Evaluate the effects of two dipeptidyl peptidase-IV (DPP-4) inhibitors, sitagliptin and vildagliptin, known to have different efficacy on mean amplitude of glycemic excursions (MAGE), on oxidative stress, and on systemic inflammatory markers in patients with type 2 diabetes.
RESEARCH DESIGN AND METHODS
A prospective, randomized, open-label PROBE design (parallel group with a blinded end point) study was performed in 90 patients with type 2 diabetes inadequately controlled by metformin. The study assigned 45 patients to receive sitagliptin (100 mg once daily; sitagliptin group) and 45 patients to receive vildagliptin (50 mg twice daily; vildagliptin group) for 12 weeks. MAGE, evaluated during 48 h of continuous subcutaneous glucose monitoring, allowed an assessment of daily glucose fluctuations at baseline and after 12 weeks in all patients. Assessment of oxidative stress (nitrotyrosine) and systemic levels of inflammatory markers interleukin (IL)-6 and IL-18 was performed at baseline and after 12 weeks in all patients.
HbA1c, fasting and postprandial glucose, MAGE, and inflammatory and oxidative stress markers were similar between the groups at baseline. After 12 weeks, MAGE (P < 0.01) was lower in the vildagliptin group than in the sitagliptin group. After treatment, HbA1c and postprandial glucose evidenced similar changes between the groups (P = NS). Vildagliptin treatment was associated with a stronger decrease in nitrotyrosine (P < 0.01), IL-6 (P < 0.05), and IL-18 (P < 0.05) than sitagliptin treatment. Nitrotyrosine and IL-6 changes significantly correlated with changes in MAGE but not in fasting glucose and HbA1c.
MAGE reduction is associated with reduction of oxidative stress and markers of systemic inflammation in type 2 diabetic patients. These effects were greater in the vildagliptin group than in the sitagliptin group.
The importance of genetics and epigenetic changes in the pathogenesis of non alcoholic fatty liver disease (NAFLD) has been increasingly recognized. Adiponectin has a central role in regulating glucose and lipid metabolism and controlling inflammation in insulin-sensitive tissues and low adiponectin levels have been linked to NAFLD. APPL1 and APPL2 are adaptor proteins that interact with the intracellular region of adiponectin receptors and mediate adiponectin signaling and its effects on metabolism. The aim of our study was the evaluation of a potential association between variants at APPL1 and APPL2 loci and NAFLD occurrence. The impact on liver damage and hepatic steatosis severity has been also evaluated. To this aim allele frequency and genotype distribution of APPL1- rs3806622 and -rs4640525 and APPL2-rs 11112412 variants were evaluated in 223 subjects with clinical diagnosis of NAFLD and compared with 231 healthy subjects. The impact of APPL1 and APPL2 SNPs on liver damage and hepatic steatosis severity has been also evaluated. The minor-allele combination APPL1-C/APPL2-A was associated with an increased risk of NAFLD (OR = 2.50 95% CI 1.45–4.32; p<0.001) even after adjustment for age, sex, body mass index, insulin resistance (HOMA-IR), triglycerides and adiponectin levels. This allele combination carrier had higher plasma alanine aminotransferase levels (Diff = 15.08 [7.60–22.57] p = 0.001) and an increased frequency of severe steatosis compared to the reference allele combination (OR = 3.88; 95% CI 1.582–9.531; p<0.001). In conclusion, C-APPL1/A-APPL2 allele combination is associated with NAFLD occurrence, with a more severe hepatic steatosis grade and with a reduced adiponectin cytoprotective effect on liver.
Age-related mechanisms that lead to sarcopenia are not entirely understood. Basal leg blood flow declines with aging by augmented sympathetic vasoconstriction and arterial stiffening, thus a dysfunction in blood vessel dynamics may have an independent role on sarcopenia. We determined whether pulse wave velocity (PWV), marker of arterial stiffness, was associated with skeletal muscle decline. Observational cohort study of older adults(70–79 years) living in Pittsburgh, PA, USA or Memphis, TN, USA. Analyses included 2,405 participants. Correlations among muscle parameters including skeletal muscle density and intermuscular adipose tissue using mid-thigh CT scans were assessed. Linear mixed models tested the association between the change in the sarcopenic index (SI) (assessed by dual energy X-ray absorptiometry) over time and baseline PWV independently of multiple confounders. SI was defined: appendicular lean mass/squared height and calculated at every follow-up (n = 6). Baseline PWV was significantly higher in black women compared to white women (930 ± 431 vs. 843 ± 366; p = 0.0001), while there were no significant differences between black and white men (943 ± 402 vs. 911 ± 375; p = 0.1786). Baseline analyses showed an independent negative association between PWV and muscle parameters after adjusting for confounders in both genders. The PWV-by-race interaction was significant in women and analyses are reported separately by race. Prospective mixed models showed that PWV was an independent determinant of the SI in all men (β = −0.1043; p = 0.0065) and in white women (β = −0.1091; p = 0.0192). In analyses examining the effect of arterial stiffness on limb lean mass over time, PWV correlated with lower leg (β = −0.2196; p = 0.0002)and arm mass (β = −0.0985; p = 0.0011) in all men and lower leg mass(β = −0.1608; p = 0.0027)in white women. In older persons, arterial stiffening is associated with skeletal muscle mass decline differently for race and gender.
Aging; Sarcopenia; Pulse wave velocity; Vascular stiffness
A large array of gene involved in human longevity seems to be in relationship with insulin/IGF1 pathway. However, if such genes interact each other, or with other genes, to reduce the age-related metabolic derangement and determine the long-lived phenotype has been poorly investigated. Thus, we tested the role of interchromosomal interactions among IGF1R, IRS2, and UCP2 genes on the probability to reach extreme old age in 722 unrelated Italian subjects (401 women and 321 men; mean age, 62.83 ± 25.30 years) enrolled between 1998 and 1999. In particular, the G/A-IGF1R, Gly/Asp-IRS2, and Ala/Val-UCP2 allele combination was tested for association with longevity, metabolic profile and energy expenditure parameters. The effect on all-cause and cause-specific mortality rate was also assessed after a mean follow-up of 6 years. The analysis revealed that AAV allele combination is associated with a decreased all-cause mortality risk (HR, 0.72; 95% CI, 0.63–0.91; p = 0.03) and with a higher probability to reach the extreme of old age (OR, 3.185; 95% CI, 1.63–6.19; p = 0.0006). The analysis also revealed lower HOMA-IR (Diff, −0.532, 95% CI, 0.886–0.17; p = 0.003), higher respiratory quotient (Diff, 0.0363, 95% CI, 0.014–0.05; p = 0.001), and resting metabolic rate (Diff, 101.80693, 95% CI, −5.26–204.278; p = 0.038) for AAV allele combination. In conclusion, A-IGF1R/Asp-IRS2/Val-UCP2 allele combination is associated with a decreased all-cause mortality risk and with an increased chance of longevity. Such an effect is probably due to the combined effect of IGF1R, IRS2, and UCP2 genes on energy metabolism and on the age-related metabolic remodeling capacity.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9210-z) contains supplementary material, which is available to authorized users.
IGF1R/IRS2/UCP2 haplotype; Metabolic profile; Energy expenditure; Longevity; Mortality rate
The pathophysiology of chronic diabetic ulcers is complex and still incompletely understood, both micro- and macroangiopathy strongly contribute to the development and delayed healing of diabetic wounds, through an impaired tissue feeding and response to ischemia. With adequate treatment, some ulcers may last only weeks; however, many ulcers are difficult to treat and may last months, in certain cases years; 19–35% of ulcers are reported as nonhealing. As no efficient therapy is available, it is a high priority to develop new strategies for treatment of this devastating complication. Because experimental and pathological studies suggest that incretin hormone glucagon-like peptide-1 may improves VEGF generation and promote the upregulation of HIF-1α through a reduction of oxidative stress, the study evaluated the effect of the augmentation of GLP-1, by inhibitors of the dipeptidyl peptidase-4, such as vildagliptin, on angiogenesis process and wound healing in diabetic chronic ulcers. Although elucidation of the pathophysiologic importance of these aspects awaits further confirmations, the present study evidences an additional aspect of how DPP-4 inhibition might contribute to improved ulcer outcome.
Both type 2 diabetes (T2D) and chronic hepatitis C (CHC) infection are associated with increased risk of developing hepatocellular carcinoma (HCC). Cytokines are known to play an important role not only in the mechanisms of insulin resistance and glucose disposal defects but also in the pathological processes occurring in the liver during viral infection. We evaluated the serum levels of many cytokines, chemokines, adipokines and growth factors in patients with type 2 diabetes, CHC, CHC-related cirrhosis, CHC and type 2 diabetes and CHC-related cirrhosis and type 2 diabetes by BioPlex assay. The obtained data evidenced that the serum levels of some proteins are significantly up-regulated in all the patients or in those with only one disease and are often higher, even if in different amounts, when both diseases are associated. In particular, our results can be useful for the clinical monitoring of patients because they give specific information in regard to the progression from CHC to LC and CHD to LCD. Moreover, some molecules have shown significant correlations with clinical/biochemical data, suggesting the possibility to define mini-panels that can be used as specific markers for the different disease staging. However, our observations demonstrate that an integrated approach is much more powerful than isolated measurements to evaluate specific stages of these two complex pathologies (type 2 diabetes and chronic CHC hepatitis) alone or when they are concomitant in a patient. In fact it has emerged as an accurate, simple, specific, noninvasive, reproducible and less expensive method that, in future, could be included in routine clinical practice to monitor the association of type 2 diabetes and/or CHC to liver cirrhosis and, possibly, to cancer, and to improve the prognosis of these diseases.
Understanding the molecular regulatory mechanisms controlling for myocardial lipid metabolism is of critical importance for the development of new therapeutic strategies for heart diseases. The role of PPARγ and thiazolidinediones in regulation of myocardial lipid metabolism is controversial. The aim of our study was to assess the role of PPARγ on myocardial lipid metabolism and function and differentiate local/from systemic actions of PPARs agonists using cardiomyocyte-specific PPARγ –knockout (CM-PGKO) mice. To this aim, the effect of PPARγ, PPARγ/PPARα and PPARα agonists on cardiac function, intra-myocyte lipid accumulation and myocardial expression profile of genes and proteins, affecting lipid oxidation, uptake, synthesis, and storage (CD36, CPT1MIIA, AOX, FAS, SREBP1-c and ADPR) was evaluated in cardiomyocyte-specific PPARγ –knockout (CM-PGKO) and littermate control mice undergoing standard and high fat diet (HFD). At baseline, protein levels and mRNA expression of genes involved in lipid uptake, oxidation, synthesis, and accumulation of CM-PGKO mice were not significantly different from those of their littermate controls. At baseline, no difference in myocardial lipid content was found between CM-PGKO and littermate controls. In standard condition, pioglitazone and rosiglitazone do not affect myocardial metabolism while, fenofibrate treatment significantly increased CD36 and CPT1MIIA gene expression. In both CM-PGKO and control mice submitted to HFD, six weeks of treatment with rosiglitazone, fenofibrate and pioglitazone lowered myocardial lipid accumulation shifting myocardial substrate utilization towards greater contribution of glucose. In conclusion, at baseline, PPARγ does not play a crucial role in regulating cardiac metabolism in mice, probably due to its low myocardial expression. PPARs agonists, indirectly protect myocardium from lipotoxic damage likely reducing fatty acids delivery to the heart through the actions on adipose tissue. Nevertheless a direct non- PPARγ mediated mechanism of PPARγ agonist could not be ruled out.
We examined whether adherence to a Mediterranean-style diet has positive effects on mobility assessed over a nine-year follow-up in a representative sample of older adults. This research is part of the InCHIANTI Study, a prospective population-based study of older persons in Tuscany, Italy. The sample for this analysis included 935 women and men aged 65 years and older. Adherence to the Mediterranean diet was assessed at baseline by the standard 10-unit Mediterranean diet score (MDS). Lower extremity function was measured at baseline, and at the 3, 6 and 9-year follow-up visits using the Short Physical Performance Battery (SPPB). At baseline, higher adherence to Mediterranean diet was associated with better lower body performance. Participants with higher adherence experienced less decline in SPPB score, which was of 0.9 points higher (p<.0001) at the 3-year-follow, 1.1 points higher (p= 0.0004) at the 6-year follow-up and 0.9 points higher (p= 0.04) at the 9-year follow-up compared to those with lower adherence. Among participants free of mobility disability at baseline, those with higher adherence had a lower risk (HR=0.71,95%CI=0.51–0.98, p=0.04) of developing new mobility disability. High adherence to a Mediterranean-style diet is associated with a slower decline of mobility over time in community dwelling older persons. If replicated, this observation is highly relevant in terms of public health.
Mediterranean diet; mobility; SPPB; aging
Variants in transcription factor 7-like 2 (266096218TCF7L2266096218USuser266096218Gene names have been italicized per house style. Please check and confirm whether there are other instances that need to be italicized or instances where italics have been inappropriately applied.) gene have been found strongly associated with an increased risk of type 2 diabetes, as well as with an impairment of glucagon-like peptide-1 (GLP-1) signalling chain. In rats, stimulation of central GLP-1 receptors increases heart rate and activates autonomic regulatory neurons. We aimed to evaluate the potential role of TCF7L2 gene polymorphisms on sympathovagal response in relation to changes in plasma insulin and/or GLP-1 concentration after glucose ingestion. Genotyping was performed for rs12255372 and rs7903146 TCF7L2 gene variants in 250 non-related healthy volunteers (mean age 27±3 years). Consistent with previous reports, both single-nucleotide polymorphisms were in strong linkage disequilibrium (D′=0.87, r2=0.76). A subset of 167 patients underwent an oral glucose tolerance test while a continuous recording of heart rate variability was performed. At baseline, no differences in fasting plasma insulin, in GLP-1 levels and in LF/HF (low frequency/high frequency) ratio between the three genotypes were found. Along with glucose ingestion TT subjects had lower INSAUC (insulin area under curve), as well as higher LF/HFAUC (LF/HF area under curve) values. No difference in GLP-1AUC (GLP-1 area under curve) between TCF7L2 gene variants was found. A multivariate analysis including multiple covariates showed that only INSAUC, GLP-1AUC and TCF7L2 gene variants were independently associated with LF/HFAUC. In conclusion, TT genotype of rs12255372 and rs7903146 TCF7L2 gene variants is associated with lower insulin secretion and higher cardiosympathetic activity. Moreover, such effect is independent of GLP-1 and insulin plasma concentrations suggesting a potential role of such gene variants in increasing cardiovascular risk through enhanced sympathetic nervous system activity.
gene polymorphism; glucose metabolism; cardiac electrophisiology
The mean amplitude of glycemic excursions (MAGE) is a significant determinant of overall metabolic control as well as increased risk for diabetes complications. Older individuals with type 2 diabetes are more likely to have moderate cognitive deficits and structural changes in brain tissue. Considering that poor metabolic control is considered a deranging factor for cognitive performance in diabetic patients, we evaluated whether the contributions of MAGE to cognitive status in older patients with type 2 diabetes were independent from the main markers of glycemic control, such as sustained chronic hyperglycemia (A1C), postprandial glycemia (PPG), and fasting plasma glucose (FPG).
RESEARCH DESIGN AND METHODS
In 121 older patients with type 2 diabetes, 48-h continuous subcutaneous glucose monitoring (CSGM) were assessed. MAGE and PPG were evaluated during CSGM. The relationship of MAGE to performance on cognitive tests was assessed, with adjustment for age, glycemic control markers, and other determinants of cognitive status. The cognitive tests were a composite score of executive and attention functioning and the Mini Mental Status Examination (MMSE).
MAGE was significantly correlated with MMSE (r = 0.83; P < 0.001) and with cognition composite score (r = 0.68; P < 0.001). Moreover, MAGE was associated with the MMSE (P < 0.001) and cognition composite score (P < 0.001) independently of age, sex, BMI, waist-to-hip (WHR) ratio, drug intake, physical activity, mean arterial blood pressure, FPG, PPG, and A1C.
MAGE during a daily period was associated with an impairment of cognitive functioning independent of A1C, FPG, and PPG. The present data suggest that interventional trials in older patients with type 2 diabetes should target not only A1C, PPG, and FPG but also daily acute glucose swings.
Diabetes is associated with an increased risk of heart failure, in part explained by endoplasmic reticulum stress and apoptosis. Protein disulfide isomerase (PDI) prevents stressed cardiomyocytes apoptosis. We hypothesized that diabetes impairs PDI function by an alteration in its oxido-reductive state. Myocardial biopsies harvested from the anterolateral left ventricular wall from diabetic (n = 7) and nondiabetic (n = 8) patients were used to assess PDI expression and cardiomyocyte death. A mouse model of diabetes (streptozotocin injection, 130 mg/mL) was used to study PDI expression and its redox state after ischemia/reperfusion injury induced by 30-min occlusion of the left anterior coronary artery followed by reperfusion. Transthoracic echocardiography was performed to assess cardiac remodeling after 1 wk. Western blot analysis was used to analyze PDI expression, and methoxy-polyethyleneglycol-maleimide was used to assess its redox state. Dehydroascorbate (DHA) administration was used to restore the PDI redox state. Diabetic patients had a greater number of transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells than nondiabetic patients despite a greater myocardial PDI expression suggesting altered PDI function. Diabetic mice had a worse postinfarction remodeling associated with an altered PDI redox state. DHA treatment restored functional PDI redox state and ameliorated post–myocardial infarction remodeling. An increase in PDI levels with a paradoxical decrease of its active form occurs in the diabetic heart after ischemia and may explain the lack of protective effects of PDI in diabetes. Restoration of PDI redox state prevents adverse remodeling. The potential significance of these findings deserves to be validated in a clinical setting.
Studies have suggested that insulin resistance plays a role in cognitive impairment in individuals with type 2 diabetes. We aimed to determine whether an improvement in insulin resistance could explain cognitive performance variations over 36 weeks in older individuals with mild cognitive impairment (MCI) and type 2 diabetes.
RESEARCH DESIGN AND METHODS
A total of 97 older individuals (mean ± SD age 76 ± 6 years) who had recently (<2 months) started an antidiabetes treatment of metformin (500 mg twice a day) (n = 30) or metformin (500 mg/day)+rosiglitazone (4 mg/day) (n = 32) or diet (n = 35) volunteered. The neuropsychological test battery consisted of the Mini-Mental State Examination (MMSE), Rey Verbal Auditory Learning Test (RAVLT) total recall, and Trail Making Tests (TMT-A and TMT-B) performed at baseline and every 12 weeks for 36 weeks along with clinical testing.
At baseline, no significant differences were found between groups in clinical or neuropsychological parameters. Mean ± SD values in the entire population were as follows: A1C 7.5 ± 0.5%, fasting plasma glucose (FPG) 8.6 ± 1.3 mmol/l, fasting plasma insulin (FPI) 148 ± 74 pmol/l, MMSE 24.9 ± 2.4, TMT-A 61.6 ± 42.0, TMT-B 162.8 ± 78.7, the difference between TMT-B and TMT-A [DIFFBA] 101.2 ± 58.1, and RAVLT 24.3 ± 2.1. At follow-up, ANOVA models tested changes in metabolic control parameters (FPI, FPG, and A1C). Such parameters improved in the metformin and metformin/rosiglitazone groups (Ptrend < 0.05 in both groups). ANCOVA repeated models showed that results for the metformin/rosiglitazone group remained stable for all neuropsychological tests, and results for the diet group remained stable for the MMSE and TMT-A and declined for the TMT-B (Ptrend = 0.024), executive efficiency (DIFFBA) (Ptrend = 0.026), and RAVLT memory test (Ptrend = 0.011). Results for the metformin group remained stable for the MMSE and TMTs but declined for the RAVLT (Ptrend = 0.011). With use of linear mixed-effects models, the interaction term, FPI × time, correlated with cognitive stability on the RAVLT in the metformin/rosiglitazone group (β = −1.899; P = 0.009).
Rosiglitazone may protect against cognitive decline in older individuals with type 2 diabetes and MCI.
Common variation in the FTO gene is associated with BMI and type 2 diabetes. Increased BMI is associated with diabetes risk factors, including raised insulin, glucose, and triglycerides. We aimed to test whether FTO genotype is associated with variation in these metabolic traits.
RESEARCH DESIGN AND METHODS
We tested the association between FTO genotype and 10 metabolic traits using data from 17,037 white European individuals. We compared the observed effect of FTO genotype on each trait to that expected given the FTO-BMI and BMI-trait associations.
Each copy of the FTO rs9939609 A allele was associated with higher fasting insulin (0.039 SD [95% CI 0.013–0.064]; P = 0.003), glucose (0.024 [0.001– 0.048]; P = 0.044), and triglycerides (0.028 [0.003– 0.052]; P = 0.025) and lower HDL cholesterol (0.032 [0.008 – 0.057]; P = 0.009). There was no evidence of these associations when adjusting for BMI. Associations with fasting alanine aminotransferase, γ-glutamyl-transferase, LDL cholesterol, A1C, and systolic and diastolic blood pressure were in the expected direction but did not reach P < 0.05. For all metabolic traits, effect sizes were consistent with those expected for the per allele change in BMI. FTO genotype was associated with a higher odds of metabolic syndrome (odds ratio 1.17 [95% CI 1.10 –1.25]; P = 3 × 10−6).
FTO genotype is associated with metabolic traits to an extent entirely consistent with its effect on BMI. Sample sizes of >12,000 individuals were needed to detect associations at P < 0.05. Our findings highlight the importance of using appropriately powered studies to assess the effects of a known diabetes or obesity variant on secondary traits correlated with these conditions.
The increasing prevalence of metabolic syndrome (MS) with age in older men has been linked with decreasing testosterone levels. Interestingly, while testosterone levels decline with age, estradiol (E2) levels remain relatively stable resulting in a decreased testosterone/estradiol ratio. Because E2 levels tend to be elevated in morbid obesity, insulin resistance and diabetes, it is reasonable to hypothesize that high E2 levels are associated with MS in older men.
We studied the relationship of total and free E2 with MS after adjustment for multiple confounders including age, BMI, smoking, alcohol consumption, physical activity, interleukin-6 (IL-6), fasting insulin and testosterone.
452 men 65 yr or older (age range 65–96) had complete data on estradiol, testosterone, fasting insulin, sex hormone binding globulin, interleukin-6 (IL-6), and albumin. Concentrations of free estradiol and free testosterone were calculated using the mass action equations. MS was defined according to ATPIII criteria.
Participants with MS had significantly higher serum free and total E2 (p<.001) (p=0.003). After adjusting for confounders, including age, smoking, alcohol consumption, physical activity, log (IL-6), log (insulin), participants with higher log (total E2) (OR: 2.31, 95 % CI 1.39–4.70, p=0.02) and higher log (free E2) (OR: 2.69, 1.38–5.24, p<0.001) had an increased risk of having MS. Log (free E2) (p=0.04) maintained significant correlation with MS even after further adjustment for BMI.
In older men high E2 is independently associated with MS. Whether confirmed in other studies, assessment of E2 should be also considered in older men. Whether changes in this hormonal pattern play a role in the development of MS should be further tested in longitudinal studies.
estradiol; metabolic syndrome; older men
We evaluated the efficacy of malabsorptive bariatric surgery on daily blood glucose fluctuations and oxidative stress in type 2 diabetic obese patients.
RESEARCH DESIGN AND METHODS
The 48-h continuous subcutaneous glucose monitoring was assessed in type 2 diabetic patients before and 1 month after biliopancreatic diversion (BPD) (n = 36), or after diet-induced equivalent weight loss (n = 20). The mean amplitude of glycemic excursions and oxidative stress (nitrotyrosine) were evaluated during continuous subcutaneous glucose monitoring. During a standardized meal, glucagon-like peptide (GLP)-1, glucagon, and insulin were measured.
Fasting and postprandial glucose decreased equally in surgical and diet groups. A marked increase in GLP-1 occurred during the interprandial period in surgical patients toward the diet group (P < 0.01). Glucagon was more suppressed during the interprandial period in surgical patients compared with the diet group (P < 0.01). Mean amplitude of glycemic excursions and nitrotyrosine levels decreased more after BPD than after diet (P < 0.01).
Oxidative stress reduction after biliopancreatic diversion seems to be related to the regulation of glucose fluctuations resulting from intestinal bypass.
To investigate the relationship between total estradiol (E2) levels and 9-year mortality in older postmenopausal women not taking hormone replacement therapy (HRT).
Population-based study of persons living in the Chianti geographic area (Tuscany, Italy).
A representative sample of 509 women aged 65 and older with measures of total E2.
Serum total E2 was measured at the University of Parma using ultrasensitive radioimmunoassay (RIA).
Women who died (n = 135) during 9 years of follow up were older; had higher total E2 levels; and were more likely to have evidence of stroke, hypertension, diabetes mellitus, and congestive heart failure at baseline than survivors. Higher E2 levels were associated with a greater likelihood of death (hazard ratio (HR) = 1.03, 95% confidence interval (CI) = 1.01–1.06), and the relationship was independent of age, waist:hip ratio, C-reactive protein, education, cognitive function, physical activity, caloric intake, smoking, and chronic disease (HR = 1.08 pg/mL, 95% CI = 1.03–1.13, P = .003). The excessive risk of death associated with higher total E2 was not attenuated after adjustment for total testosterone (HR = 1.12, 95% CI = 1.02–1.18, P<.001) and after further adjustment for insulin resistance evaluated using the homeostasis model assessment (HR = 1.07, 95% CI = 1.03–1.17, P<.001).
Total E2 was highly predictive of death after more than 5 years (HR = 1.42: CI 1.01–1.91, P = .04) and not predictive of death for less than 5 years (P = .78).
Higher total E2 concentration predicts mortality in older women not taking HRT.
estradiol; older postmenopausal women; mortality
The mechanisms related to cognitive impairment in older persons with Type 2 diabetes (DM) remains unclear. We tested if adiposity parameters and body fat distribution could predict cognitive decline in older persons with DM vs. normal glucose tolerance (NGT).
693 older persons with no dementia were enrolled: 253 with DM in good metabolic control; 440 with NGT (age range:65–85 years). Longitudinal study comparing DM and NGT individuals according to the association of baseline adiposity parameters (body mass index (BMI), waist-hip-ratio (WHR), waist circumference (WC) and total body fat mass) to cognitive change (Mini Mental State Examination (MMSE), a composite score of executive and attention functioning (CCS) over time.
At baseline, in DM participants, MMSE correlated with WHR (β = −0.240; p = 0.043), WC (β = −0.264; p = 0.041) while CCS correlated with WHR (β = −0.238; p = 0.041), WC (β = −0.326; p = 0.013) after adjusting for confounders. In NGT subjects, no significant correlations were found among any adiposity parameters and MMSE, while CCS was associated with WHR (β = −0.194; p = 0.036) and WC (β = −0.210; p = 0.024). Participants with DM in the 3rd tertile of total fat mass showed the greatest decline in cognitive performance compared to those in 1st tertile (tests for trend: MMSE(p = 0.007), CCS(p = 0.003)). Logistic regression models showed that 3rd vs. 1st tertile of total fat mass, WHR, and WC predicted an almost two-fold decline in cognitive function in DM subjects at 2nd yr (OR 1.68, 95%IC 1.08–3.52).
Total fat mass and central adiposity predict an increased risk for cognitive decline in older person with DM.
Due to supporting evidence that dietary patterns may have a significant role in the maintenance of good physical performance with aging, we tested whether plasma fatty acids, saturated fatty acids (SFA), and polyunsaturated (PUFA) fatty acids are cross-sectionally associated with different physical performance and predict changes in physical performance over a 3-year period. Data were from the InCHIANTI study, a population-based study of older Italians. Plasma fatty acids were measured at enrollment (1998–2000), and outcome variables, Summary Physical Performance Battery (SPPB), and time to walk 7 meters (m) were measured at enrollment and after 3 years (2001–2004). At enrollment, 330 participants had significantly impaired lower extremity performance (defined as a SPPB score ≤9). Adjusting for age, participants with a SPPB score >9 had higher levels of total PUFA, n−3 PUFA, and n−6 PUFA, while significantly lower levels of SFA than those with a SPPB score <9. Baseline SPPB scores were also associated with n−3 PUFA (β = 0.148, p = 0.031), whereas the 7-m walk time was associated with total PUFA (β = −0.068, p = 0.008), after adjusting for potential confounders. Of the 884 participants with a SPPB score >9 at baseline, 114 (12.9%) developed impaired lower extremity performance (SPPB ≤9). In fully adjusted logistic models, baseline n−3 PUFA levels were inversely related to the risk of developing a decline in SPPB to ≤9 (odds ratio [OR] = 0.21; 95% confidence interval [CI] = 0.08–0.53), while the n−6/n−3 ratio was associated with a higher risk of SPPB decline to ≤9 (OR = 5.23; 95% CI = 2.02–13.51). In multivariate regression models, the n−6/n−3 ratio was associated with a longer time to walk 7 m (β = 0.396, p = 0.037). n−3 PUFA plasma levels, which most likely reflect dietary intake, seem to protect against accelerated decline of physical performance. A higher n−6/n−3 ratio was associated with higher risk of developing poor physical performance and slower walking speed.
Due to supporting evidence that dietary patterns may have a significant role in the maintenance of good physical performance with aging, we tested whether plasma fatty acids, saturated fatty acids (SFA), and polyunsaturated (PUFA) fatty acids are cross-sectionally associated with different physical performance and predict changes in physical performance over a 3-year period. Data were from the InCHIANTI study, a population-based study of older Italians. Plasma fatty acids were measured at enrollment (1998–2000), and outcome variables, Summary Physical Performance Battery (SPPB), and time to walk 7 meters (m) were measured at enrollment and after 3 years (2001–2004). At enrollment, 330 participants had significantly impaired lower extremity performance (defined as a SPPB score ≤9). Adjusting for age, participants with a SPPB score >9 had higher levels of total PUFA, n-3 PUFA, and n-6 PUFA, while significantly lower levels of SFA than those with a SPPB score <9. Baseline SPPB scores were also associated with n-3 PUFA (β = 0.148, p = 0.031), whereas the 7-m walk time was associated with total PUFA (β = −0.068, p = 0.008), after adjusting for potential confounders. Of the 884 participants with a SPPB score >9 at baseline, 114 (12.9%) developed impaired lower extremity performance (SPPB ≤9). In fully adjusted logistic models, baseline n-3 PUFA levels were inversely related to the risk of developing a decline in SPPB to ≤9 (odds ratio [OR] = 0.21; 95% confidence interval [CI] = 0.08–0.53), while the n-6/n-3 ratio was associated with a higher risk of SPPB decline to ≤9 (OR = 5.23; 95% CI = 2.02–13.51). In multivariate regression models, the n-6/n-3 ratio was associated with a longer time to walk 7 m (β = 0.396, p = 0.037). n-3 PUFA plasma levels, which most likely reflect dietary intake, seem to protect against accelerated decline of physical performance. A higher n-6/n-3 ratio was associated with higher risk of developing poor physical performance and slower walking speed.
Epidemiological studies consistently show that circulating sex hormone binding globulin (SHBG) levels are lower in type 2 diabetes patients than non-diabetic individuals, but the causal nature of this association is controversial. Genetic studies can help dissect causal directions of epidemiological associations because genotypes are much less likely to be confounded, biased or influenced by disease processes. Using this Mendelian randomization principle, we selected a common single nucleotide polymorphism (SNP) near the SHBG gene, rs1799941, that is strongly associated with SHBG levels. We used data from this SNP, or closely correlated SNPs, in 27 657 type 2 diabetes patients and 58 481 controls from 15 studies. We then used data from additional studies to estimate the difference in SHBG levels between type 2 diabetes patients and controls. The SHBG SNP rs1799941 was associated with type 2 diabetes [odds ratio (OR) 0.94, 95% CI: 0.91, 0.97; P = 2 × 10−5], with the SHBG raising allele associated with reduced risk of type 2 diabetes. This effect was very similar to that expected (OR 0.92, 95% CI: 0.88, 0.96), given the SHBG-SNP versus SHBG levels association (SHBG levels are 0.2 standard deviations higher per copy of the A allele) and the SHBG levels versus type 2 diabetes association (SHBG levels are 0.23 standard deviations lower in type 2 diabetic patients compared to controls). Results were very similar in men and women. There was no evidence that this variant is associated with diabetes-related intermediate traits, including several measures of insulin secretion and resistance. Our results, together with those from another recent genetic study, strengthen evidence that SHBG and sex hormones are involved in the aetiology of type 2 diabetes.
To determine whether low levels of testosterone, sex hormone binding globulin (SHBG), insulin-like growth factor-1 (IGF-1), and dehydroepiandrosterone sulfate (DHEAS) and high levels of cortisol and leptin would be associated with metabolic syndrome (MS).
Population-based sample of older Italian men.
Four hundred fifty-two men aged 65 and older enrolled in the Invecchiare in Chianti (InCHIANTI) study.
Complete data on testosterone, cortisol, DHEAS, SHBG, fasting insulin, IGF-1 and leptin. MS was defined according to Adult Treatment Panel III criteria.
MS was present in 73 men (15.8% of the sample). After adjusting for confounders, total testosterone (P<.05) and log (SHBG) (P<.001) were inversely associated, whereas log (leptin) was positively associated with MS (P<.001). Independent of age, log (SHBG) was positively associated with high-density lipoprotein cholesterol (P<.05) and negatively associated with abdominal obesity (P<.001) and triglycerides (P<.001). Log (leptin) was significantly associated with each component of MS. Cortisol, DHEAS, free and bioavailable testosterone, and IGF-1 were not associated with MS. Having three or more hormones in the lower (for hormones lower in MS) or the upper (for hormones higher in MS) quartile was associated with three times the risk of being affected by MS (odds ratio =2.8, 95% confidence interval =1.3–6.9) (P=.005), compared with not having this condition.
Total testosterone and SHBG are negatively and leptin is positively associated with MS in older men. Whether specific patterns of hormonal dysregulation predict the development of MS should be tested in longitudinal studies.
SHBG; testosterone; hormonal dysregulation; older men; metabolic syndrome
Low levels of high density lipoprotein cholesterol (HDL-C) are associated with increased incidence of coronary heart disease (CHD). A better understanding of the mechanisms leading to low HDL-C and CHD is essential for planning treatment strategies. Clinical studies have demonstrated that cytokines might affect both concentration and composition of plasma lipoproteins, including HDLs.
We investigated the possible association between low HDL-C levels, defined as ≤10th gender specific percentile, and circulating markers of inflammation (IL-1β, TNF-α, IL-6, IL-10, IL-18, and CRP) in a population of 1044 community dwelling older Italian subjects from the InChianti study.
Using logistic regression analysis we demonstrated that IL-6 levels (III versus I tertile, OR: 2.10; 1.10–3.75), TG (III versus I tertile OR: 27.45; 8.47–88.93), fasting insulin (III versus I tertile OR: 2.84; 1.50–5.42), and age (OR: 1.038; 1.002–1.075) were associated with low HDL-C independent of smoking, BMI, waist circumference, hypertension, diabetes, physical activity, alcohol intake, oral hypoglycaemics, CRP, IL-18, and TNF-α levels. The adjusted attributable risk of low HDL-C in the exposed group (III tertile of IL-6) was 54%.
The present study provides the epidemiological evidence that besides triglycerides, fasting insulin, and age, IL-6 is one of the main correlates of low HDL-C levels in older individuals.
HDL-cholesterol; Inflammation; Interleukin 6; Metabolic syndrome
Metabolic syndrome (MetS) is a strong risk factor for type 2 diabetes and cardiovascular disease. Conditions associated with hyperandrogenism are often associated with glucose intolerance and other features of MetS in young women. As the prevalence of MetS increases with age and is probably multifactorial, it is reasonable to hypothesize that age-related changes in androgens and other hormones might contribute to the development of MetS in older persons. However, this hypothesis has never been tested in older women. We hypothesized that high levels of testosterone, dehydroepiandrosterone sulfate (DHEA-S), and cortisol and low levels of sex hormone-binding globulin (SHBG) and IGF-I would be associated with MetS in a representative cohort of older Italian women independently of confounders (including inflammatory markers). After exclusion of participants on hormone replacement therapy and those with a history of bilateral oophorectomy, 512 women (≥65 yr) had complete data on testosterone, cortisol, DHEA-S, SHBG, fasting insulin, total and free IGF-I, IL-6, and C-reactive protein (CRP). MetS was defined according to ATP-III criteria. Insulin resistance was calculated according to HOMA. MetS was found in 145 women (28.3%). Participants with vs. those without MetS had higher age-adjusted levels of bioavailable testosterone (P < 0.001), IL-6 (P < 0.001), CRP (P < 0.001), and HOMA (P < 0.001) and lower levels of SHBG (P < 0.001). After adjustment for potential confounders, participants with decreased SHBG had an increased risk of MetS (P < 0.0001) vs. those with low SHBG. In a further model including all hormones and confounders, log SHBG was the only independent factor associated with MetS (OR: 0.44, 95% CI 0.21–0.91, P = 0.027). In older women, SHBG is negatively associated with MetS independently of confounders, including inflammatory markers and insulin resistance. Further studies are needed to support the notion that raising SHBG is a potential therapeutic target for prevention and treatment of MetS.
sex hormone-binding globulin; hormonal dysregulation; insulin-like growth factor I; androgens
There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts – cis effects, and elsewhere in the genome – trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8×10−57), CCL4L1 (p = 3.9×10−21), IL18 (p = 6.8×10−13), LPA (p = 4.4×10−10), GGT1 (p = 1.5×10−7), SHBG (p = 3.1×10−7), CRP (p = 6.4×10−6) and IL1RN (p = 7.3×10−6) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8×10−40), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways.
One of the central dogmas of molecular genetics is that DNA is transcribed to RNA which is translated to protein and alterations to proteins can influence human diseases. Genome-wide association studies have recently revealed many new DNA variants that influence human diseases. To complement these efforts, several genome-wide studies have established that DNA variation influences mRNA expression levels. Loci influencing mRNA levels have been termed “eQTLs”. In this study we have performed the first genome-wide association study of the third piece in this jigsaw – the role of DNA variation in relation to protein levels, or “pQTLs”. We analysed 42 proteins measured in blood fractions from the InCHIANTI study. We identified eight cis effects including common variants in or near the IL6R, CCL4, IL18, LPA, GGT1, SHBG, CRP and IL1RN genes, all associated with blood levels of their respective protein products. Mechanisms implicated included altered transcription (GGT1) but also rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA) and variation in gene copy number (CCL4). Blood levels of many of these proteins are correlated with human diseases and the identification of “pQTLs” may in turn help our understanding of disease.