Bergamot Polyphenols Improve Dyslipidemia and Pathophysiological Features in a Mouse Model of Non-Alcoholic Fatty Liver Disease.

There is a need for continued drug development for nonalcoholic steatohepatitis (NASH). Bergamot is a plant whose fruit juice is enriched with flavonoids and phenolic compounds which improves dyslipidemia and markers of systemic inflammation in patients with Metabolic Syndrome. The aim of this study was to perform a preclinical "proof of concept" study of Bergamot polyphenolic formulation (BPF99) for the treatment of NASH. A disease reversal study was performed in the diet-induced animal model of NAFLD (DIAMOND). Groups of 8 weeks old mice were randomly assigned to receive chow diet, high fat diet with sugar in drinking water (Western diet- WD). Mice on WD were further randomized to continue on WD gavaged with vehicle or continue on WD with additional gavage of BPF99 (50 mg/kg) after 16 weeks of diet. Mice were euthanized after 11 additional weeks. The primary endpoint was resolution of NASH. Secondary endpoints included changes in individual histological features, body weight, liver enzymes, dyslipidemia, markers of oxidative stress and molecular markers of disease activity and fibrosis. The results showed that BPF99 reduced ALT (mean 71.6 vs 44.6 IU/l, p < 0.01), triglycerides (38.8 vs 28.1 mg/dl, p < 0.05), LDL-C (39.2 vs 23.7 mg/dl, p < 0.001). It significantly improved NASH resolution (p < 0.001) and the SAF scores (p < 0.05) while the NAS improvement approached significance. BPF99 reduced markers of oxidative stress, along with reduced JNK and p38 MAP kinase activity. BPF99 did not reduce the number of mice with fibrosis but improved collagen proportional area (p < 0.04) and procollagen I and III expression. Collectively our results showed that BPF99 resolves NASH and ameliorates key histological and pathophysiological features of NASH along with improvement in ALT and dyslipidemia in the DIAMOND mice.

Effect of Calf Gender on Milk Yield and Fatty Acid Content in Holstein Dairy Cows.

The scale of sexed semen use to avoid the birth of unwanted bull calves in the UK dairy industry depends on several economic factors. It has been suggested in other studies that calf gender may affect milk yield in Holsteins- something that would affect the economics of sexed semen use. The present study used a large milk recording data set to evaluate the effect of calf gender (both calf born and calf in utero) on both milk yield and saturated fat content. Linear regression was used to model data for first lactation and second lactation separately. Results showed that giving birth to a heifer calf conferred a 1% milk yield advantage in first lactation heifers, whilst giving birth to a bull calf conferred a 0.5% advantage in second lactation. Heifer calves were also associated with a 0.66kg reduction in saturated fatty acid content of milk in first lactation, but there was no significant difference between the genders in second lactation. No relationship was found between calf gender and milk mono- or polyunsaturated fatty acid content. The observed effects of calf gender on both yield and saturated fatty acid content was considered minor when compared to nutritional and genetic influences.

Bergamot polyphenol fraction prevents nonalcoholic fatty liver disease via stimulation of lipophagy in cafeteria diet-induced rat model of metabolic syndrome.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized countries. Defective autophagy of lipid droplets (LDs) in hepatocytes, also known as lipophagy, has recently been identified as a possible pathophysiological mechanism of NAFLD. Experimental and epidemiological evidence suggests that dietary polyphenols may prevent NAFLD. To address this hypothesis and analyze the underlying mechanisms, we supplemented bergamot polyphenol fraction (BPF) to cafeteria (CAF) diet-fed rats, a good model for pediatric metabolic syndrome and NAFLD. BPF treatment (50 mg/kg/day supplemented with drinking water, 3 months) potently counteracted the pathogenic increase of serum triglycerides and had moderate effects on blood glucose and obesity in this animal model. Importantly, BPF strongly reduced hepatic steatosis as documented by a significant decrease in total lipid content (-41.3% ± 12% S.E.M.), ultrasound examination and histological analysis of liver sections. The morphometric analysis of oil-red stained sections confirmed a dramatic reduction in LDs parameters such as total LD area (48.5% ± 15% S.E.M.) in hepatocytes from CAF+BPF rats. BPF-treated livers showed increased levels of LC3 and Beclin 1 and reduction of SQSTM1/p62, suggesting autophagy stimulation. Consistent with BPF stimulation of lipophagy, higher levels of LC3II were found in the LD subcellular fractions of BPF-expose livers. This study demonstrates that the liver and its lipid metabolism are the main targets of bergamot flavonoids, supporting the concept that supplementation of BPF is an effective strategy to prevent NAFLD.

Quantifying inter-group variability in lactation curve shape and magnitude with the MilkBot(®) lactation model.

Genetic selection programs have driven development of most lactation models, to estimate the magnitude of animals' productive capacity from sampled milk production data. There has been less attention to management and research applications, where it may also be important to quantify the shape of lactation curves, and predict future daily milk production for incomplete lactations since residuals between predicted and actual daily production can be used to quantify the response to an intervention. A model may decrease the confounding effects of lactation stage, parity, breed, and possibly other factors depending on how the model is constructed and used, thus increasing the power of statistical analyses. Models with a mechanistic derivation may allow direct inference about biology from fitted production data. The MilkBot(®) lactation model is derived from abstract suppositions about growth of udder capacity. This permits inference about shape of the lactation curve directly from parameter values, but not direct conclusions about physiology. Individual parameters relate to the overall scale of the lactation, the ramp , or rate of growth around parturition, decay describing the senescence of productive capacity (inversely related to persistence ), and the relatively insignificant time offset between calving and the physiological start of milk secretion. A proprietary algorithm was used to fit monthly test data from two parity groups in 21 randomly selected herds, and results displayed in box-and-whisker charts and Z-test tables. Fitted curves are constrained by the MilkBot(®) equation to a single peak that blends into an exponential decline in late lactation. This is seen as an abstraction of productive capacity, with actual daily production higher or lower due to random error plus short-term environmental effects. The four MilkBot(®) parameters, and metrics calculated directly from them including fitting error, peak milk and cumulative production, can be used to describe and compare individual lactations or groups of lactations. There is considerable intra-herd and inter-herd variability in scale, ramp, decay, RMSE, peak milk, and cumulative production, suggesting that management and environment have significant influence on both shape and magnitude of normal lactation curves.

Effect of antioxidants on X-ray-induced γ-H2AX foci in human blood lymphocytes: preliminary observations.

PURPOSE: To investigate the effect of a radioprotective oral agent containing a formulation of antioxidants and glutathione-elevating compounds on the extent of x-ray-induced γ-H2AX foci formation. MATERIALS AND METHODS: The study was approved by local ethics committee and informed consent was obtained from each subject. In vitro experiments with blood lymphocytes of 25 healthy volunteers were performed without antioxidants and with antioxidants added either before or immediately after irradiation (10 mGy). For in vivo/in vitro tests, blood samples were obtained before, 15, 30, and 60 minutes (n=17) after, and 2, 3, and 5 hours (n=11) after oral ingestion of antioxidant pills and were irradiated (10 mGy). DNA double-strand breaks (DSBs) were quantified in isolated lymphocytes 5 minutes (in vitro and in vivo/in vitro) and 15 minutes (in vitro) after irradiation by enumerating γ-H2AX foci. To validate the data, additional in vitro experiments with use of 53BP1 as another independent marker for DSBs were performed. Nonirradiated samples served as controls. Statistical analyses were performed by using Wilcoxon rank-sum tests (in vitro), repeated-measures test, and Dunnett test (in vivo/in vitro). RESULTS: In the in vitro experiments, 15-minute preincubation with antioxidants significantly reduced mean γ-H2AX foci levels by 23% (P<.0001), whereas addition of antioxidants immediately after irradiation did not lead to a reduction of x-ray-induced foci (P=.6905). Mean 53BP1 foci were also reduced by preincubation with the radioprotectant. In the in vivo/in vitro tests, oral pretreatment with antioxidants also led to a significant reduction of γ-H2AX foci formation; administration 60 minutes before irradiation resulted in a mean foci reduction of 58% (P<.0001). CONCLUSION: The tested formulation of antioxidants significantly reduced formation of γ-H2AX and 53BP1 foci after irradiation at a radiologic radiation dose typical for computed tomographic imaging; administration 60 minutes prior to irradiation seems to be appropriate and leads to a significant reduction in foci.

Lipoprotein-associated phospholipase A2 activity predicts progression of subclinical coronary atherosclerosis.

BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a lipoprotein-associated enzyme that cleaves oxidized phosphatidylcholines, generating pro-atherosclerotic lysophosphatidylcholine and oxidized free fatty acids. Lp-PLA2 is independently associated with cardiovascular disease (CVD) in a variety of populations. Coronary calcium is a measure of subclinical CVD, and progression of coronary calcification predicts future CVD events. In type 1 diabetes there is an increase in coronary calcium and CVD despite a favorable lipid profile. Levels of Lp-PLA2 in type 1 diabetes are not known, nor is the relationship between Lp-PLA2 and progression of coronary calcification. METHODS: The Coronary Artery Calcification in Type 1 Diabetes study measured coronary calcium by electron-beam computed tomography twice over a 2.6 ± 0.3-year interval. Lp-PLA2 mass and activity were measured at baseline (n = 1,097 subjects, 506 with and 591 without type 1 diabetes). RESULTS: In type 1 diabetes Lp-PLA2 mass was marginally higher (285 ± 79 vs. 278 ± 78 ng/mL, P = 0.1), and Lp-PLA2 activity was significantly lower (137 ± 30 vs. 146 ± 36 nmol/min/mL, P < 0.0001) than in those without diabetes. There was a greater proportion of those with progression of coronary calcification in type 1 diabetes compared with those without diabetes (24% vs. 10%, P < 0.0001). Lp-PLA2 activity was independently associated with progression of coronary calcification in multivariate analysis (4th quartile verses bottom three quartiles, odds ratio = 1.77 [1.08-2.91], P = 0.02). LpPLA2 mass was not significantly associated with progression of coronary calcification in this cohort (P = 0.09). CONCLUSIONS: Lp-PLA2 activity predicts progression of subclinical atherosclerosis in individuals with and without type 1 diabetes.

Reduced heart rate variability predicts progression of coronary artery calcification in adults with type 1 diabetes and controls without diabetes.

AIM: Reduced heart rate variability (HRV) is a manifestation of cardiac autonomic neuropathy, a known complication of type 1 diabetes (T1D). We evaluated whether HRV predicted coronary artery calcium (CAC) progression. METHODS: Subjects between 19 and 56 years of age with T1D or those without diabetes from the Coronary Artery Calcification in Type 1 Diabetes study underwent supine deep breathing 12-lead electrocardiograms. The SD of consecutive RR intervals was used as a measure of HRV. CAC was measured at two visits 6.0 ± 0.5 years apart. Progression of CAC was defined as an increase in square root transformed CAC volume of ≥ 2.5 mm(3), excluding patients who had cardiovascular events during follow-up. RESULTS: Reduced HRV was associated with older age, higher hemoglobin A1c, elevated albuminuria, CAC volume at baseline, and increased fibrinogen. Higher HRV at baseline was associated with lower likelihood CAC progression (odds ratio = 0.71, 95% confidence interval 0.56-0.90, P = 0.005), and the adjustment for known cardiovascular risk factors did not change this strong association, including adjustment for inflammatory markers. CONCLUSIONS: Reduced HRV predicted progression of CAC in adults with and without T1D. This association further supports the participation of autonomic neuropathy in the atherosclerosis process.

Reproductive history and hormonal birth control use are associated with coronary calcium progression in women with type 1 diabetes mellitus.

CONTEXT: Coronary artery disease is increased in women with type 1 diabetes (T1D), compared with nondiabetic (Non-DM) women. Women with T1D have more menstrual dysfunction and are less likely to use hormonal birth control (BC) than Non-DM women. OBJECTIVE: The purpose of this study was to determine whether coronary artery calcium (CAC) is associated with menstrual dysfunction and BC use in women with T1D. MATERIALS AND METHODS: This was a prospective cohort study, and participants were followed up for an average of 2.4 yr. PATIENTS: Patients included 612 women (293 T1D, 319 Non-DM) between the ages of 19 and 55 yr who had CAC measured twice by electron beam tomography. RESULTS: Irregular menses and amenorrhea were more common in T1D than Non-DM women (22.1 vs. 14.9%, P < 0.05 and 16.6 vs. 7.0%, P < 0.001). T1D women reported less BC use than Non-DM women (79.8 vs. 89.9%, P < 0.001) and reached menarche at an older age (13.1 +/- 1.8 vs. 12.8 +/- 1.5 yr, P < 0.05). Use of BC was associated with less CAC progression in all women, but this association was stronger in T1D women (P value for interaction = 0.02). Irregular menses were associated with greater CAC progression only among T1D women. CONCLUSIONS: A prior history of BC use is associated with reduced CAC progression among all women, with a stronger association in T1D than in Non-DM women. Women with T1D who report irregular menses have increased CAC progression, compared with those with regular menses.

Coronary artery calcium scanning: Clinical paradigms for cardiac risk assessment and treatment.

BACKGROUND: Coronary artery calcium (CAC) scanning is being increasingly used for cardiac risk assessment in asymptomatic patients, particularly in those with a Framingham 10-year risk of 10% to 20%. Physician awareness of this technology and its appropriate uses and limitations is crucial to appropriate use. METHODS: With the goal of establishing clinical paradigms, this document integrates the results of key published articles, Framingham Risk Score, National Cholesterol Education Program Adult Treatment Plan III guidelines, American College of Cardiology/American Heart Association exercise testing and angiographic guidelines, and the authors' extensive clinical experience. RESULTS: Coronary artery calcium scanning is best used in the asymptomatic population with a 10% to 20% risk of cardiac events over 10 years, with selected application in higher and lower risk categories. In the 10%-20% risk patient, coronary artery calcium scores >100 or >75th percentile for age and sex transform the moderately high-risk patient to higher risk status with the attendant recommendation for more aggressive therapy; scores from 11 to 100 and <75th percentile are consistent with the 10%-20% 10-year risk status and scores from 0 to 10 and <75th percentile convert the patient to lesser risk categories. If stress testing is planned in the asymptomatic patient, it should be preceded by coronary artery calcium scanning and performed only for scores >400; it should always precede coronary angiography in these patients. CONCLUSIONS: Coronary artery calcium scanning is an important risk assessment tool with direct clinical applications; it is of particular utility in the Framingham 10%-20% 10-year risk population.

A randomized trial of pegylated interferon alpha-2b plus ribavirin in the retreatment of chronic hepatitis C.

OBJECTIVES: The efficacy of combination therapy with pegylated interferon (PEG IFN) alpha plus ribavirin (RBV) in the retreatment of chronic hepatitis C (CHC) in patients who previously failed combination standard IFN plus RBV or IFN monotherapy has not been well established. METHODS: Three hundred and twenty-one CHC patients including virologic nonresponders to combination IFN plus RBV (n = 219) or IFN monotherapy (n = 47), and relapsers to combination therapy (n = 55) were randomized to receive PEG IFN alpha-2b 1.5 microg/kg per wk plus RBV 800 mg per day (Regimen A, n = 160) or PEG IFN alpha-2b 1.0 microg/kg per wk plus RBV 1,000-1,200 mg per day (Regimen B, n = 161) for 48 wks. RESULTS: Sustained virologic response (SVR) occurred in 16% of the overall study population (Regimen A vs B, 18%vs 13%, p= 0.21), in 8% of the combination therapy nonresponders (10%vs 6%, p= 0.35), in 21% of the IFN monotherapy nonresponders (16%vs 27%, p= 0.35), and in 42% of the combination therapy relapsers (50%vs 32%, p= 0.18). In nonresponders to prior combination therapy, HCV ribonucleic acid levels <100,000 copies/mL at the end of the prior treatment course were associated with an increased SVR compared with levels >or=100,000 copies/mL (21%vs 5%, p= 0.002). In the overall study population, genotype 1 patients had lower SVR rates than others (14%vs 33%, p= 0.01), and African Americans had lower SVR than Caucasians (4%vs 18%, p= 0.01). CONCLUSION: Combination therapy with PEG IFN alpha-2b plus RBV is more effective in patients who relapsed after combination standard IFN plus RBV than in nonresponders to either combination therapy or IFN monotherapy. There was no significant effect of dosing regimen.

Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis.

BACKGROUND: Hemodialysis patients are at increased risk for progressive coronary artery calcification; however, the development and progression of this disease process in patients new to hemodialysis is unknown. METHOD: One hundred and twenty-nine patients new to hemodialysis were randomized to receive calcium containing phosphate binders or the noncalcium phosphate binder sevelamer hydrochloride. Subjects underwent electron beam computed tomography scanning (EBCT) at entry into the study and again at 6, 12, and 18 months. RESULTS: One hundred and nine patients underwent baseline and at least one additional assessment of coronary calcification. At baseline, 37% of sevelamer treated and 31% of calcium treated patients had no evidence of coronary calcification. No subject with a zero coronary artery calcium score (CACS) at baseline progressed to a CACS >30 over 18 months. Subjects with a CACS > 30 at baseline showed progressive increases in CACS in both treatment arms (P < 0.05 for each time point in both groups). Subjects treated with calcium containing phosphate binders showed more rapid and more severe increases in CACS when compared with those receiving sevelamer hydrochloride (P= 0.056 at 12 months, P= 0.01 at 18 months). CONCLUSION: New hemodialysis patients with no evidence of coronary calcification showed little evidence of disease development over 18 months independent of phosphate binder therapy. However, subjects with evidence of at least mild coronary calcification had significant progression at 6, 12, and 18 months. Use of calcium containing phosphate binders resulted in more rapid progression of coronary calcification than did use of sevelamer hydrochloride.

Low plasma adiponectin levels predict progression of coronary artery calcification.

BACKGROUND: Circulating adiponectin levels are lower in men than in women and lower in advanced coronary artery disease, obesity, and type 2 but not type 1 diabetes. However, it is not known whether low adiponectin levels predict development of atherosclerosis independently of other cardiovascular risk factors. METHODS AND RESULTS: Progression of coronary artery calcification (CAC) over an average of 2.6 years (range, 1.6 to 3.3) was assessed in a cohort of patients with type 1 diabetes and nondiabetic subjects 19 to 59 years of age. In this nested case-control substudy, plasma adiponectin levels were measured in 101 cases with significant CAC progression and in 205 controls. Controls were oversampled on the basis of age, gender, diabetes status, and presence of baseline CAC. In conditional logistic regression adjusted for baseline CAC volume and other significant predictors of CAC progression, adiponectin levels were inversely related to progression of CAC in diabetic (OR, 0.47; 95% CI, 0.24 to 0.94) and nondiabetic (OR, 0.15; 95% CI, 0.05 to 0.40 for a doubling in adiponectin levels) subjects. Adjustment for additional cardiovascular risk factors did not change this association. In conditional logistic regression models by quartiles of plasma adiponectin levels, the probability value for trend was statistically significant for all participants (P<0.001) and nondiabetic participants (P<0.001) and was borderline for type 1 diabetics (P=0.08). CONCLUSIONS: Low plasma adiponectin levels are associated with progression of CAC in type 1 diabetic and nondiabetic subjects independently of other cardiovascular risk factors.

Hypertension prevalence, awareness, treatment, and control in an adult type 1 diabetes population and a comparable general population.

OBJECTIVE: To compare the prevalence, awareness, treatment, and control of hypertension in a population-representative sample of adults with type 1 diabetes and comparable nondiabetic control subjects. RESEARCH DESIGN AND METHODS: In 2000-2002, the Coronary Artery Calcification in Type 1 Diabetes Study enrolled 1,416 individuals aged 19-56 years with no known history of coronary artery disease: 652 type 1 diabetic patients (46% male, mean age 37 years) and 764 nondiabetic control subjects (50% male, mean age 39 years). Subjects were asked if they had been told by a physician that they had hypertension or were on a blood pressure medication. Blood pressure was measured using standardized Joint National Committee (JNC) protocol. RESULTS: Type 1 diabetic subjects, compared with nondiabetic subjects, had higher rates of hypertension prevalence (43 vs. 15%, P < 0.001), awareness (53 vs. 45%, P = 0.11), treatment (87 vs. 47%, P < 0.001), and control (55 vs. 32%, P < 0.001) for the JNC 6 goal (130/85 mmHg). Only 42% of all type 1 diabetic hypertensive subjects met the new JNC 7 goal (130/80 mmHg). Type 1 diabetic subjects had better blood pressure control (72 vs. 32%, P < 0.0001), using 140/90 mmHg as a common measure. The majority of treated subjects were on a single antihypertensive agent (75 vs. 64%). CONCLUSIONS: Subjects with type 1 diabetes have higher rates of hypertension prevalence, treatment, and control than nondiabetic subjects. However, hypertension remains largely uncontrolled, even if treated in high-risk populations, such as type 1 diabetic subjects and undiagnosed individuals in the general population. Achieving more stringent blood pressure goals will require increased attention and may necessitate the use of multiple antihypertensive agents.

Evaluating changes in coronary artery calcium: an analytic method that accounts for interscan variability.

OBJECTIVE: Coronary calcium measured by electron beam CT is associated with coronary disease and can be used to predict coronary disease events. Studies investigating changes in coronary calcium need to address interscan variability as it relates to the overall coronary calcium score in defining progression or regression of coronary calcium over time. SUBJECTS AND METHODS. Electron beam CT was performed on 1,074 participants. Coronary calcium volume scores were repeated 5 min apart. Interscan variability was examined using Bland-Altman plots and homogeneity tests. Transformations of the Box-Cox family (including power, roots, and logarithm) were applied to calcium volume scores. The transformation that stabilized the variation in calcium volume scores was applied to progression of calcium volume scores in 109 subjects with diabetes. RESULTS: The variability in calcium volume score increased as the level of coronary calcium increased (rho = 0.67, p < 0.001 for the relation between the absolute difference and the mean value of calcium volume scores). This heterogeneity was removed using the square root transformation of the calcium volume score (rho = 0.09, p < 0.15 for the relation between the absolute difference in the square root of the calcium volume score and the mean square root of the calcium volume score). This transformation was applied to calcium volume scores taken a mean of 2.7 years apart in 109 subjects with diabetes. A significant change in calcium volume score was defined as a difference between the square root-transformed to calcium volume scores greater than or equal to 2.5 mm(3) (> 99th percentile of interscan variability). Significant progression was observed in 10% of the subjects. The square root of the calcium volume score corrected for the bias in progression of calcium volume because of the level of coronary calcium. CONCLUSION: Using the square root of the calcium volume score stabilized interscan variability across the range of coronary calcium. Defining change in coronary calcium as greater than or equal to 2.5 mm(3) of the difference in the square root-transformed calcium volume scores provided an estimate that was unbiased with respect to baseline coronary calcium. This analytic technique may facilitate investigations of the relevance of changes in coronary calcium to clinical outcomes and the use of changes in coronary calcium as a measure of the therapeutic impact on subclinical disease in clinical trials.

Coronary and aortic calcifications in patients new to dialysis.

BACKGROUND: Vascular calcification has been associated with all cause and cardiovascular mortality in patients with end-stage kidney disease (ESRD). Whether vascular calcification is present in persons with advanced chronic kidney disease starting dialysis or develops in patients on dialysis is unknown. The purpose of this study was to examine the prevalence of vascular and coronary calcification in patients new to hemodialysis. METHODS: A total of 129 subjects new to dialysis were evaluated using electron beam computed tomography. The primary outcome was the presence and extent of coronary artery, aortic, and valvular calcification. RESULTS: Forty-three percent of subjects had no significant coronary artery calcification (total score

Effect of type 1 diabetes on the gender difference in coronary artery calcification: a role for insulin resistance? The Coronary Artery Calcification in Type 1 Diabetes (CACTI) Study.

The objective of this is study was to examine whether estimated insulin resistance and insulin resistance-related factors are associated with coronary artery calcification (CAC) in 1,420 asymptomatic participants in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study. A total of 656 patients with type 1 diabetes and 764 control subjects aged 20-55 years were examined. CAC was assessed by electron-beam computed tomography. Insulin resistance was computed with linear regression based on an equation previously validated in clamp studies on type 1 diabetic adults. Insulin resistance was associated with CAC (OR 1.6 in type 1 diabetes and 1.4 in control subjects, P < 0.001), independent of coronary artery disease risk factors. There was a male excess of CAC in control subjects (OR 2.7, adjusted for age, smoking, and LDL and HDL cholesterol levels) and in type 1 diabetic patients (OR 2.2, adjusted for the same factors and diabetes duration). After adjusting for insulin resistance, the CAC male excess in diabetic patients decreased from OR 2.2 (P < 0.001) to 1.8 (P = 0.04). After adjustment for waist-to-hip ratio, waist circumference, or visceral fat, the gender difference in CAC was not significant in diabetic subjects. In conclusion, gender differences in insulin resistance-associated fat distribution may explain why type 1 diabetes increases coronary calcification in women relatively more than in men.

Progression of coronary artery calcification in type 1 diabetes: the importance of glycemic control.

OBJECTIVE: Coronary artery disease (CAD) occurs earlier in life and is more often fatal in people with type 1 diabetes. This excess risk seems to be higher than in those with type 2 diabetes and is poorly explained by conventional risk factors. The role of glycemic control is controversial and has not been previously addressed in a prospective manner using a reliable marker for subclinical CAD, such as coronary artery calcification (CAC), measured by electron beam computed tomography (EBCT). RESEARCH DESIGN AND METHODS: We measured CAC twice during an interval of 2.7 years in 109 men and women with type 1 diabetes (aged 22-50 years). Progression of CAC was found in 21 patients, based on change in the square root-transformed volume score. RESULTS: In multiple logistic regression, CAC progression was associated with baseline hyperglycemia (odds ratio [OR] 7.11, 95% CI 1.38-36.6, P = 0.02), adjusted for the presence of CAC at baseline (P = 0.01), duration of diabetes (P = 0.02), sex (P = 0.09), and age (P = 0.27). There was also a significant interactive effect of higher insulin dose and higher BMI (P = 0.03). CONCLUSIONS: In conclusion, in this young cohort with type 1 diabetes, suboptimal glycemic control (HbA(1c) >7.5%) was a strong risk factor for progression of CAC. Insulin resistance may also play a role.