peptide as continuous variables, where the unit of analysis was a one log-SD increa in insulin
or c-peptide.
All statistical analys were performed using SAS©, version 9.1 (SAS Institute, Inc., Cary,
NC, USA). Statistical tests were two-sided with alpha level t at 0.05.
Analys of covariates and potential confounders—In linear regression models, we
included the following: age (years), history of hypertension (yes, no), history of dyslipidemia
(yes, no), history of confirmed major CVD event (heart attack or stroke – yes/no), history of
depression (lf-reported diagnosis of depression or antidepressant treatment – yes/no),
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cigarette smoking (never, current, past), alcohol intake (never/rare, 1–6 drinks per week, 1+
drinks per day), body mass index (kg/m 2), and frequency of vigorous exerci (never/rare, 1–
4 times per week, 5+ times per week). We did not adjust for education, as this is identical across
our sample of physicians. Information on covariates was determined from questionnaires
nearest to the time of blood collection – except age, CVD and depression, which were
determined as of the start of cognitive testing.RESULTS Samples characteristics by insulin and c-peptide levels Participants’ characteristics demonstrated expected associations with both plasma fasting insulin and c-peptide (Tables 1 and 2). Increasing insulin and c-peptide were both associated with increasing prevalence of hypertension, dyslipidemia and heart dia. Daily alcohol intake was most prominent among tho with the lowest fasting insulin levels. Trends of increasing age, depression prevalence, lower physical activity and obesity were more consistent for increasing c-peptide than for increasing insulin; only two men in the lowest c-peptide group were obe.Prospective analys of cognitive decline Figure 1 depicts the results for cognitive change according to fasting insulin levels. Overall,wor cognitive decline was obrved at higher vs. lower levels of insulin. There were significant multivariable-adjusted associations between higher fasting insulin and decline on the TICS (p-trend=0.04). To help interpret the mean difference of −0.62 points (95% CI: −1.15,−0.09) between tho with the highest vs. lowest levels of insulin, we contrasted it wi
th the estimate for age. Each additional year of age was associated with a mean decline of 0.09 points (p<0.0001) on the TICS; thus, tho in the group with the highest fasting insulin had declines equivalent to tho we obrved for subjects approximately 7 years older. There was a non-significant trend between higher fasting insulin and decline on the global score (p=0.10), and
there was a borderline significant mean difference (95% CI) comparing extreme insulin
quartiles = −0.11 units (−0.23, 0.01; p=0.08). On category fluency, there was significantly
greater decline comparing men with the highest vs. lowest fasting insulin levels (mean
difference again comparable to 7 years of age); however, the association was slightly stronger
dininghallwhen adjusted only for age: mean difference (95% CI) = −1.29 words (−2.29, −0.28) (data not
shown in table), compared to a mean difference of −1.15 (−2.24, −0.06) after control for CVD
and risk factors. Attenuation after adjustment for vascular factors was only obrved for the
category fluency outcome. There was no association between fasting insulin and verbal
memory.
Differences in cognitive change according to c-peptide level are shown in Figure 2. As obrved
with fasting insulin, there was an overall pattern of wor cognitive decline comparing tho
with the highest vs. lowest c-peptide. The mean difference in decline, comparing the extreme
c-peptide groups, was statistically significant for the global score (p-trend=0.03); this was
cognitively equivalent to aging by about 5.5 years. The mean decline in verbal memory
associated with the highest c-peptide group was borderline significant, compared to tho with
the lowest c-peptide (mean difference=−0.13, p=0.07). As with fasting insulin, there was
notable attenuation of estimates relating c-peptide to change in category fluency scores after
adjustment for vascular factors: e.g., there was a significant age-adjusted trend of wor decline
in category fluency with increasing c-peptide (p-trend=0.02); however, the trend was
borderline significant (p-trend=0.07) after multivariable adjustment.
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