The association of sleep disturbances with glycemia and obesity in youth at risk for or with recently diagnosed type 2 diabetes.

OBJECTIVE: Poor sleep may increase obesity and type 2 diabetes (T2D) risk in youth. We explored whether subjective sleep duration, sleep quality, or risk for obstructive sleep apnea (OSA) are associated with glycemia, body mass index (BMI), or blood pressure (BP) in overweight/obese youth. METHODS: Two-hundred and fourteen overweight/obese youth of 10 to 19 years of age at risk for or recently diagnosed with T2D who were screened for the Restoring Insulin Secretion (RISE) Study had a 2-hour oral glucose tolerance test (OGTT) and completed a Cleveland Adolescent Sleepiness questionnaire and a Sleep Disturbances Scale questionnaire. Independent associations between sleep variables and measures of glycemia, BMI, and BP were evaluated with regression models. RESULTS: The multiethnic cohort was 67% female, 14.1 ± 2.1 years, and BMI 35.9 ± 6.5 kg/m2 . Habitual sleep duration <8 hours was reported in 74%. Daytime sleepiness was reported in 51%, poor sleep quality in 26%, and 30% had high obstructive sleep apnea (OSA) risk. Daytime sleepiness was associated with higher HbA1c (0.2%, P = .02) and 2-hour glucose (13.6 mg/dL, P < .05). Sleep duration, sleep quality, and OSA risk were not associated with the evaluated outcomes. Poor sleep quality and OSA risk were associated with higher BMI (2.9 kg/m2 , P = .004 and 2.83 kg/m2 , P < .003, respectively). CONCLUSIONS: In overweight/obese youth with or at risk for T2D, daytime sleepiness was associated with higher HbA1c. In addition, poor sleep quality and OSA risk were associated with higher BMI. These findings support intervention studies aimed at improving sleep quality in obese youth.

Metformin therapy for the reproductive and metabolic consequences of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS), the most common hormonal disorder among women of reproductive age, has various metabolic and reproductive consequences. Metformin was originally shown to lower testosterone levels in women with PCOS in the 1990s, an effect presumably related to its insulin sensitising actions. However, the precise mechanisms of metformin action in PCOS remain unclear and there is considerable heterogeneity in the clinical response to this therapy in women with PCOS. Recent evidence indicates that genetic factors may play a significant role in predicting response to metformin therapy in PCOS and future studies are needed to further identify women who are most likely to benefit from this therapy. At present, there is no clear evidence to support broad metformin use in PCOS. Well-designed prospective trials are needed to establish clear benefit for metformin use in the treatment of the reproductive and metabolic consequences associated with PCOS.

Metabolic dysfunction in obese Hispanic women with polycystic ovary syndrome.

STUDY QUESTION: Are certain ethnic groups with polycystic ovary syndrome (PCOS) at increased risk of metabolic disorders? SUMMARY ANSWER: Obese Hispanic women with PCOS are at increased risk of metabolic disorders compared with age- and BMI-matched obese non-Hispanic white women with PCOS in the USA. WHAT IS KNOWN ALREADY: Ethnic differences in body composition and metabolic risk are well established. PCOS is a common disorder in women of reproductive age and is associated with high rates of insulin resistance, glucose intolerance and dyslipidemia. STUDY DESIGN, SIZE, DURATION: A cross-sectional observational study was performed at an Academic Medical Center on 60 women of reproductive age with PCOS. PARTICIPANTS/MATERIALS, SETTING, METHODS: Blood was obtained after fasting from 17 Hispanic, 22 non-Hispanic black and 21 non-Hispanic white women with PCOS who were similar in age and BMI. Anthropometric parameters, insulin, lipid and lipoprotein levels (measured by nuclear magnetic resonance) were compared between the three groups. MAIN RESULTS AND THE ROLE OF CHANCE: Age and BMI did not differ between the groups. Hispanic women with PCOS had higher waist-to-hip ratio (WHR) (P = 0.02), homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.03) and a more atherogenic lipid and lipoprotein profile consisting of lower high-density lipoprotein (HDL) (P = 0.02), higher low-density lipoprotein (LDL) particle number (P = 0.02), higher very low-density lipoprotein particle (VLDL) size (P = 0.03) and lower LDL (P = 0.03) and HDL particle size (P = 0.005) compared with non-Hispanic white women. The differences in HDL, HOMA-IR, VLDL and LDL size did not persist after adjustment for WHR while differences in LDL particle number (P = 0.04) and HDL size (P = 0.01) persisted. LIMITATIONS, REASON FOR CAUTION: The sample size for the three groups was small but the findings were still significant. The women were mostly obese so the ethnic differences in metabolic disorders may not apply to non-obese women with PCOS. WIDER IMPLICATIONS OF THE FINDINGS: Independent of BMI, obese, reproductive age, Hispanic women with PCOS in the USA had a greater degree of abdominal obesity, insulin resistance and dyslipidemia. Hispanic women with PCOS may benefit from more focused management of metabolic parameters. STUDY FUNDING/COMPETING INTERESTS: This project was supported by the following National Institutes of Health grants: K23 DK080988-01A1 to S.S. and UL1RR029879 to CTSA at University of Illinois. None of the authors report any conflict of interests.

Weight loss and ß-cell responses following gastric banding or pharmacotherapy in adults with impaired glucose tolerance or type 2 diabetes: a randomized trial.

OBJECTIVE: The extent to which weight loss contributes to increases in insulin sensitivity (IS) and ß-cell function after surgical or medical intervention has not been directly compared in individuals with impaired glucose tolerance or newly diagnosed type 2 diabetes. METHODS: The Restoring Insulin Secretion (RISE) Study included adults in the Beta-Cell Restoration Through Fat Mitigation Study (n = 88 randomized to laparoscopic gastric banding or metformin [MET]) and the Adult Medication Study (n = 267 randomized to placebo, MET, insulin glargine/MET, or liraglutide + MET [L + M]). IS and ß-cell responses were measured at baseline and after 12 months by modeling of oral glucose tolerance tests and during arginine-stimulated hyperglycemic clamps. Linear regression models assessed differences between and within treatments over time. RESULTS: BMI decreased in all treatment groups, except placebo, at 12 months. IS increased in all arms except placebo and was inversely correlated with changes in BMI. L + M was the only treatment arm that enhanced multiple measures of ß-cell function independent of weight loss. Insulin secretion decreased in the laparoscopic gastric banding arm proportional to increases in IS, with no net benefit on ß-cell function. CONCLUSIONS: Reducing demand on the ß-cell by improving IS through weight loss does not reverse ß-cell dysfunction. L + M was the only treatment that enhanced ß-cell function.

Polycystic ovary syndrome is associated with atherogenic changes in lipoprotein particle number and size independent of body weight.

OBJECTIVE: Adverse changes in lipoprotein particle number and size are common with insulin resistance and are associated with increased cardiovascular risk. Comprehensive information regarding lipoprotein particle number and size, and how these parameters relate to body weight, insulin resistance and hyperandrogenemia is lacking in polycystic ovary syndrome (PCOS). We tested the hypothesis that PCOS is associated with atherogenic changes in lipoprotein profile independent of body weight and examined the role of insulin resistance and androgens in these atherogenic changes. DESIGN: Case-control study performed at Clinical Research Center at an Academic Medical Center in the United States. PATIENTS AND MEASUREMENTS: Fasting blood was obtained from 25 PCOS and 25 control women of similar age and body mass index (BMI). Lipoprotein particle number and size was determined by nuclear magnetic resonance and compared between the groups. RESULTS: The mean BMI for both groups was <30 kg/m(2) (P = 0·33). Women with PCOS had an increase in very low-density lipoprotein (VLDL) particle number (P = 0·005), low-density lipoprotein (LDL) particle number (P = 0·02) and a decrease in high-density lipoprotein (HDL) size (P = 0·04). LDL size was borderline decreased (P = 0·09). These differences persisted after adjustment for ethnicity, alcohol and tobacco intake and exercise. In stepwise regression models, bioavailable testosterone was the only predictor of LDL cholesterol, triglyceride, VLDL and LDL particle number. Sex hormone binding globulin (SHBG) was the only predictor of LDL and HDL size. CONCLUSIONS: Independent of body weight, PCOS was associated with changes in lipoprotein profile that increases risk for cardiovascular disease. These changes were present in a mostly nonobese group of women and were more closely related to androgens than fasting insulin.

Role of obstructive sleep apnea in metabolic risk in PCOS.

Women with polycystic ovary syndrome (PCOS) have a substantially increased risk for diabetes and cardiovascular disease. Obstructive sleep apnea (OSA) is the most common sleep disorder in PCOS. Recent population-based studies indicate a high incidence of OSA among adult women with PCOS. Obesity and increasing age are the main factors for this association. There is strong evidence indicating that OSA is an important modulator of metabolic risk in the general population. There is also some evidence to suggest that OSA may contribute to insulin resistance and glucose intolerance among women PCOS, and thus increase their metabolic risk. The potential mechanisms for adverse metabolic consequences of OSA are likely to be multiple. Whether treatment of OSA in PCOS improves metabolic outcomes requires further rigorous research.

Obstructive Sleep Apnea, Glucose Tolerance, and ß-Cell Function in Adults With Prediabetes or Untreated Type 2 Diabetes in the Restoring Insulin Secretion (RISE) Study.

OBJECTIVE: Obstructive sleep apnea (OSA) is associated with insulin resistance and has been described as a risk factor for type 2 diabetes. Whether OSA adversely impacts pancreatic islet ß-cell function remains unclear. We aimed to investigate the association of OSA and short sleep duration with ß-cell function in overweight/obese adults with prediabetes or recently diagnosed, treatment-naive type 2 diabetes. RESEARCH DESIGN AND METHODS: Two hundred twenty-one adults (57.5% men, age 54.5 ± 8.7 years, BMI 35.1 ± 5.5 kg/m2) completed 1 week of wrist actigraphy and 1 night of polysomnography before undergoing a 3-h oral glucose tolerance test (OGTT) and a two-step hyperglycemic clamp. Associations of measures of OSA and actigraphy-derived sleep duration with HbA1c, OGTT-derived outcomes, and clamp-derived outcomes were evaluated with adjusted regression models. RESULTS: Mean ± SD objective sleep duration by actigraphy was 6.6 ± 1.0 h/night. OSA, defined as an apnea-hypopnea index (AHI) of five or more events per hour, was present in 89% of the participants (20% mild, 28% moderate, 41% severe). Higher AHI was associated with higher HbA1c (P = 0.007). However, OSA severity, measured either by AHI as a continuous variable or by categories of OSA severity, and sleep duration (continuous or <6 vs. ≥6 h) were not associated with fasting glucose, 2-h glucose, insulin sensitivity, or ß-cell responses. CONCLUSIONS: In this baseline cross-sectional analysis of the RISE clinical trial of adults with prediabetes or recently diagnosed, untreated type 2 diabetes, the prevalence of OSA was high. Although some measures of OSA severity were associated with HbA1c, OSA severity and sleep duration were not associated with measures of insulin sensitivity or ß-cell responses.

Baseline Predictors of Glycemic Worsening in Youth and Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes in the Restoring Insulin Secretion (RISE) Study.

OBJECTIVE: To identify predictors of glycemic worsening among youth and adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes in the Restoring Insulin Secretion (RISE) Study. RESEARCH DESIGN AND METHODS: A total of 91 youth (10-19 years) were randomized 1:1 to 12 months of metformin (MET) or 3 months of glargine, followed by 9 months of metformin (G-MET), and 267 adults were randomized to MET, G-MET, liraglutide plus MET (LIRA+MET), or placebo for 12 months. All participants underwent a baseline hyperglycemic clamp and a 3-h oral glucose tolerance test (OGTT) at baseline, month 6, month 12, and off treatment at month 15 and month 21. Cox models identified baseline predictors of glycemic worsening (HbA1c increase ≥0.5% from baseline). RESULTS: Glycemic worsening occurred in 17.8% of youth versus 7.5% of adults at month 12 (P = 0.008) and in 36% of youth versus 20% of adults at month 21 (P = 0.002). In youth, glycemic worsening did not differ by treatment. In adults, month 12 glycemic worsening was less on LIRA+MET versus placebo (hazard ratio 0.21, 95% CI 0.05-0.96, P = 0.044). In both age-groups, lower baseline clamp-derived ß-cell responses predicted month 12 and month 21 glycemic worsening (P < 0.01). Lower baseline OGTT-derived ß-cell responses predicted month 21 worsening (P < 0.05). In youth, higher baseline HbA1c and 2-h glucose predicted month 12 and month 21 glycemic worsening, and higher fasting glucose predicted month 21 worsening (P < 0.05). In adults, lower clamp- and OGTT-derived insulin sensitivity predicted month 12 and month 21 worsening (P < 0.05). CONCLUSIONS: Glycemic worsening was more common among youth than adults with IGT or recently diagnosed type 2 diabetes, predicted by lower baseline ß-cell responses in both groups, hyperglycemia in youth, and insulin resistance in adults.

Selective destruction of mouse islet beta cells by human T lymphocytes in a newly-established humanized type 1 diabetic model.

Type 1 diabetes (T1D) is caused by a T cell-mediated autoimmune response that leads to the loss of insulin-producing beta cells. The optimal preclinical testing of promising therapies would be aided by a humanized immune-mediated T1D model. We develop this model in NOD-scid IL2rgamma(null) mice. The selective destruction of pancreatic islet beta cells was mediated by human T lymphocytes after an initial trigger was supplied by the injection of irradiated spleen mononuclear cells (SMC) from diabetic nonobese diabetic (NOD) mice. This resulted in severe insulitis, a marked loss of total beta-cell mass, and other related phenotypes of T1D. The migration of human T cells to pancreatic islets was controlled by the beta cell-produced highly conserved chemokine stromal cell-derived factor 1 (SDF-1) and its receptor C-X-C chemokine receptor (CXCR) 4, as demonstrated by in vivo blocking experiments using antibody to CXCR4. The specificity of humanized T cell-mediated immune responses against islet beta cells was generated by the local inflammatory microenvironment in pancreatic islets including human CD4(+) T cell infiltration and clonal expansion, and the mouse islet beta-cell-derived CD1d-mediated human iNKT activation. The selective destruction of mouse islet beta cells by a human T cell-mediated immune response in this humanized T1D model can mimic those observed in T1D patients. This model can provide a valuable tool for translational research into T1D.

Pathogenesis and Consequences of Disordered Sleep in PCOS.

Polycystic ovary syndrome (PCOS) is a common hormonal disorder that is characterized by hyperandrogenism and menstrual irregularity. Affected women have a high prevalence of insulin resistance and related metabolic complications. The frequency of sleep disturbances appears to be increased in women with PCOS, although most studies so far have included more severely affected obese women with PCOS who are referred to tertiary care clinics and may not represent the general population of women with PCOS. This article provides an overview of sleep disturbances in PCOS with the focus on obstructive sleep apnea (OSA), the most commonly reported sleep disturbance among these women. The pathogenesis and risk factors for OSA in PCOS and its association with metabolic disorders is discussed in detail.

Endocrine implications of bariatric surgery: a review on the intersection between incretins, bone, and sex hormones.

Bariatric surgery is now the most widely used intervention for the treatment of human obesity. A large body of literature has demonstrated its efficacy in sustained weight loss and improvement in its associated comorbidities. Here, we review the effect of bariatric surgery in gut hormone physiology, bone remodeling and the reproductive axis. Rapid improvements in insulin release and sensitivity appear to be weight loss independent and occur immediately after surgery. These effects on pancreatic beta cells are mostly due to increased gut hormone secretion due to augmented nutrient delivery to the small intestine. Bone remodeling is also affected by gut hormones. Phenotypic skeletal changes observed in mice deficient in GLP-1 or GIP suggest that increased incretins may improve bone density. However, these positive effects may be counterbalanced by the association between weight loss and a reduction in bone density. Finally, studies have shown a marked improvement following bariatric surgery in infertility and PCOS in women and hypogonadism in men. Thus, the net effect on endocrine systems after bariatric surgery will likely vary on an individual basis and depend on factors such as comorbidities, peri-menopausal state, amount of weight loss, and likelihood to adhere to vitamin supplementation after surgery.

Association of Self-Reported Sleep and Circadian Measures With Glycemia in Adults With Prediabetes or Recently Diagnosed Untreated Type 2 Diabetes.

OBJECTIVE: Sleep disturbances and circadian misalignment (social jet lag, late chronotype, or shift work) have been associated with worse glycemic control in type 2 diabetes (T2D). Whether these findings apply to adults with prediabetes is yet unexplored. We hypothesized that self-reported short sleep, poor sleep quality, and/or circadian misalignment are associated with higher glycemia, BMI, and blood pressure (BP) in adults with prediabetes or recently diagnosed, untreated T2D. RESEARCH DESIGN AND METHODS: Our cohort included 962 overweight/obese adults ages 20-65 years with prediabetes or recently diagnosed, untreated T2D who completed a 2-h oral glucose tolerance test and validated sleep questionnaires. Independent associations of sleep and circadian variables with glycemia, BMI, and BP were evaluated with regression models. RESULTS: The multiethnic cohort was 55% men, with mean ± SD age 52.2 ± 9.5 years and BMI 34.7 ± 5.5 kg/m2. Mean sleep duration was 6.6 ± 1.3 h. Poor sleep quality was reported by 54% and high risk for obstructive sleep apnea by 64%. HbA1c was significantly higher in those reporting <5 or >8 h sleep per night. Sleep duration >8 h was also associated with higher fasting glucose and <6 h with higher BMI. Shift work was also associated with higher BMI. Social jet lag and delayed chronotype were associated with higher BP. CONCLUSIONS: In our cohort, self-reported short and long sleep were both associated with adverse measures of glycemia, and short sleep and shift work were associated with higher BMI. Further research using objective measures of sleep is needed to better delineate the relationship between sleep and glycemia in adults with prediabetes or T2D.

Normal physiology of hypothalamic pituitary regulation.

The anterior pituitary is a complex heterogeneous gland that exerts a central role in the integration of several regulatory systems. Its six key hormones affect peripheral glands or target tissues and are essential for reproduction, growth and development, metabolism, adaptation to external environmental changes, and stress. Each of the pituitary hormones is regulated by the central nervous system through neuroendocrine pathways involving the hypothalamus, by feedback effects from peripheral target gland hormones, and by intrapituitary mechanisms. The hormones are secreted in a pulsatile manner, which is distinct for each hormone and reflects the influence of its individual neuroendocrine control mechanisms.

Evidence for pancreatic beta-cell dysfunction in brothers of women with polycystic ovary syndrome.

Hyperandrogenemia and insulin resistance are heritable traits in sisters of women with polycystic ovary syndrome (PCOS). Hyperandrogenemia also appears to be the male reproductive phenotype; however, it is less clear whether male relatives are at risk for the metabolic disorders associated with PCOS. In this study, we tested the hypothesis that brothers of women with PCOS have defects in insulin action and/or secretion. Twenty-three non-Hispanic white brothers of women with PCOS and 23 non-Hispanic white control men of comparable age matched for body mass index underwent a modified frequently sampled intravenous glucose tolerance test. Parameters of insulin sensitivity and secretion were determined using minimal-model Bergman protocol. Disposition index was significantly decreased (2540 [1080, 3172] vs 2901 [2096, 4487], P = .009) independent of a family history of diabetes mellitus, and glucose effectiveness was significantly increased (2.4 [1.9, 2.7] vs 2.0 [1.8, 2.2], P = .02) in brothers compared with control men. We conclude that brothers of women with PCOS have evidence for pancreatic beta-cell dysfunction and may be at increased risk for type 2 diabetes mellitus.

Differential effect of subcutaneous abdominal and visceral adipose tissue on cardiometabolic risk.

Metabolic and cardiovascular diseases are increasing worldwide due to the rise in the obesity epidemic. The metabolic consequences of obesity vary by distribution of adipose tissue. Visceral and ectopic adipose accumulation are associated with adverse cardiometabolic consequences, while gluteal-femoral adipose accumulation are negatively associated with these adverse complications and subcutaneous abdominal adipose accumulation is more neutral in its associations. Gender, race and ethnic differences in adipose tissue distribution have been described and could account for the observed differences in risk for cardiometabolic disease. The mechanisms behind the differential impact of adipose tissue on cardiometabolic risk have started to be unraveled and include differences in adipocyte biology, inflammatory profile, connection to systemic circulation and most importantly the inability of the subcutaneous adipose tissue to expand in response to positive energy balance.

Identification of a polycystic ovary syndrome susceptibility variant in fibrillin-3 and association with a metabolic phenotype.

CONTEXT: Polycystic ovary syndrome (PCOS), the most common reproductive endocrine disorder of premenopausal women, is also associated with metabolic abnormalities including insulin resistance and an increased risk for diabetes mellitus. We previously mapped a PCOS susceptibility locus to chromosome 19p13.2 near the dinucleotide repeat marker D19S884. OBJECTIVE: Our objective is to localize the chromosome 19p13.2 PCOS susceptibility locus and determine its impact on metabolic features of PCOS. DESIGN: Resequencing and family-based association testing were used to examine the effect of sequence variation within 100 kb of D19S884 on the reproductive and metabolic phenotypes of PCOS. SETTING: The study was conducted in an academic medical center. SUBJECTS: Genetic analyses were performed on DNA obtained from1723 individuals in 412 families with 412 index cases and 43 affected sisters of predominantly European origin (>94%). Genotype-phenotype associations were assessed in 601 women with PCOS and 168 brothers of affected women. RESULTS: D19S884 allele 8 (A8) within intron 55 of the fibrillin-3 (FBN3) gene showed the strongest evidence for association with PCOS of 53 variants tested (P(corrected) = 0.0037). A8 was also associated with higher levels of fasting insulin and homeostasis model assessment for insulin resistance in women with PCOS and higher fasting levels of proinsulin and proinsulin/insulin ratio in brothers. CONCLUSIONS: These findings strongly suggest that A8 of D19S884 is the chromosome 19p13.2 PCOS susceptibility locus. The association of D19S884 with markers of insulin resistance and pancreatic beta-cell dysfunction suggests that the same variant contributes to the reproductive and metabolic abnormalities of PCOS in affected women and their brothers.

Exaggerated glucagon responses to hypoglycemia in women with polycystic ovary syndrome.

CONTEXT: Premenopausal women have blunted counter-regulatory hormone responses (CRR) to hypoglycemia compared to men. Postmenopausal women have CRR similar to men; the premenopausal pattern can be restored by estrogen. However, glucagon and pancreatic polypeptide (PP) responses remain lower in postmenopausal women than in men. Since hyperandrogenemia contributes to the metabolic phenotype of polycystic ovary syndrome (PCOS), we hypothesize that CRR to hypoglycemia especially of glucagon and PP is exaggerated in premenopausal women with PCOS compared to premenopausal control women. STUDY SUBJECTS AND METHODS: Ten obese women with PCOS and 9 control women of similar ethnicity, age and BMI underwent determination of CRR in response to hypoglycemia during 180-min 60mU/m2/min insulin dose hypoglycemic clamp with isotopic assessment of endogenous glucose production (EGP). To assess CRR to hypoglycemia, glucagon, cortisol, growth hormone (GH), epinephrine, norepinephrine, PP, lactate, free fatty acid (FFA), ß-hydroxybutyrate, and glycerol levels were sampled at 15-min intervals throughout the clamp. MAIN FINDINGS: Incremental glucagon levels were ~3-fold higher during hypoglycemia (P=0.03) in PCOS. Postabsorptive, steady-state and incremental GH, cortisol, epinephrine, norepinephrine, PP, FFA, glycerol and ß-hydroxybutyrate did not differ. At target glucose levels of ~52mg/dL, insulin mediated glucose disposal (IMGD) was decreased by ~40% (P=0.02) in PCOS, compared to control women, despite ~20% higher steady-state insulin levels (P=0.03). Neither postabsorptive nor steady-state EGP differed. However, postabsorptive lactate levels were ~50% higher (P=0.02). PCOS status (P=0.04) and IMGD (P=0.02) predicted the differential glucagon response to hypoglycemia in separate regression models, however, neither parameter remained an independent predictor in a combined model. PRINCIPAL CONCLUSIONS: Glucagon responses were increased in PCOS, whereas other CRR did not differ. Women with PCOS were insulin resistant under hypoglycemic conditions and higher postabsorptive lactate levels in PCOS were consistent with this finding. Insulin resistance may have contributed to exaggerated glucagon response to hypoglycemia in PCOS.

Dyslipidemia and metabolic syndrome in the sisters of women with polycystic ovary syndrome.

CONTEXT: Dyslipidemia is a feature of polycystic ovary syndrome (PCOS), but its pathogenesis remains controversial. OBJECTIVE: The objective of this study was to test the hypothesis that dyslipidemia is a heritable trait in sisters of women with PCOS. DESIGN: A case-control design was used. SETTING: The study took place at General Clinical Research Centers in four academic medical centers in the United States. PATIENTS: The subjects included 385 sisters of women with PCOS with the following reproductive phenotypes: sisters with PCOS (n = 51), sisters with hyperandrogenemia and regular menses (HA) (n = 38), unaffected sisters (n = 143), and unknown phenotypes (n = 153). One hundred twenty-five control women of comparable age, body mass index, and ethnicity to women with PCOS were included. INTERVENTIONS: Fasting blood was obtained for measurements of lipid profile, reproductive hormones, glucose, and insulin levels. MAIN OUTCOME MEASURES: The main outcome measures included lipid and lipoprotein levels and prevalence of metabolic syndrome. RESULTS: Sisters with PCOS and HA phenotypes had higher total (P < or = 0.001) and low-density lipoprotein cholesterol levels (P < or = 0.01) compared with unaffected sisters and control women. Triglyceride levels were elevated only in sisters with the PCOS phenotype (P < 0.05). The prevalence of metabolic syndrome was increased in sisters with the PCOS (n = 29) and HA (n = 17) phenotypes compared with unaffected sisters (n = 85) (P < 0.001 and P < 0.05, respectively). CONCLUSIONS: Low-density lipoprotein levels are increased in affected sisters of women with PCOS consistent with a heritable trait. The prevalence of metabolic syndrome is increased in affected sisters.