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1.  Insulin-like Growth Factor I Reduces Lipid Oxidation and Foam Cell Formation via Downregulation of 12/15-lipoxygenase 
Atherosclerosis  2014;238(2):313-320.
We have shown that insulin-like growth factor I (IGF-1) infusion in Apoe−/− mice decreased atherosclerotic plaque size and plaque macrophage and lipid content suggesting that IGF-1 suppressed formation of macrophage-derived foam cells. Since 12/15-lipoxygenase (12/15-LOX) plays an important role in OxLDL and foam cell formation, we hypothesized that IGF-1 downregulates 12/15-LOX, thereby suppressing lipid oxidation and foam cell formation.
Approach and Results
We found that IGF-1 decreased 12/15-LOX plaque immunopositivity and serum OxLDL levels in Apoe−/− mice. IGF-1 reduced 12/15-LOX protein and mRNA levels in cultured THP-1 macrophages and IGF-1 also decreased expression of STAT6 transcription factor. IGF-1 reduction in macrophage 12/15-LOX was mediated in part via a PI3 kinase- and STAT6-dependent transcriptional mechanism. IGF-1 suppressed THP-1 macrophage ability to oxidize lipids and form foam cells. IGF-1 downregulated 12/15-LOX in human blood-derived primary macrophages and IGF-1 decreased LDL oxidation induced by these cells. IGF-1 reduced LDL oxidation and formation of foam cells by wild type murine peritoneal macrophages, however these effects were completely blocked in 12/15-LOX-null macrophages suggesting that the ability of IGF-1 to reduce LDL oxidation and foam cells formation is dependent on its ability to downregulate 12/15-LOX.
Overall our data demonstrate that IGF-1 reduces lipid oxidation and foam cell formation via downregulation of 12/15-LOX and this mechanism may play a major role in the anti-atherosclerotic effects of IGF-1.
PMCID: PMC4298481  PMID: 25549319
Atherosclerosis; LDL/Oxidation/antioxidants; Lipoxygenase; Macrophages / monocytes; Oxidized lipids; Foam cells
2.  Reproductive History and Chronic Hepatic Steatosis in the Michigan Study of Women's Health Across the Nation 
Journal of Women's Health  2015;24(1):42-48.
Background: Reproductive history, particularly maternal age at most recent birth, may reflect lower risk for chronic disease and mortality due to socioeconomic factors, lifestyle behaviors, or genetics. Reproductive history has not been examined with respect to hepatic steatosis, the most common liver disease in the United States. Our objective was to examine the association between reproductive history and hepatic steatosis.
Methods: We examined the association between reproductive history characteristics—specifically age at most recent birth—and the odds of moderate to severe hepatic steatosis using a population-based retrospective cohort study of women who underwent hepatic ultrasound at the Michigan site of the Study of Women's Health Across the Nation (n=331).
Results: Women who gave birth at ≥35 years of age comprised 19% of the study population and were similar to other women regarding sociodemographic history and health behaviors. In multivariable analyses adjusting for age, race/ethnicity, chronic disease, and medications associated with hepatic steatosis, age at birth ≥35 years was associated with significantly decreased odds of hepatic steatosis (adjusted odds ratio [OR] 0.41, 95% confidence interval [CI] 0.20–0.87), which was attenuated after adjustment for waist circumference (OR 0.51, 95% CI 0.24–1.10). Other reproductive factors including gravidity, parity, miscarriages and abortions, recall of gestational weight gain, breastfeeding, age at first birth, and age at final menstrual period were not associated with hepatic steatosis.
Conclusions: Women who were older at their most recent birth had a reduced odds of hepatic steatosis, possibly associated with their lower waist circumference.
PMCID: PMC4303017  PMID: 25548857
3.  Weight loss results in a small decrease in follicle stimulating hormone in overweight glucose-intolerant postmenopausal women 
Obesity (Silver Spring, Md.)  2014;23(1):228-233.
Structured Abstract
To examine the impact of a weight loss intervention upon follicle stimulating hormone (FSH) levels in postmenopause.
Design and Methods
Participants were postmenopausal, overweight, glucose-intolerant women not using exogenous estrogen (n=382) in the Diabetes Prevention Program. Women were randomized to intensive lifestyle change (ILS) with the goals of weight reduction of at least 7% of initial weight and 150 minutes per week of moderate intensity exercise, metformin 850 mg, or placebo administered twice a day.
Randomization to ILS led to small increases in FSH between baseline and 1-year follow-up vs. placebo (2.3 IU/l vs. -0.81 IU/l, p<0.01). Increases in FSH were correlated with decreases in weight (r=-0.165, p<0.01) and E2 (r=-0.464, p<0.0001) after adjustment for age, race/ethnicity, and randomization arm. Changes in FSH were still significantly associated with changes in weight even after adjustment for E2 levels. Metformin users had reductions in weight but non-significant changes in FSH and E2 levels vs. placebo.
Weight loss leads to small increases in FSH among overweight, postmenopausal women, potentially through pathways mediated by endogenous estrogen as well as other pathways.
PMCID: PMC4276440  PMID: 25294746
follicle stimulating hormone; menopause; weight
4.  Lactation Intensity and Fasting Plasma Lipids, Lipoproteins, Non-esterified Free Fatty Acids, Leptin and Adiponectin in Postpartum Women with Recent Gestational Diabetes Mellitus: The SWIFT cohort 
Lactation may influence future progression to type 2 diabetes after gestational diabetes mellitus (GDM). However, biomarkers associated with progression to glucose intolerance have not been examined in relation to lactation intensity among postpartum women with previous GDM. This study investigates whether higher lactation intensity is related to more favorable blood lipids, lipoproteins and adipokines after GDM pregnancy independent of obesity, socio-demographics and insulin resistance.
The Study of Women, Infant Feeding, and Type 2 Diabetes (SWIFT) is a prospective cohort study that recruited 1,035 women diagnosed with GDM by the 3-hour 100 g oral glucose tolerance tests (OGTTs) after delivery of a live birth in 2008–2011. Research staff conducted 2-hour 75 gram OGTTs, and assessed lactation intensity, anthropometry, lifestyle behaviors and socio-demographics at 6–9 weeks postpartum (baseline). We assayed fasting plasma lipids, lipoproteins, non-esterified free fatty acids, leptin and adiponectin from stored samples obtained at 6–9 weeks postpartum for in 1,007 of the SWIFT participants who were free of diabetes at baseline. Mean biomarker concentrations were compared among lactation intensity groups using multivariable linear regression models.
Increasing lactation intensity showed graded monotonic associations with fully adjusted mean biomarkers: 5–8% higher high-density lipoprotein cholesterol (HDL-cholesterol), 20–28% lower fasting triglycerides, 15–21% lower leptin (all trend P-values<0.01), and with 6% lower adiponectin, but only after adjustment for insulin resistance (trend P-value=0.04).
Higher lactation intensity was associated with more favorable biomarkers for type 2 diabetes, except for lower plasma adiponectin, after GDM delivery. Long-term follow-up studies are needed to assess whether these effects of lactation persist to predict progression to glucose intolerance.
PMCID: PMC4076292  PMID: 24931281
Adipokines; Insulin Resistance; Diabetes Mellitus; Gestational Diabetes Mellitus (GDM); Breastfeeding; Postpartum; Metabolism
5.  Risk of Incident Coronary Heart Disease Events in Men Compared to Women by Menopause Type and Race 
We examined whether type of menopause affects sex differences in coronary heart disease (CHD) events and whether the impact is similar in blacks and whites.
Methods and Results
Participants were enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort between 2003 and 2007 without CHD at baseline (n=23 086). Cox regression models were used to calculate the hazard of incident nonfatal CHD (definite or probable myocardial infarction) and acute CHD death, adjusting for age, age at last menstrual period <45 years, region, education level, income, diabetes, smoking, systolic blood pressure, lipid levels, albumin-creatinine ratio, physical activity, C-reactive protein, body mass index, waist circumference, and medication use. White women in natural menopause (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.31, 0.66) and surgical menopause (HR, 0.65; 95% CI, 0.42, 0.99) had a reduced hazard of nonfatal events, compared to white men. Black women in natural menopause (HR, 0.69; 95% CI, 0.47, 1.03), but not surgical menopause (HR, 0.81; 95% CI, 0.51, 1.29), had a marginally reduced hazard of nonfatal events, compared to black men. Women had lower risk of acute CHD death than men regardless of their menopause type and race.
Sex differences in the risk of incident CHD events were larger among whites than blacks and varied by type of menopause. Women consistently had a lower risk of incident CHD death than men, but the magnitude of sex differences was greater in whites than blacks for nonfatal events, regardless of menopause type.
PMCID: PMC4608073  PMID: 26133958
coronary disease; epidemiology; sex; women
6.  Sex differences in the association of fasting and postchallenge glucose levels with grip strength among older adults: the Rancho Bernardo Study 
Persons with diabetes have accelerated muscle loss. The association of fasting and postchallenge glucose levels per se to grip strength, a clinical marker of poor physical function, and potential sex differences in this relationship has not been previously described.
Longitudinal cohort.
Participants were community-dwelling older adults (mean age 71.3 years) without self-reported diabetes and/or use of diabetes medication with glucose measured at baseline (1992–1996).
Fasting plasma glucose (FPG) was measured in 1019 women and 636 men. Two-hour glucose (2HG) levels after a 75 g oral glucose tolerance test were also available (women, n=870; men, n=559). Dominant hand grip strength was assessed using a hand-held dynamometer at 3.0±1.6 visits over a median 7.0 years. Mixed linear models examined the association of baseline glucose levels with grip strength, accounting for repeated visits, and adjusting for covariates.
Sex-specific FPG quartiles were associated with unadjusted differences in grip strength among women (p=0.03) but not men (p=0.50). However, in men, adjusting for age, education, height, weight, peripheral neuropathy, physical activity, and comorbidities, each SD (SD=17 mg/dL) higher FPG was associated with persistently lower grip strength (−0.44±0.22 kg, p=0.049); 2HG (SD=50 mg/dL) was unrelated to grip strength (−0.39±0.25 kg, p=0.13). In women, neither FPG (SD=16 mg/dL) nor 2HG (SD=45 mg/dL) was associated with grip strength (0.02±0.12 kg, p=0.90; and −0.20±0.14 kg, p=0.14; respectively) after adjustment. The rate of change in grip strength did not differ across FPG or 2HG quartiles in either sex.
In age-adjusted analyses, elevated fasting glucose levels are associated with persistently lower grip strength in older men, but not women. Future studies are needed to elucidate reasons for these sex differences and may provide further insight into accelerated loss of muscle function as a complication of diabetes in older adults.
PMCID: PMC4419462  PMID: 25969742
Elderly; Sex Difference; Muscle Weakness; Epidemiology
7.  Does hormone therapy affect blood pressure changes in the Diabetes Prevention Program? 
Menopause (New York, N.Y.)  2014;21(5):477-483.
To examine whether blood pressure reductions differ by estrogen use among overweight glucose-intolerant women.
We conducted a secondary analysis of postmenopausal Diabetes Prevention Program participants who used oral estrogen with or without progestogen at baseline and at 1-year follow-up (n=324) vs. those who did not use at either time point (n=382). Systolic (SBP) and diastolic blood pressure (DBP) changes were examined by randomization arm (intensive lifestyle change (ILS), metformin 850 mg twice daily, or placebo). Associations between changes in blood pressure with changes in sex hormone binding globulin, estradiol, testosterone, and dehydroepiandrosterone were also examined.
Estrogen users and non-users had similar prevalences of baseline hypertension (33% vs. 34%, p=0.82) and use of blood pressure medications at baseline (p=0.25) and follow-up (p=0.10). Estrogen users and non-users randomized to ILS had similar decreases in SBP (-3.3 vs. -4.7 mmHg, p=0.45) and DBP (-3.1 vs. -4.7 mmHg, p=0.16). Among estrogen users, women randomized to ILS had significant declines in SBP (p=0.016) and DBP (p=0.009) vs. placebo. Among non-users, women randomized to ILS had significant declines in DBP (p=0.001) vs. placebo, but declines in SBP were not significant (p=0.11). Metformin was not associated with blood pressure reductions vs. placebo regardless of estrogen therapy. Blood pressure changes were not associated with changes in sex hormones regardless of estrogen therapy.
Among overweight women with dysglycemia, the magnitude of blood pressure reductions after ILS was unrelated to postmenopausal estrogen use.
PMCID: PMC3858523  PMID: 23942251
lifestyle change; hypertension; postmenopausal hormone therapy
8.  Prepregnancy SHBG Concentrations and Risk for Subsequently Developing Gestational Diabetes Mellitus 
Diabetes Care  2014;37(5):1296-1303.
Lower levels of sex hormone–binding globulin (SHBG) have been associated with increased risk of diabetes among postmenopausal women; however, it is unclear whether they are associated with glucose intolerance in younger women. We examined whether SHBG concentrations, measured before pregnancy, are associated with risk of gestational diabetes mellitus (GDM).
This was a nested case-control study among women who participated in the Kaiser Permanente Northern California Multiphasic Health Check-up examination (1984–1996) and had a subsequent pregnancy (1984–2009). Eligible women were free of recognized diabetes. Case patients were 256 women in whom GDM developed. Two control subjects were selected for each case patient and were matched for year of blood draw, age at examination, age at pregnancy, and number of intervening pregnancies.
Compared with the highest quartile of SHBG concentrations, the odds of GDM increased with decreasing quartile (odds ratio 1.06 [95% CI 0.44–2.52]; 2.33 [1.07–5.09]; 4.06 [1.90–8.65]; P for trend < 0.001), after adjusting for family history of diabetes, prepregnancy BMI, race/ethnicity, alcohol use, prepregnancy weight changes, and homeostasis model assessment of insulin resistance. Having SHBG levels below the median (<64.5 nmol/L) and a BMI ≥25.0 kg/m2 was associated with fivefold increased odds of GDM compared with normal-weight women with SHBG levels at or above the median (5.34 [3.00–9.49]).
Low prepregnancy SHBG concentrations were associated with increased risk of GDM and might be useful in identifying women at risk for GDM for early prevention strategies.
PMCID: PMC3994937  PMID: 24561392
9.  Are Gestational Diabetes Mellitus and Preconception Diabetes Mellitus Less Common in Non-Hispanic Black Women than in Non-Hispanic White Women? 
Maternal and child health journal  2014;18(3):698-706.
Based on their higher risk of type 2 diabetes, non-Hispanic blacks (NHBs) would be expected to have higher gestational diabetes mellitus (GDM) risk compared to non-Hispanic whites (NHWs). However, previous studies have reported lower GDM risk in NHBs versus NHWs. We examined whether GDM risk was lower in NHBs and NHWs, and whether this disparity differed by age group. The cohort consisted of 462,296 live singleton births linked by birth certificate and hospital discharge data from 2004 to 2007 in Florida. Using multivariable regression models, we examined GDM risk stratified by age and adjusted for body mass index (BMI) and other covariates. Overall, NHBs had a lower prevalence of GDM (2.5 vs. 3.1 %, p < 0.01) and a higher proportion of preconception DM births (0.5 vs. 0.3 %, p ≤ 0.01) than NHWs. Among women in their teens (risk ratio 0.56, p < 0.01) and 20–29 years of age (risk ratio 0.85, p < 0.01), GDM risk was lower in NHBs than NHWs. These patterns did not change with adjustment for BMI and other covariates. Among women 30–39 years (risk ratio 1.18, p < 0.01) and ≥40 years (risk ratio 1.22, p < 0.01), GDM risk was higher in NHBs than NHWs, but risk was higher in NHWs after adjustment for BMI. Associations between BMI and GDM risk did not vary by race/ethnicity or age group. NHBs have lower risk of GDM than NHWs at younger ages, regardless of BMI. NHBs had higher risk than NHWs at older ages, largely due to racial/ethnic disparities in overweight/obesity at older ages.
PMCID: PMC3884046  PMID: 23793482
Race; Ethnicity; Birth certificates; Prenatal; Gestational diabetes; Diabetes mellitus; Type 2 diabetes mellitus
10.  Genetic Risk of Progression to Type 2 Diabetes and Response to Intensive Lifestyle or Metformin in Prediabetic Women With and Without a History of Gestational Diabetes Mellitus 
Diabetes Care  2014;37(4):909-911.
The Diabetes Prevention Program (DPP) trial investigated rates of progression to diabetes among adults with prediabetes randomized to treatment with placebo, metformin, or intensive lifestyle intervention. Among women in the DPP, diabetes risk reduction with metformin was greater in women with prior gestational diabetes mellitus (GDM) compared with women without GDM but with one or more previous live births.
We asked if genetic variability could account for these differences by comparing β-cell function and genetic risk scores (GRS), calculated from 34 diabetes-associated loci, between women with and without histories of GDM.
β-Cell function was reduced in women with GDM. The GRS was positively associated with a history of GDM; however, the GRS did not predict progression to diabetes or modulate response to intervention.
These data suggest that a diabetes-associated GRS is associated with development of GDM and may characterize women at risk for development of diabetes due to β-cell dysfunction.
PMCID: PMC3964494  PMID: 24271189
11.  Endogenous Sex Hormones, Metabolic Syndrome, and Diabetes in Men and Women 
Current cardiology reports  2014;16(4):467.
Endogenous sex hormones predict impairments of glucose regulation. Cross-sectional studies suggest that lower levels of testosterone in men and higher levels in women increase risk of metabolic syndrome and diabetes, while lower levels of sex hormone binding globulin in both men and women increase risk of metabolic syndrome and diabetes. In a systematic review, we summarize existing longitudinal studies, which suggest similar patterns. However, these studies are often limited to a single sex steroid measure. Whether these associations are primarily a marker of adiposity, and whether these associations differ between younger eugonadal vs. older hypogonadal adults is also uncertain. The impact of exogenous sex steroid therapy may not reflect relationships between sex hormones and impaired glucose regulation that occur without supplementation. Therefore, examination of endogenous sex steroid trajectories and obesity trajectories within individuals might aid our understanding of how sex steroids contribute to glucose regulation.
PMCID: PMC4010316  PMID: 24585109
estradiol; testosterone; androgens; sex hormone binding globulin; metabolic syndrome; diabetes; endogenous sex hormones; men; women
The Journal of urology  2014;193(3):786-793.
Previous studies have demonstrated lower prostate-specific antigen (PSA) concentrations in men with type 2 diabetes (T2DM), paralleling the reported lower prevalence of prostate cancer among diabetic men. Data on PSA in men with type 1 diabetes (T1DM), in whom insulin and obesity profiles differ from those in T2DM, are lacking. The objective of this study was to examine the relationship between long-term glycemic control and PSA in men with T1DM.
Total PSA was measured at one time in 639 men in the Epidemiology of Diabetes Interventions and Complications (EDIC) study, the observational follow up of participants in the Diabetes Control and Complications Trial (DCCT). The relationship between DCCT/EDIC weighted mean HbA1c and log PSA was assessed using linear regression modeling after adjusting for age, body mass index (BMI), total testosterone, statin and thiazide medication use, diabetes duration, and DCCT randomization arm and cohort.
The subjects had a median age of 52 years, BMI of 28.4 kg/m2 and DCCT/EDIC time weighted HbA1c of 7.9%. Total median (interquartile range) for PSA levels was 0.64 (0.43, 1.05). PSA levels increased significantly with age (p<0.0001) and with lower time weighted HbA1c (p<0.0001). Each 10% increase in HbA1c was accompanied by an 11% reduction in PSA (p=0.0001).
PSA levels decrease as HbA1c increases in men with T1DM. This relationship is independent of age, BMI, androgen levels, medication use and measures of diabetes severity, which suggest that factors related to glycemia may be directly affecting PSA levels.
PMCID: PMC4363040  PMID: 25218922
Glycemic Control; Diabetes; PSA
13.  Effect of Glycemic Treatment and Microvascular Complications on Menopause in Women With Type 1 Diabetes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Cohort 
Diabetes Care  2014;37(3):701-708.
We examined the impact of intensive versus conventional diabetes treatment upon menopause among women with type 1 diabetes in the Diabetes Control and Complications Trial (DCCT), a randomized controlled trial of intensive diabetes treatment, and its observational follow-up, the Epidemiology of Diabetes Interventions and Complications (EDIC) study.
In a secondary analysis of women in the DCCT/EDIC (n = 657), outcomes were the cumulative incidences of natural menopause and surgical menopause. Cox regression analyses were used to examine associations with treatment group, time-varying estimates of hemoglobin A1c (HbA1c), insulin dosage, BMI, and microvascular complications (retinopathy, nephropathy, and neuropathy).
By EDIC year 18, after an average of 28 years of follow-up, 240 (38%) women had experienced natural menopause and 115 (18%) women had experienced surgical menopause. Age at natural menopause was similar in the intensive versus conventional groups (49.9 vs. 49.0 years; P = 0.28), and age at surgical menopause was similar in the intensive versus conventional groups (40.8 vs. 42.0 years; P = 0.31). In multivariable models, treatment group, HbA1c, and microvascular complications were not associated with risk of natural or surgical menopause. Each 10 unit/day increase in insulin dosage decreased risk of natural menopause (hazard ratio [HR] 0.91, 95% CI 0.75–0.98) and each kg/m2 increase in BMI increased risk of surgical menopause (HR 1.08, 95% CI 1.00–1.16).
In the DCCT/EDIC, intensive versus conventional treatment group and HbA1c level were not associated with menopause risk. Greater insulin dose was associated with lower menopause risk.
PMCID: PMC3931380  PMID: 24170751
14.  Hyperglycemia, Hyperinsulinemia, Insulin Resistance and the Risk of BPH/LUTS Severity and Progression Over Time in Community Dwelling Black Men: The Flint Men’s Health Study 
Urology  2013;82(4):881-886.
To examine the associations between fasting serum glucose, insulin concentrations, and insulin resistance and BPH in a population-based cohort of African-American men.
Using the Flint Men’s Health Study (FMHS), we examined how fasting serum glucose and insulin concentrations and calculated HOMA-IR related to burden and progression of clinical markers of BPH in African-American men aged 40–79.
Among 369 men at baseline, mean age was 56.6 years and approximately 70% were overweight/obese (BMI≥25 kg/m2). 148 men (34.4%) reported moderate to severe lower urinary tract symptoms (LUTS) (AUASI≥8). There were no significant trends of metabolic disturbances as measured by serum glucose, insulin or HOMA-IR in men with indications of BPH compared to those without.
In this population-based study of African-American men aged 40–79, we did not observe any significant associations between hyperglycemia, hyperinsulinemia and insulin resistance and burden and progression of BPH after adjustment for age and BMI. This may be due in part to the single measurement and glucose and insulin which may not adequately reflect average glucose metabolism. Further studies examining measures of long-term glycemic control and BPH in racially diverse populations are warranted.
PMCID: PMC3788001  PMID: 23915515
diabetes; BPH; LUTS; diabetes; men; aging
15.  Guidelines and interventions for obesity during pregnancy 
Obesity is a growing worldwide epidemic among women of reproductive age, including pregnant women. The increased prevalence of obesity has been accompanied by an increase in gestational weight gain. Maternal obesity has deleterious consequences for both mother and child.
To review the recent guidelines from the National Institute for Health and Clinical Excellence and the Institute of Medicine regarding gestational weight gain and interventions to treat obesity during pregnancy.
Guidelines on gestational weight gain from these organizations, as well as reports of gestational weight gain in the published literature, are summarized.
Many normal and overweight parturients exceed the recommendations in the guidelines, which may contribute to postpartum obesity.
Lifestyle changes, including dieting and increased activity, may help to limit excessive gestational weight gain but the optimal strategy remains unclear.
PMCID: PMC4151459  PMID: 22809971
Gestational weight gain; Maternal nutrition; Obesity; Pregnancy
16.  Sex steroid levels and response to weight loss interventions among postmenopausal women in the Diabetes Prevention Program 
Obesity (Silver Spring, Md.)  2013;22(3):882-887.
To examine whether estrogen use potentiates weight loss interventions via sex steroid levels and whether endogenous sex steroid levels predict response to weight loss interventions among women not using estrogen.
Design and Methods
The Diabetes Prevention Program randomized overweight or obese dysglycemic participants to lifestyle change with the goals of weight reduction of >7% of initial weight and 150 minutes per week of exercise; metformin; or placebo. In this secondary analysis, we examined sex steroid levels and reductions in weight and waist circumference (WC) among postmenopausal women using (n=324) and not using (n=382) oral estrogen.
Estrogen users and non-users randomized to lifestyle change and metformin both lost significant amounts of weight compared to placebo. Reductions in weight and WC over 1 year associated with randomization arm were not associated with baseline sex steroid levels among estrogen users or non-users.
Among estrogen users, baseline sex steroids were not associated with reductions in weight or WC, suggesting that exogenous estrogen does not potentiate weight loss by altering sex steroids. Among non-estrogen users, baseline sex steroids were not associated with reductions in weight or WC.
PMCID: PMC3818475  PMID: 23804582
sex steroids; waist circumference; weight loss
17.  The Association of Elective Hormone Therapy with Changes in Lipids Among Glucose Intolerant Postmenopausal Women in the Diabetes Prevention Program 
It is unclear how lipids change in response to lifestyle modification or metformin among postmenopausal glucose intolerant women using and not using hormone therapy (HT). We examined the one-year changes in lipids among postmenopausal, prediabetic women in the Diabetes Prevention Program (DPP), and whether changes were mediated by sex hormones.
We performed a secondary analysis of a randomized controlled trial of 342 women who used HT at baseline and year 1 and 382 women who did not use HT at either time point. Interventions included intensive lifestyle (ILS) with goals of weight reduction of at least 7% of initial weight and 150 minutes per week of moderate intensity exercise, or metformin or placebo administered 850 mg up to twice a day. Women were not randomized to HT. Main outcome measures were changes between baseline and study year 1 in low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides.
Compared to placebo, both ILS and metformin significantly reduced LDL-C and raised HDL-C among HT users, changes partially explained by change in estradiol and testosterone but independent of changes in waist circumference and 1/fasting insulin. In contrast, DPP interventions had no effect on LDL-C and HDL-C among non-HT users. ILS significantly lowered triglycerides among non-users but did not significantly change triglycerides among HT users. Metformin did not significantly change triglycerides among non-users but increased triglycerides among HT users.
The beneficial effects of ILS and metformin on lowering LDL-C and raising HDL-C differ depending upon concurrent HT use.
PMCID: PMC3755098  PMID: 23660512
sex hormones; lifestyle intervention; hormone therapy; lipids; women
18.  Are Health-Related Quality-of-Life and Self-Rated Health Associated with Mortality? Insights from Translating Research Into Action for Diabetes (TRIAD) 
Primary care diabetes  2009;3(1):37-42.
To determine if health-related quality-of-life and self-rated health are associated with mortality in persons with diabetes.
Survey and medical record data were obtained from 7,892 patients with diabetes in Translating Research Into Action for Diabetes (TRIAD), a multicenter prospective observational study of diabetes care in managed care. Vital status at follow-up was determined from the National Death Index. Multivariable proportional hazards models were used to determine if a generic measure of health-related quality-of-life (EQ-5D) and self-rated health measured at baseline were associated with 4-year all-cause, cardiovascular, and noncardiovascular mortality.
At baseline, the mean EQ-5D score for decedents was 0.73 (SD=0.20) and for survivors was 0.81 (SD=0.18) (p<0.0001). Fifty-five percent of decedents and 36% of survivors (p<0.0001) rated their health as fair or poor. Lower EQ-5D scores and fair or poor self-rated health were associated with higher rates of mortality after adjusting for the demographic, socioeconomic, and clinical risk factors for mortality.
Health-related quality-of-life and self-rated health predict mortality in persons with diabetes. Health-related quality-of-life and self-rated health may provide additional information on patient risk independent of demographic, socioeconomic, and clinical risk factors for mortality.
PMCID: PMC4138696  PMID: 19269911
diabetes; mortality; QoL
19.  Self-efficacy, social support, and associations with physical activity and body mass index among women with histories of gestational diabetes mellitus 
The Diabetes educator  2008;34(4):719-728.
To examine the associations between 2 potential facilitators of healthy behaviors (self-efficacy and social support), and both physical activity and body mass index (BMI) among women with histories of gestational diabetes mellitus (GDM)
We surveyed 228 women with histories of GDM enrolled in a managed care plan. In a cross-sectional analysis, we assessed the association between women’s social support from family and friends for physical activity and self-efficacy for physical activity with women’s physical activity levels. We also examined the association between women’s social support from family and friends for healthy diet and self-efficacy for not overeating and their dietary habits. Finally, we assessed the association between all of these psychosocial constructs and body mass index (BMI) before and after adjustment for covariates.
Participants reported low to moderate social support and self-efficacy scores, suboptimal performance of physical activity, suboptimal dietary scores, and high BMIs. Self-efficacy and social support from family and friends for physical activity were associated with physical activity. Social support from family and friends for a healthy diet was associated with better dietary scores and the association between self-efficacy for not overeating and healthy diet bordered on significance. No significant associations existed between psychosocial constructs and BMI.
Psychosocial constructs such as social support and self-efficacy are associated with physical activity and dietary habits. However, associations with BMI are weak. Further exploration of constructs associated with BMI may be needed to design effective weight-loss interventions in this population.
PMCID: PMC4139034  PMID: 18669814
20.  Managing women with gestational diabetes mellitus in the postnatal period 
Diabetes, obesity & metabolism  2009;12(1):20-25.
Guidelines for management of women with a history of gestational diabetes mellitus (GDM) in the postpregnancy period have lagged behind the recognition that this is an important time for medical intervention. However, in the past decade, the evidence-base for screening algorithms, contraceptive management, diabetes prevention strategies and implications for offspring has expanded. In this review, we discuss current recommendations for managing women with GDM in the postnatal period, with particular attention to postpartum diabetes screening, prevention of future glucose intolerance and family planning.
PMCID: PMC4139039  PMID: 19788432
gestational diabetes; postpartum; women
22.  Reductions in glucose among postmenopausal women who use and do not use estrogen therapy 
Menopause (New York, N.Y.)  2013;20(4):393-400.
Among postmenopausal women who do not use estrogen hormone therapy (HT) we have previously reported that intensive lifestyle intervention (ILS) leads to increases in sex hormone binding globulin (SHBG), and such increases were associated with reductions in fasting plasma glucose (FPG) and 2-hour post-challenge glucose (2HG). Oral HT decreases FPG and increases 2HG, while increasing both SHBG and estradiol (E2). It is unknown if ILS reduces glucose among HT users, if changes in SHBG and E2 might mediate any glucose decreases in HT users, and if these patterns differ from non-HT users.
We conducted a secondary analysis of postmenopausal women in the Diabetes Prevention Program who used HT at baseline and 1 year follow-up (n=324) and who did not use HT at either time point (n=382). Participants were randomized to ILS, metformin, or placebo administered 850 mg twice a day.
HT users were younger, more often white, and more likely to have had bilateral oophorectomy than non-HT users. Among HT users, ILS reduced FPG (p<0.01) and 2HG (p<0.01), and metformin reduced FPG (p<0.01) but not 2HG (p=0.56), compared to placebo. Associations between SHBG and total E2 with FPG and 2HG were not significant among women randomized to ILS or to metformin. These patterns differed from those observed among women who did not use HT.
We conclude that among glucose intolerant HT users, interventions to reduce glucose are effective but possibly mediated through different pathways than among women who did not use HT.
PMCID: PMC3582709  PMID: 23168523
menopause; estrogen; progestogen; hormone therapy; glucose
23.  Gestational Diabetes Mellitus in Korean Women: Similarities and Differences from Other Racial/Ethnic Groups 
Diabetes & Metabolism Journal  2014;38(1):1-12.
Gestational diabetes mellitus (GDM) reflects defects in insulin secretion in response to the metabolic demands of pregnancy. While GDM is increasingly common worldwide due in large part to the obesity epidemic, its frequency is relatively low in Korean women. In this report, the prevalence and risk factors for GDM, perinatal outcomes, and postpartum course are compared in non-Korean and Korean women. While Koreans and non-Koreans with GDM share pathophysiology and complications, there may be differences in the role of obesity and thus the effectiveness of interventions targeting obesity in GDM women. Further investigations of the effectiveness of weight loss interventions and pharmacotherapy specifically among Korean women are needed. Dietary and other lifestyle data from Korean populations could inform prevention and treatment strategies in other countries which suffer from significantly higher prevalences of GDM.
PMCID: PMC3950189  PMID: 24627822
Diabetes, gestational; Epidemiology; Postpartum period; Pregnancy
24.  Physician reimbursement perception for outpatient procedures and procedures among managed care patients with diabetes 
To examine the association between physicians’ reimbursement perceptions and outpatient test performance. Previous studies have documented an association between reimbursement perceptions and electrocardiogram performance, but not for other common outpatient procedures.
Cross-sectional analysis.
Participants were physicians (n = 766) and their managed care patients with diabetes mellitus (n = 2758) enrolled in 6 plans in 2003. Procedures measured included electrocardiograms, radiographs or x-rays, urine microalbumin measures, hemoglobin A1cs, and Pap smears for women. Hierarchical logistic regression models were adjusted for health plan and physician level clustering and for physician and patient covariates. To minimize confounding by unmeasured health plan variables, we adjusted for plan as a fixed effect. Thus, we estimated variation between physicians using only the variance within health plans.
Patients of physicians who reported reimbursement for electrocardiograms were more likely to receive electrocardiograms than patients of physicians who did not perceive reimbursement (unadjusted mean difference 4.9% (95% confidence interval, 1.1% to 8.9%)) and adjusted mean difference 3.9% (95% confidence interval, 0.21% to 7.8%)). For the other tests examined, no significant differences in procedure performance were found between patients of physicians who perceived reimbursement and patients of physicians who did not perceive reimbursement.
Our findings suggest that reimbursement perception was associated with electrocardiograms, but not with other commonly performed outpatient procedures. Future research should investigate how associations change with perceived amount of reimbursement and interactions with other influences upon test-ordering behavior such as perceived appropriateness.
PMCID: PMC3833066  PMID: 19146362
managed care; reimbursement; outpatient
25.  Changes in Iron Measures over Menopause and Associations with Insulin Resistance 
Journal of Women's Health  2012;21(8):872-877.
No longitudinal studies have examined how iron measures change over menopause. Our objectives were to examine iron measures in individual women at premenopause and at postmenopause and, secondarily, to determine if any changes contributed to insulin resistance.
In a subset of participants (n=70) in a longitudinal study of menopause, we measured ferritin, transferrin, and soluble transferrin receptor (sTfR) once in the premenopause and once in the postmenopause. We also examined associations between menopausal status and change in iron markers after adjustment for age at menopause, race/ethnicity, and waist circumference. In linear regression models, we examined associations between premenopause iron measures and changes in iron markers over menopause with homeostasis model assessment of insulin resistance (HOMA-IR) changes over menopause, before and after adjustment for age at menopause, race/ethnicity, changes in waist circumference, C-reactive protein (CRP), and sex hormone-binding globulin (SHBG) levels.
Women had lower ferritin (p<0.01), higher sTfR:ferritin levels (p<0.01), lower HOMA-IR (p=0.022), and lower glucose (p=0.05) in premenopause compared to postmenopause. After adjustment, lower premenopausal iron levels (sTfR:ferritin levels β=11.0, 95% confidence interval [CI] 0.017-22.0) and larger increases in iron over menopause (changes in sTfR:ferritin β=13.6, 95% CI 0.93-26.3) were associated with larger increases in HOMA-IR.
From premenopause to postmenopause, women on average have increases in measures of iron stores. Women who had the greatest changes in iron over menopause (lower measures of premenopausal iron and greater increases in iron measures over the menopause) had the strongest associations between changes in iron and changes in insulin resistance.
PMCID: PMC3411341  PMID: 22731657

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