Adiponectin and the development of type 2 diabetes: the atherosclerosis risk in communities study

Adipocyte-derived secretory proteins have been increasingly linked to diabetes. To investigate whether adiponectin, a major adipocyte secretory protein, predicts diabetes, we conducted a case-cohort study representing the approximately 9-year experience of the 10,275 middle-aged, U.S. African-American and white participants of the Atherosclerosis Risk in Communities (ARIC) study. Adiponectin was measured on stored plasma of 581 incident diabetes case subjects and 572 noncase subjects. Overall hazard ratios (95% CIs) for developing diabetes, for those in the second, third, and fourth (versus the first) quartile of adiponectin were 0.57 (0.41-0.78), 0.39 (0.27-0.56), and 0.18 (0.11-0.27), respectively, after adjustment for age, sex, ethnicity, study center, parental history of diabetes, and hypertension and 0.72 (0.48-1.09), 0.67 (0.43-1.04), and 0.58 (0.34-0.99), respectively, after additional adjustment for BMI, waist-to-hip ratio, fasting glucose, insulin, and a score composed of six inflammation markers. The association was of similar magnitude in men and women and in whites and African Americans, but was absent in smokers and in those with a greater inflammation score (interaction P < 0.01 for each). In conclusion, in this community-based sample of U.S. adults, higher adiponectin levels were associated with a lower incidence of diabetes.     

Markers of inflammation predict the long-term risk of developing chronic kidney disease: a population-based cohort study

In animal models, inflammatory processes have been shown to have an important role in the development of kidney disease. In humans, however, the independent relation between markers of inflammation and the risk of chronic kidney disease (CKD) is not known. To clarify this, we examined the relationship of several inflammatory biomarker levels (high-sensitivity C-reactive protein, tumor necrosis factor-α receptor 2, white blood cell count, and interleukin-6) with the risk of developing CKD in a population-based cohort of up to 4926 patients with 15 years of follow-up. In cross-sectional analyses, we found that all these inflammation markers were positively associated with the outcome of interest, prevalent CKD. However, in longitudinal analyses examining the risk of developing incident CKD among those who were CKD-free at baseline, only tumor necrosis factor-α receptor 2, white blood cell count, and interleukin-6 levels (hazard ratios comparing highest with the lowest tertile of 2.10, 1.90, and 1.45, respectively), and not C-reactive protein (hazard ratio 1.09), were positively associated with incident CKD. Thus, elevations of most markers of inflammation predict the risk of developing CKD. Each marker should be independently verified.     

Smoking and cardiovascular outcomes in dialysis patients: the United States Renal Data System Wave 2 study

BACKGROUND: Smoking has received surprisingly little research attention in dialysis populations, a group at monumental cardiovascular risk. METHODS: Medicare claims data were used to study associations between smoking and new-onset cardiovascular outcomes, and death in the prospective, inception Wave 2 cohort (N = 4024), assembled in 1996 and 1997. RESULTS: Of the participants, 56.4% were lifetime nonsmokers, 3.6% were smokers with unknown current status, 20.0% had quit for more than 1 year, 5.8% had quit less than 1 year ago, and 14.2% were current smokers. Subjects with cardiovascular disease at baseline were more likely to be former smokers, less likely never to have smoked and less likely to be current smokers (P < 0.001). Patients were followed until December 31, 1998. When adjustment was made for baseline age, demographic variables, mode of dialysis therapy, and comorbidity, smoking status was associated with new-onset congestive heart failure (adjusted hazards ratio 1.59 comparing current to nonsmokers, P = 0.004), new-onset peripheral vascular disease (adjusted hazards ratio 1.68, P < 0.001), and mortality (adjusted hazards ratio 1.37, P < 0.001). Former smokers, in contrast, had adjusted event risks similar to lifelong nonsmokers. CONCLUSION: Smoking is a major, modifiable, cardiovascular risk factor in patients starting dialysis therapy.     

High white blood cell count is associated with a worsening of insulin sensitivity and predicts the development of type 2 diabetes.

Chronic low-grade inflammation may be involved in the pathogenesis of insulin resistance and type 2 diabetes. We examined whether a high white blood cell count (WBC), a marker of inflammation, predicts a worsening of insulin action, insulin secretory function, and the development of type 2 diabetes in Pima Indians. We measured WBC in 352 nondiabetic Pima Indians (215 men and 137 women, aged 27 +/- 6 years [means +/- SD], body fat 32 +/- 8%, WBC 8,107 +/- 2,022 cells/mm(3)) who were characterized for body composition (by hydrodensitometry or dual-energy X-ray absorptiometry), glucose tolerance (by 75-g oral glucose tolerance test), insulin action (M; by hyperinsulinemic clamp), and acute insulin secretory response (AIR; by 25-g intravenous glucose challenge). Among 272 subjects who were normal glucose tolerant (NGT) at baseline, 54 developed diabetes over an average follow-up of 5.5 +/- 4.4 years. Among those who remained nondiabetic, 81 subjects had follow-up measurements of M and AIR. Cross-sectionally, WBC was related to percent body fat (r = 0.32, P < 0.0001) and M (r = -0.24, P < 0.0001), but not to AIR (r = 0.06, P = 0.4). In a multivariate analysis, when adjusted for age and sex, both percent body fat (P < 0.0001) and M (P = 0.03) were independently associated with WBC. A high WBC value predicted diabetes (relative hazard 90th vs. 10th percentiles [95%CI] of 2.7 [1.3-5.4], P = 0.007) when adjusted for age and sex. The predictive effect of WBC persisted after additional adjustment for established predictors of diabetes, i.e., percent body fat, M, and AIR (relative hazard 2.6 [1.1-6.2], P = 0.03). After adjustment for follow-up duration, a high WBC at baseline was associated with a subsequent worsening of M (P = 0.003), but not a worsening of AIR. A high WBC predicts a worsening of insulin action and the development of type 2 diabetes in Pima Indians. These findings are consistent with the hypothesis that a chronic activation of the immune system may play a role in the pathogenesis of type 2 diabetes.     

Association of Trabecular Bone Score (TBS) With Incident Clinical and Radiographic Vertebral Fractures Adjusted for Lumbar Spine BMD in Older Men: A Prospective Cohort Study

The association of trabecular bone score (TBS) with incident clinical and radiographic vertebral fractures in older men is uncertain. TBS was estimated from baseline spine dual‐energy X‐ray absorptiometry (DXA) scans for 5831 older men (mean age 73.7 years) enrolled in the Osteoporotic Fractures in Men (MrOS) study. Cox proportional hazard models were used to determine the association of TBS (per 1 SD decrease) with incident clinical vertebral fractures. Logistic regression was used to determine the association between TBS (per 1 SD decrease) and incident radiographic vertebral fracture among the subset of 4309 men with baseline and follow‐up lateral spine radiographs (mean 4.6 years later). We also examined whether any associations varied by body mass index (BMI) category. TBS was associated with a 1.41‐fold (95% confidence interval [CI] 1.23 to 1.63) higher aged‐adjusted odds of incident radiographic fracture, and this relationship did not vary by BMI (p value = 0.22 for interaction term). This association was no longer significant with further adjustment for lumbar spine bone mineral density (BMD; odds ratio [OR] = 1.11, 95% CI 0.94 to 1.30). In contrast, the age‐adjusted association of TBS with incident clinical vertebral fracture was stronger in men with lower BMI (≤ median value of 26.8 kg/m²; hazard ratio [HR] = 2.28, 95% CI 1.82 to 2.87) than in men with higher BMI (> median; HR = 1.60, 95% CI 1.31 to 1.94; p value = 0.0002 for interaction term). With further adjustment for lumbar spine BMD, the association of TBS with incident clinical vertebral fracture was substantially attenuated in both groups (HR = 1.30 [95% CI 0.99 to 1.72] among men with lower BMI and 1.11 [95% CI 0.87 to 1.41] among men with higher BMI). In conclusion, TBS is not associated with incident clinical or radiographic vertebral fracture after consideration of age and lumbar spine BMD, with the possible exception of incident clinical vertebral fracture among men with lower BMI. © 2017 American Society for Bone and Mineral Research.     

Baseline peritoneal solute transport rate is not associated with markers of systemic inflammation or comorbidity in incident Korean peritoneal dialysis patients.

BACKGROUND: It is controversial whether comorbid status or systemic inflammation has an influence on the peritoneal solute transport rate (PSTR). Our aim is to elucidate whether baseline PSTR is associated with markers of systemic inflammation or degree of comorbidity in incident peritoneal dialysis (PD) patients. METHODS: One hundred and ninety-five incident PD patients were prospectively included. Results of their baseline peritoneal equilibration test (PET) using 3.86% glucose PD fluid were analysed. Clinical and laboratory parameters of inflammation, comorbidity, nutritional status, dialysis adequacy and residual renal function (RRF) were assessed at the time of PET. RESULTS: Mean dialysate-to-plasma ratio for creatinine at 4 h (D/Pcr(4)) of our patients was 0.72 +/- 0.11. High-sensitivity C-reactive protein (hsCRP), serum interleukin-6 (IL-6) and serum albumin concentrations were closely interrelated to one another and these markers of systemic inflammation were also related to the Davies comorbidity score. No differences in age, sex ratio, body mass index, body surface area and presence of diabetes were found among four transport groups. RRF, total Kt/V, haemoglobin, nitrogen appearance and the Davies comorbidity score were not different either. High-sensitivity CRP, serum IL-6 and albumin concentrations were not associated with the baseline PSTR. By multiple linear regression analysis, only the serum albumin concentration measured at the time of PET (beta = -0.081 +/- 0.020, P < 0.001) remained significantly associated with D/Pcr(4). CONCLUSION: In our study with incident Korean PD patients, the baseline PSTR was not influenced by markers of systemic inflammation or comorbidity. For a subgroup of PD patients without serious comorbidity, other mechanisms of high baseline PSTR need to be elucidated.     

Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study

Elevated serum levels of acute-phase proteins, indicating chronic subclinical inflammation, have been associated with cardiovascular disease as well as the insulin resistance syndrome. Chronic inflammation may also be a risk factor for developing type 2 diabetes. We studied the concentrations of C-reactive protein (CRP), fibrinogen, and plasminogen activator inhibitor-1 (PAI-1) in 1,047 nondiabetic subjects in relation to incident diabetes within 5 years in the Insulin Resistance Atherosclerosis Study. Subjects with diabetes at follow-up (n = 144) had higher baseline levels of fibrinogen (mean +/- SD; 287.8 +/- 58.8 vs. 275.1 +/- 56.0 mg/dl; P = 0.013) as well as of CRP (median [interquartile range]; 2.40 [1.29, 5.87] vs. 1.67 mg/l [0.75, 3.41]; P = 0.0001) and PAI-1 (24 [15, 37.5] vs. 16 ng/ml [9, 27]; P = 0.0001) than nonconverters. The odds ratio (OR) of converting to diabetes was significantly increased with increasing baseline concentrations of the inflammatory markers. In contrast to PAI-1, the association of CRP and fibrinogen with incident diabetes was significantly attenuated after adjustment for body fat (BMI or waist circumference) or insulin sensitivity (S(I)), as assessed by a frequently sampled intravenous glucose tolerance test. In a logistic regression model that included age, sex, ethnicity, clinical center, smoking, BMI, S(I), physical activity, and family history of diabetes, PAI-1 still remained significantly related to incident type 2 diabetes (OR [95% CI] for 1 SD increase: 1.61 [1.20-2.16]; P = 0.002). Chronic inflammation emerges as a new risk factor for the development of type 2 diabetes; PAI-1 predicts type 2 diabetes independent of insulin resistance and other known risk factors for diabetes.     

Flow measurement before and after papaverine injection in above-knee prosthetic femoropopliteal bypass

OBJECTIVE: To investigate the value of intraoperative blood flow measurements on early and long-term patency of above-knee prosthetic femoropopliteal bypass. METHODS: Flow was measured with a transit time flowmeter before (basal flow) and after an intragraft injection of papaverine (papaverine flow) in 87 operations (86 patients) between January 1990 and December 2001. Sixty-one grafts were of polyester, and 26 were of polytetrafluoroethylene. The operations were done under epidural anesthesia. The preoperative angiographic run-off score and clinical risk factors were recorded. Patency rates were analyzed with the product limit method and compared with the log-rank test. Variables found to be near significantly related to patency rates (P < .1) were included in a multivariate analysis performed with the Cox proportional hazard model. RESULTS: Basal flow measurements were not related to patency. The 2- and 5-year patency rates for grafts with a papaverine flow < or = 500 mL/min were 48% and 18% compared with 66% and 52% for grafts with a papaverine flow > or = 500 mL/min. These differences were statistically significant (P = .012, hazard ratio, 2.6). Two- and 5-year patency rates for smokers vs nonsmokers were 44% and 18% vs 69% and 54%. The patency rates for patients with poor vs good run-off were 42% and 27% vs 66% and 31%. Smoking (P = .008, hazard ratio, 2.75) and poor run-off score (P = .009, hazard ratio, 2.38) were found to be independent risk factors for reduced patency rates. Poor run-off score did not correlate with low values of measured basal or papaverine flow. CONCLUSIONS: Papaverine flow of < or = 500 mL/min is associated with reduced mid- and long-term patency rates. Additional antithrombotic medication and frequent follow-up for these grafts should be considered. The inferior patency rates of smokers and patients with poor run-off indicate that prosthetic bypass is less suitable for these groups of patients.     

Insulin resistance, the metabolic syndrome, and incident cardiovascular events in the Framingham Offspring Study

The metabolic syndrome and insulin resistance have been related to incident cardiovascular disease (CVD), but it is uncertain if metabolic syndrome predicts CVD independent of insulin resistance. Our study sample included 2,898 people without diabetes or CVD at baseline. Metabolic syndrome was defined by the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) criteria. Insulin resistance was defined by the homeostasis model assessment (HOMA-IR) and by Gutt et al.'s insulin sensitivity index (ISI(0,120)). Age- and sex-adjusted proportional hazards regression models assessed the association of baseline metabolic syndrome and insulin resistance to 7-year CVD risk (186 events). Metabolic syndrome and both measures of insulin resistance were individually related to incident CVD (age- and sex-adjusted hazard ratio [HR] for metabolic syndrome [present versus absent]: 2.0 [95% CI 1.5-2.6], P = 0.0001; for HOMA-IR: 1.9 [1.2-2.9], P = 0.003; and for ISI(0,120) [both highest versus lowest quartile]: 0.5 [0.3-0.7], P = 0.001). In models adjusted for age, sex, LDL cholesterol, and smoking status and including metabolic syndrome, ISI(0,120) levels were independently related to incident CVD (0.5 [0.3-0.8], P = 0.004), whereas HOMA-IR levels were not (1.3 [0.8-2.1], P = 0.24); metabolic syndrome was associated with increased CVD risk in both models (HR 1.6, P < or = 0.007 in both). In conclusion, metabolic syndrome and ISI(0,120) but not HOMA-IR independently predicted incident CVD. Metabolic syndrome may not capture all the CVD risk associated with insulin resistance.     

Insulin-like growth factor axis and risk of type 2 diabetes in women

IGF-I shares structural homology and in vitro metabolic activity with insulin. Laboratory models suggest that IGF-I and its binding proteins IGFBP-1 and IGFBP-2 have potentially beneficial effects on diabetes risk, whereas IGFBP-3 may have adverse effects. We therefore conducted a prospective nested case-control investigation of incident diabetes (n = 742 case subjects matched 1:1 to control subjects) and its associations with IGF-axis protein levels in the Nurses' Health Study, a cohort of middle-aged women. The median time to diabetes was 9 years. Statistical analyses were adjusted for multiple risk factors, including insulin and C-reactive protein. Diabetes risk was fivefold lower among women with baseline IGFBP-2 levels in the top versus bottom quintile (odds ratio [OR](q5-q1) = 0.17 [95% CI 0.08-0.35]; P trend < 0.0001) and was also negatively associated with IGFBP-1 levels (OR(q5-q1) = 0.37 [0.18-0.73]; P trend = 0.0009). IGFBP-3 was positively associated with diabetes (OR(q5-q1) = 2.05 [1.20-3.51]; P trend = 0.002). Diabetes was not associated with total IGF-I levels, but free IGF-I and diabetes had a significant association that varied (P interaction = 0.003) by insulin levels above the median (OR(q5-q1) = 0.48 [0.26-0.90]; P trend = 0.0001) versus below the median (OR(q5-q1) = 2.52 [1.05-6.06]; P trend < 0.05). Thus, this prospective study found strong associations of incident diabetes with baseline levels of three IGFBPs and free IGF-I, consistent with hypotheses that the IGF axis might influence diabetes risk.     

Risk of Respiratory Complications and Wound Infection in Patients Undergoing Ambulatory Surgery: Smokers versus Nonsmokers

Background: Smoking is considered to be a risk factor for patients undergoing surgery and anesthesia, but it is unclear whether this is applicable to patients undergoing ambulatory surgery. The aim of this study was to determine the risk of respiratory complications and wound infection among smokers.

Methods: The authors studied a random selection of 489 adult patients undergoing ambulatory surgery. Smoking status was determined by self-report and confirmed with end-expired carbon monoxide analysis. The risk of respiratory complications (i.e., desaturation, cough, laryngospasm, bronchospasm, breath-holding, or apnea) and wound infection (i.e., wound redness or discharge +/- positive microbial culture, requiring antibiotic therapy) in smokers versus nonsmokers was ascertained. Odds ratios were estimated from multivariable logistic regression and adjusted for age, gender, body mass index, partner's smoking status, domiciliary smoking exposure, and extent and duration of surgery.

Results: Most smokers continued to smoke up until the day of surgery. Smokers had a higher rate of respiratory complications (32.8%vs. 25.9%; adjusted odds ratio, 1.71; 95% confidence interval, 1.03-2.84;P = 0.038) and wound infection (3.6%vs. 0.6%; odds ratio, 16.3; 95% confidence interval, 1.58-175;P = 0.019). Odds ratios comparing current plus ex-smokers with nonsmokers were of similar magnitude for most of these complications.     

Elevations in markers of liver injury and risk of type 2 diabetes: the insulin resistance atherosclerosis study

A limited number of studies have reported associations of markers of liver injury, including elevated concentrations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), with prospective risk of type 2 diabetes. However, only one study has adjusted for a detailed measure of insulin sensitivity (insulin sensitivity index [S(i)]), which is important given associations of obesity and S(i) with nonalcoholic fatty liver disease (NAFLD). Our objective was to investigate the associations of elevated AST and ALT with incident type 2 diabetes among 906 participants in the Insulin Resistance Atherosclerosis Study who were nondiabetic at baseline. S(i) and acute insulin response (AIR) were measured directly from the frequently sampled intravenous glucose tolerance test among black, Hispanic, and non-Hispanic white participants aged 40-69 years. After 5.2 years, 148 individuals had developed type 2 diabetes. Baseline AST and ALT were positively correlated with fasting insulin (r = 0.22 and r = 0.35, respectively), waist circumference (r = 0.18 and r = 0.34), and fasting glucose (r = 0.13 and r = 0.29) and inversely with S(i) (r = -0.18 and r = -0.30; all P < 0.0001). In separate logistic regression models adjusting for age, sex, ethnicity, clinical center, and alcohol consumption, participants in the highest quartiles (Q4) of AST and ALT were at significantly increased risk of incident type 2 diabetes compared with those in the lowest three quartiles (Q1-Q3): AST: odds ratio (OR) 1.73 (95% CI 1.17-2.57); ALT: OR 2.32 (1.36-3.75). After further adjustment for smoking, waist circumference, triglyceride, HDL, impaired glucose tolerance, S(i), and AIR, both AST and ALT remained significantly associated with incident type 2 diabetes: AST, Q4 vs. Q1-Q3: OR 1.98 (1.23-3.17); ALT, Q4 vs. Q1-Q3: OR 2.00 (1.22-3.28). There were no interactions of sex, ethnicity, obesity, impaired glucose tolerance, or S(i) with AST or ALT in the prediction of type 2 diabetes. When entered into the same model with adjustment for demographic variables, both C-reactive protein and ALT independently predicted type 2 diabetes. In addition, AST and ALT were positively associated with incident type 2 diabetes after excluding former and moderate to heavy drinkers. In conclusion, AST and ALT independently predict type 2 diabetes. Baseline elevations of these markers may reflect NAFLD or related pathologies.     

Gamma globulin levels predict type 2 diabetes in the Pima Indian population.

It has been proposed that inflammation or infection may contribute to the development of type 2 diabetes. We examined whether serum gamma globulin, a nonspecific measure of the humoral immune system, predicted changes in glucose tolerance in 2,530 members of the Pima Indian population, a group with a marked predisposition to type 2 diabetes. Cross-sectionally, gamma globulin was positively related to age (r = 0.08, P < 0.0005), BMI (r = 0.09; P < 0.0001), and female sex (P < 0.0001). Gamma globulin concentrations were familial, being positively correlated among siblings (r = 0.23; P < 0.0001) and between parents and their children (mother/child: r = 0.17, P < 0.0001; father/child: r = 0.25, P < 0.0001). Gamma globulin concentrations were higher with greater degrees of American Indian heritage (P < 0.004, with adjustment for age, sex, and BMI) and in the presence of a family history of type 2 diabetes (P < 0.04). Higher gamma globulin levels predicted risk of diabetes. In univariate analysis, a 1 SD difference in gamma globulin was associated with a 20% higher incidence of diabetes in those who were normal glucose tolerant at baseline (hazard rate ratio 1.20 [CI 1.11-1.30]; P < 0.0001) and remained as a significant predictor of diabetes, even when controlled for effects of sex, BMI, and 2-h glucose as additional predictors (hazard rate ratio for 1 SD difference in gamma globulin, 1.14 [1.05-1.24]; P = 0.002). Gamma globulin was also associated in univariate analysis with later development of impaired glucose tolerance (IGT) (hazard rate ratio 1.15 [1.07-1.23]; P < 0.0001), but not with the transition from IGT to diabetes (hazard rate ratio 1.04 [0.90-1.20]; P = 0.6). Thus, gamma globulin levels predict increased risk of diabetes in the Pima population. We suggest that immune function or activation may play a role in the development of type 2 diabetes.     

Hemostatic markers of endothelial dysfunction and risk of incident type 2 diabetes: the Framingham Offspring Study

Endothelial dysfunction may precede development of type 2 diabetes. We tested the hypothesis that elevated levels of hemostatic markers of endothelial dysfunction, plasminogen activator inhibitor-1 (PAI-1) antigen, and von Willebrand factor (vWF) antigen predicted incident diabetes independent of other diabetes risk factors. We followed 2,924 Framingham Offspring subjects (54% women, mean age 54 years) without diabetes at baseline (defined by treatment, fasting plasma glucose > or =7 or 2-h postchallenge glucose > or =11.1 mmol/l) over 7 years for new cases of diabetes (treatment or fasting plasma glucose > or =7.0 mmol/l). We used a series of regression models to estimate relative risks for diabetes per interquartile range (IQR) increase in PAI-1 (IQR 16.8 ng/ml) and vWF (IQR 66.8% of control) conditioned on baseline characteristics. Over follow-up, there were 153 new cases of diabetes. Age- and sex-adjusted relative risks of diabetes were 1.55 per IQR for PAI-1 (95% CI 1.41-1.70) and 1.49 for vWF (1.21-1.85). These effects remained after further adjustment for diabetes risk factors (including physical activity; HDL cholesterol, triglyceride, and blood pressure levels; smoking; parental history of diabetes; use of alcohol, nonsteroidal anti-inflammatory drugs, exogenous estrogen, or hypertension therapy; and impaired glucose tolerance), waist circumference, homeostasis model assessment of insulin resistance, and inflammation (assessed by levels of C-reactive protein): the adjusted relative risks were 1.18 per IQR for PAI-1 (1.01-1.37) and 1.39 for vWF (1.09-1.77). We conclude that in this community-based sample, plasma markers of endothelial dysfunction increased risk of incident diabetes independent of other diabetes risk factors including obesity, insulin resistance, and inflammation.     

Is obesity an inflammatory disease?

BACKGROUND: Most obese individuals have elevated concentrations of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), markers of inflammation closely associated with diabetes, hypertension, and stroke. HYPOTHESIS: Obesity is a low-grade inflammatory disease, and Roux-en-Y gastric bypass (RYGB) reduces biochemical markers of inflammation and modifies gene expression in hypothalamic food intake/energy-related nuclei and subcutaneous abdominal fat (SAF). METHODS: Obesity was induced in 24 3-week-old Sprague Dawley pups fed a high-energy diet (HED). Three groups (n = 8/group) were studied: RYGB, sham-operated pair-fed, and sham-operated ad libitum HED. Controls were nonobese rats fed chow (n = 6). Rats were killed 10 days after operation, and blood was collected to measure corticosterone and SAF and mesenteric fat to measure IL-6, TNF-alpha, and corticosterone. Total mRNA from arcuate nucleus and SAF purified for gene expression profiling. Data were analyzed with analysis of variance, Mann-Whitney test, and t test. RESULTS: Before operation, the body weight of the obese groups was 493 +/- 7 g and control = 394 +/- 12g. The 10-day postoperative weight was RYGB = 417 +/- 21 g, pair-fed = 436 +/- 14 g, and ad libitum HED = 484 +/- 15 g. Mesenteric and SAF weight decreased in RYGB. Mesenteric/SAF ratio of IL-6, TNF-alpha, corticosterone, and gene profiling showed decrease of inflammation after RYGB. CONCLUSIONS: Gastric bypass reduces biochemical markers of inflammation, suggesting that obesity is an inflammatory condition.     

A genome-wide search for genes involved in type 2 diabetes in a recently genetically isolated population from the Netherlands

Multiple genes, interacting with the environment, contribute to the susceptibility to type 2 diabetes. We performed a genome-wide search to localize type 2 diabetes susceptibility genes in a recently genetically isolated population in the Netherlands. We identified 79 nuclear families with type 2 diabetes who were related within 13 generations and performed a 770-marker genome-wide scan search for shared founder alleles. Twenty-six markers yielded a logarithm of odds (LOD) score >0.59 (nominal P < 0.05), of which 7 reached LOD scores >1.17 (nominal P < 0.01). The strongest evidence for a type 2 diabetes locus was at marker D18S63 on chromosome 18p (LOD 2.3, P = 0.0006). This region was investigated further using additional markers. For one of these markers (D18S1105), we found a significant association with type 2 diabetes (odds ratio 6.7 [95% CI 1.5-30.7], P = 0.005 for the 97-bp allele, assuming a dominant model), which increased when limiting the analysis to patients with high BMI (12.25 [2.1-71], P = 0.003). A locus on chromosome 18p in patients with high BMI was suggested earlier by Parker et al. Our study is the first to confirm this locus.     

Genetic variation at the ACE gene is associated with persistent microalbuminuria and severe nephropathy in type 1 diabetes: the DCCT/EDIC Genetics Study

The development and progression of microvascular complications have been extensively documented in a cohort of type 1 diabetic subjects enrolled in the Diabetes Control and Complications Trial (DCCT) and followed in the Epidemiology of Diabetes Interventions and Complications (EDIC) study. We describe the association of genetic variation in the ACE gene in 1,365 DCCT/EDIC subjects with incident persistent microalbuminuria (n = 312) and severe nephropathy (n = 115). We studied three markers (rs1800764, insertion/deletion, and rs9896208) in the ACE gene that allowed us to capture genetic variation in the common haplotypes occurring at frequencies of >5% in Caucasians. Compared with the more frequent genotype (D/I) for the insertion/deletion polymorphism, in multivariate models, the I/I genotype conferred a lower risk for persistent microalbuminuria (hazard ratio [HR] 0.62 [95% CI 0.43-0.89], P = 0.009) and severe nephropathy (0.56 [0.32-0.96], P = 0.033). Variation at the two other markers, rs1800764 and rs9896208, were also associated with these renal outcomes. In addition, homozygosity for the common haplotype TIC (which corresponded to the T, insertion, and C alleles at the three markers, rs1800764, insertion/deletion, and rs9896208, respectively) versus the CDT/TIC haplotype pair was associated with lower risk for development of persistent microalbuminuria (HR 0.49 [0.32-0.75], P = 0.0009) and severe nephropathy (0.41 [0.22-0.78], P = 0.006). Our findings in the DCCT/EDIC cohort provide strong evidence that genetic variation at the ACE gene is associated with the development of nephropathy in patients with type 1 diabetes.     

Smoking predicts incident fractures in elderly men: Mr OS Sweden

The aim of this study was to investigate the association between smoking and bone mineral density (BMD) and radiographically verified prevalent vertebral fractures and incident fractures in elderly men. At baseline 3003 men aged 69 to 80 years of age from the Swedish Mr Os Study completed a standard questionnaire concerning smoking habits and had BMD of the hip and spine measured using dual‐energy X‐ray absorptiometry (DXA); 1412 men had an X‐ray of the thoracic‐ and lumbar spine. Radiologic registers were used to confirm reported new fractures after the baseline visit. At baseline, 8.4% were current smokers. Current smokers had a 6.2% lower BMD at the total hip and a 5.4% lower BMD at the lumbar spine (p < .001). Current smoking remained independently inversely associated with BMD at the hip and lumbar spine after adjusting for age, height, weight, calcium intake, physical activity, and centers as covariates. Prevalent vertebral fractures among current smokers were increased in unadjusted analyses [odds ratio (OR) = 1.90, 95% confidence interval (CI) 1.26–2.87] and after adjustment for lumbar BMD (OR = 1.67, 95% CI 1.09–2.55). Smokers had a high risk for two or more prevalent vertebral fractures (OR = 3.18, 95% CI 1.88–5.36). During the average follow‐up of 3.3 years, 209 men sustained an X‐ray‐verified fracture. Incident fracture risk among smokers was calculated with Cox proportional hazard models. Current smokers had an increased risk of all new fractures [hazard ratio (HR) = 1.76, 95% CI 1.19–2.61]; nonvertebral osteoporotic fractures, defined as humerus, radius, pelvis, and hip fractures (HR = 2.14, 95% CI 1.18–3.88); clinical and X‐ray‐verified vertebral fractures (HR = 2.53, 95% CI 1.37–4.65); and hip fractures (HR = 3.16, 95% CI 1.44–6.95). After adjustment for BMD, including other covariates, no significant association between smoking and incident fractures was found. Current tobacco smoking in elderly men is associated with low BMD, prevalent vertebral fractures, and incident fractures, especially vertebral and hip fractures. © 2010 American Society for Bone and Mineral Research