Insulin Resistance In Premenopausal Women Research Articles

Abstract P048: A Model Of Chronic Insufficient Sleep Increases Markers Of Insulin Resistance In Postmenopausal But Not Premenopausal Women

Introduction: Insufficient sleep is widely prevalent among US adults and is a risk factor for type 2 diabetes (T2D). Experimental studies show adverse effects of acute, severe short sleep on insulin sensitivity, but it is unclear whether these reflect risks associated with milder short sleep routinely observed in the general population. To date, no study has evaluated the impact of prolonged mild sleep curtailment on markers of insulin resistance in women or whether these effects differ by menopausal status, known to impact insulin sensitivity. Hypothesis: Glucose and insulin levels, as well as a measure of insulin resistance (HOMA-IR), will increase during 6 wk of sleep restriction (SR) relative to adequate sleep (AS). Adverse effects of prolonged short sleep will be exacerbated in postmenopausal women. Methods: Thirty-four women (age: 38±14 y; BMI: 25.6±3.6 kg/m2; n=10 postmenopausal) with adequate habitual total sleep time (TST) (453±33 min) took part in a randomized crossover study with two 6-wk phases: AS and SR. In AS, participants were asked to maintain stable nightly bed and wake times determined from 2 wk of screening with wrist actigraphy and sleep logs. In SR, bedtime was delayed to reduce TST by approximately 1.5 h/night. Sleep was measured continuously using actigraphy and verified weekly for compliance. At wk 0, 3, 4, and 6 fasting blood samples were collected. Outcomes included glucose and insulin levels as well as HOMA-IR scores, calculated from those values. Linear-mixed models tested interactions of sleep condition with week on outcome measures in the full sample and by menopausal status. Results: Sleep condition impacted the change in TST from baseline (P<0.0001), which was reduced in SR and unchanged in AS (-79±6 vs -4±6min). In the full sample, there was no sleep condition by week interactions for glucose (P=0.67), insulin (P=0.14), or HOMA-IR (P=0.16). Similar results were observed in premenopausal women (all P>0.50). However, in postmenopausal women, there was a significant effect of sleep condition on change in insulin (P=0.046) and HOMA-IR (P=0.039) over the 6 wk. In SR, insulin (slope: 0.26±0.28 μU/mL) and HOMA-IR (slope: 0.07±0.08) increased, while AS resulted in reductions in these outcomes (insulin slope: -0.56±0.29 μU/mL; HOMA-IR slope: -0.16±0.08). Conclusions: We provide the first evidence that chronic short sleep, even if mild, adversely affects insulin sensitivity in postmenopausal women. In contrast, maintenance of AS may improve glycemic regulation. Interestingly, prolonged short sleep did not impact markers of insulin resistance in premenopausal women; further investigation into these life-stage related differences, including underlying mechanisms, is warranted. Results suggest that, in postmenopausal women, a group at heightened risk of poor sleep and T2D, achieving adequate sleep may be an effective strategy to improve cardiometabolic health.

Using metabolic markers to identify insulin resistance in premenopausal women with and without polycystic ovary syndrome.

Insulin resistance (IR) is associated with increased risk for type 2 diabetes mellitus and cardiovascular disease. Quantifying IR is invasive and time-consuming, and thus not routinely used in clinical practice. Simple metabolic markers to predict IR exist, but have not been validated in premenopausal women or women with polycystic ovary syndrome (PCOS). To evaluate the ability of metabolic markers to identify premenopausal women with/without PCOS who are insulin resistant. Cross-sectional analysis. One hundred and seventy-one non-diabetic premenopausal overweight/obese women without PCOS and 71 women with PCOS. IR was quantified by the steady-state plasma glucose during the modified insulin-suppression test. Metabolic markers (BMI, lipid/lipoprotein concentrations, and fasting glucose) were evaluated for their discriminative ability to identify IR, using area under the receiver-operating-characteristic curve (AUROC) analysis. Optimal cut-points were evaluated for predictive power. In the non-PCOS group, the triglyceride/HDL cholesterol ratio (TG/HDL-C) was the best marker (AUROC 0.73). Optimal diagnostic cut-point was 1.9. In the PCOS group, the TG/HDL-C ratio, cholesterol/HDL-C ratio (TC/HDL-C), and HDL-C performed well (AUROC > 0.80), with optimal cut-points for TG/HDL-C 1.3, TC/HDL-C 3.4, and HDL-C 52mg/dL: TG/HDL-C was more sensitive, but HDL-Chad a higher PPV for IR. TG/HDL-C can identify IR in premenopausal women withand/without PCOS; diagnostic cut-points differ from those of men and postmenopausal women. HDL-C is an alternative predictor in women with PCOS. These simple metabolic markers, which are standardized between labs, inexpensive, and routinely measured, can be used to tailor lifestyle and medical interventions to improve health outcomes in insulin-resistant premenopausal women.

1620-P: Metabolites Associated with Insulin Resistance in Women with and without Type 1 Diabetes

Having type 1 diabetes (T1D) at least doubles insulin resistance (IR) compared to people without diabetes, but factors explaining this increased IR remain poorly understood. We analyzed untargeted plasma metabolomics in 30 premenopausal women aged 18-45 years (15 with and 15 without T1D) who underwent a hyperinsulinemic euglycemic clamp to measure insulin sensitivity. Sparse Partial Least Squares Discriminant Analysis (sPLS-DA) was used to identify metabolites that discriminated T1D status and diabetes-specific GIR tertile. Women with T1D had a significantly lower glucose infusion rate (GIR) than women without diabetes (5.5 ± 3.2 mg/kg/min vs. 12.8 ± 5.4 mg/kg/min, p=0.0001), indicating lower insulin sensitivity. Using sPLS-DA, we identified two components that discriminated T1D status (AUC=0.84) and two components that discriminated the lowest vs. highest group-specific GIR tertile (AUC= 0.91). Metabolite pathways discriminating T1D status and lowest vs. highest GIR tertile are shown in the Table. Common pathways discriminating both T1D and GIR tertile are in bold in the Table. Plasma metabolites mainly in the amino acid and lipid metabolism pathways differed by T1D status, and both overlapping and novel metabolites distinguished IR in premenopausal women. These data provide insight into common factors influencing IR regardless of diabetes status, as well as metabolic pathways affected by T1D. Disclosure J.K. Snell-Bergeon: Stock/Shareholder; Self; GlaxoSmithKline plc. I.E. Schauer: None. B.C. Bergman: Consultant; Spouse/Partner; Novo Nordisk Inc., Sanofi US. Research Support; Self; Eli Lilly and Company. Speaker’s Bureau; Spouse/Partner; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. K.J. Nadeau: None. M. Cree-Green: Advisory Panel; Self; Novo Nordisk Inc. A. Keshawarz: None. L. Pyle: None. Funding American Diabetes Association (7-13-CD-10 to J.K.S-B.)

Effects of two different eight-week walking programs on insulin resistance and ER stressrelated markers in pre-menopausal women / Premenopozal kadınlarda 8 haftalık farklı şiddetteki yürüyüş antrenmanlarının insülin direnci ve ER stresiyle ilişkili markerler üzerine etkileri

Abstract Objective: The relationship between exercise and endoplasmic reticulum (ER) stress, insulin resistance, and obesity is a new field of research. To our knowledge, there are no studies examining the effects of walking exercises on ER stress related markers and insulin resistance in pre-menopausal women. To examine the effect of two different eight-week walking programs on the tumor necrosis factor-alpha (TNF-α), Fetuin-A (α2 - Heremans Schmid glycoprotein), c-Jun N-terminal kinase-1 (JNK-1) and retinol- binding protein-4 (RBP-4), the related markers of ER stress and insulin resistance in pre-menopausal women. Methods: Exercise groups (moderate tempo walking group; MTWG; n=11; brisk walking group BWG; n=12) walked five days a week, starting from 30 minutes, gradually increasing up to 51 minutes. BWG walked at ~70-75% and MTWG at ~50-55 of HRRmax. Body mass index (BMI), body fat percentage (%), VO2max, serum TNF-α, Fetuin-A, JNK-1, RPB-4, blood lipids, and insulin resistance levels were determined before and after the intervention. Results: VO2max increased in both exercise groups favoring BWG; RBP-4 decreased in both exercise groups (p<0.05). Serum TNF-α and, TG (p<0.05), BMI and percent body fat (p<0.01), and insulin levels reduced significantly in BWG (p<0.05). The reductions observed in both exercise groups in insulin resistance, and the increases determined in the negative levels of JNK-1 in BWG may be clinically important. Conclusion: Both type of walking resulted in similar positive effects on RBP-4. The reduction observed in TNF-α, RBP-4, and the increases in the negative levels of JNK-1 in BWG show the positive effects of brisk walking on ER stress. The reduction in insulin resistance in relation to the possible reductions in ER stress and apoptosis in BWG may be more effective to prevent metabolic diseases.

Correlation of Serum Ferritin with Components of Metabolic Synd rome and its Relationship with the Insulin Resistance in Men in Wome n

Background: Raised serum ferritin levels are associated with insulin resistance, type 2 diabetes mellitus, prediabetic stage, metabolic syndrome (Mets) and cardiovascular risk. The association between Serum ferritin and HbA1c levels with individual components of metabolic syndrome and obesity are unclear. Objectives: The present study was designed to investigate the relationship between serum ferritin levels, fasting Blood glucose levels, waist Hip ratio, fasting insulin levels, homeostasis model assessment (HOMA-IR), and lipid profile in previously diagnosed type 2 diabetes mellitus patients, newly diagnosed patients, impaired fasting glucose subjects and healthy subjects and relationship among iron stores, the metabolic syndrome, and insulin resistance in premenopausal women, postmenopausal women and men. Subjects and methods: 1058 participants included in this study out of them 365 patients with previously diagnosed type 2 diabetes mellitus having poor glycemic control and good glycemic control, 144 patients with newly diagnosed type 2 diabetes mellitus, 189 participants with impaired fasting glucose levels and 360 healthy participants. Fasting blood glucose, Serum ferritin, serum insulin, HbA1c waist hip ratio, and lipid parameters were estimated and Homeostasis Model Assessment-Insulin resistance (HOMA-IR) was calculated. Results: Dichotomizing ferritin concentration in to 300 ng/ml for men and 150 ng/ml for women, the odd ratios for newly diagnosed diabetes were 4.94 (95% CI 3.05-8.01) for men 3.61 (2.01-6.48) for women. All multiple linear regression coefficients between ferritin concentration and concentration of insulin, glucose, and glycosylated hemoglobin were positive and significant for men and postmenopausal women. Conclusion: On basis of present studies results, it is concluded that hyperferritinaemia and iron overload may be the primary cause of insulin resistance and metabolic syndrome before overt type 2 diabetes mellitus.

Vitamin D, inflammation, and relations to insulin resistance in premenopausal women with morbid obesity.

In this study, the associations between vitamin D, insulin sensitivity, and inflammation and their relationships with adipose tissue expression of vitamin D receptor (VDR) and inflammatory markers in women with morbid obesity were determined. An oral glucose tolerance test prior to surgery was completed by healthy premenopausal women (n = 76) seeking bariatric surgery. Abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were collected during surgery. Approximately, 70% of our subjects were vitamin D sufficient or optimal, and 80% had normal glucose tolerance. No significant association between serum 25-hydroxyvitamin D [25(OH)D] with circulating inflammatory markers or insulin sensitivity was identified. In subjects with waist circumference of <139 cm (n = 42), log25(OH)D positively predicted VAT logIL-6 mRNA expression (P = 0.003). LogVDR expression was positively correlated with the expression of inflammatory markers in both SAT (logIL-1β mRNA: r = 0.95, P < 0.0001; logTNF mRNA: r = 0.82, P < 0.0001) and VAT (logIL-1β mRNA: r = 0.89, P < 0.0001; logTNF mRNA: r = 0.75, P < 0.0001). VAT logVDR expression positively predicted logHOMA-IR in non-African American subjects (P = 0.05). The beneficial effects of vitamin D on inflammation and insulin sensitivity were not supported by our findings. VDR does not appear to possess a protective effect in adipose tissue.

Abstract P139: Insulin Resistance in Premenopausal Women with Type 1 Diabetes is Explained by Abdominal Obesity, Physical Inactivity and Altered Sex Hormones

Women with type 1 diabetes (T1D) lose the premenopausal protection from cardiovascular disease (CVD) that non-diabetic (non-DM) women have compared to men, and are also more insulin resistant than non-DM women. Standard CVD risk factors have not been found to adequately predict CVD in the T1D population, but insulin resistance is emerging as a potentially important risk factor. The aim of this study was to determine whether sex hormone levels such as estradiol (E2), total testosterone (TT), and sex-hormone binding globulin (SHBG) explained any of the decreased insulin sensitivity in women with T1D, which could be important in CVD prevention. This study included 25 premenopausal women 18-45 years of age with a mean ± SD age of 33 ± 8 years who completed a three stage (4, 8 and 40 mU/m2/min) hyperinsulinemic-euglycemic clamp during the luteal phase of the menstrual cycle (T1D n=12 and non-DM n=13). A steady state was achieved during the last 30 minutes of the high insulin infusion stage and mean glucose infusion rate (GIR [mg/kg/FFM/min]) during this time was used as an estimate of the skeletal muscle glucose disposal rate. Sex hormones were compared using unpaired Student t tests between T1D and non-DM participants during each phase of the menstrual cycle and during the morning of the clamp.. Significant differences were explored in multivariable linear regression in which stepwise model selection was used to determine the final model adjusting for age and diabetes status. In age-adjusted analysis, women with T1D were less than half as insulin sensitive as non-DM women (least squares mean ± SE: 7.5±2.2 vs. 19.0±2.1, respectively, p=0.0014). SHBG was significantly higher in the T1D than the non-DM subjects the morning of the clamp (p&lt;0.0001) and during each phase of the menstrual cycle (p = 0.01). TT was significantly higher in T1D women during the early follicular phase of the menstrual cycle (p=0.02) and was negatively correlated with GIR (r = -0.54, p = 0.04). E2 during the early follicular phase was positively correlated with GIR (r = 0.83, p = 0.01). In multivariable analysis, the difference in the GIR was attenuated by 58%(1-(5.1/12.14)) (least squares mean ± SE: 10.9 ± 1.7 in T1D vs. 16.0 ± 1.5 in non-DM, p = 0.07) after adjusting for age, diabetes status, minutes of vigorous activity, average waist circumference, free estradiol index and testosterone during the early follicular phase of the menstrual cycle In conclusion, the decreased insulin sensitivity observed in premenopausal T1D women with regular menstrual cycles can be mostly explained by lower levels of physical activity, greater central adiposity and differences in sex hormone levels. Most of these factors are modifiable, and so could be important targets in the reduction of CVD.

Evaluation of body weight, insulin resistance, leptin and adiponectin levels in premenopausal women with hyperprolactinemia

The effects of hyperprolactinemia on metabolic parameters are not clear and a few data evaluating adiponectin levels in prolactinoma and idiopathic hyperprolactinemia exist. The aim of this study was to evaluate the effects of hyperprolactinemia on body weight, insulin resistance, beta cell function, and leptin and adiponectin levels in premenopausal women with hyperprolactinemia. Forty premenopausal women with prolactinoma or idiopathic hyperprolactinemia were compared to 41 age-matched healthy premenopausal women with regard to body weight, body mass index, waist and hip circumferences, waist to hip ratio, fasting plasma glucose, insulin levels, insulin resistance measured by homeostasis model assessment (HOMA)-insulin resistance index, beta cell function measured by HOMA-β index, leptin and adiponectin levels. Plasma insulin levels and HOMA indexes (both insulin resistance and beta indexes) were significantly higher in hyperprolactinemic women. The other parameters were similar between both groups. There was a positive correlation between prolactin levels and fasting plasma glucose in hyperprolactinemic women. The results of this study showed that high prolactin levels may be associated with hyperinsulinemia and insulin resistance in premenopausal women. This effect seems to be independent of body weight, leptin and adiponectin levels. High prolactin levels may directly stimulate insulin secretion from pancreas and directly cause hepatic and whole-body insulin resistance.

Evaluation of body weight, insulin resistance, leptin and adiponectin levels in premenopausal women with hyperprolactinemia

The effects of hyperprolactinemia on metabolic parameters are not clear and a few data evaluating adiponectin levels in prolactinoma and idiopathic hyperprolactinemia exist. The aim of this study was to evaluate the effects of hyperprolactinemia on body weight, insulin resistance, beta cell function, and leptin and adiponectin levels in premenopausal women with hyperprolactinemia. Forty premenopausal women with prolactinoma or idiopathic hyperprolactinemia were compared to 41 age-matched healthy premenopausal women with regard to body weight, body mass index, waist and hip circumferences, waist to hip ratio, fasting plasma glucose, insulin levels, insulin resistance measured by homeostasis model assessment (HOMA)-insulin resistance index, beta cell function measured by HOMA-β index, leptin and adiponectin levels. Plasma insulin levels and HOMA indexes (both insulin resistance and beta indexes) were significantly higher in hyperprolactinemic women. The other parameters were similar between both groups. There was a positive correlation between prolactin levels and fasting plasma glucose in hyperprolactinemic women. The results of this study showed that high prolactin levels may be associated with hyperinsulinemia and insulin resistance in premenopausal women. This effect seems to be independent of body weight, leptin and adiponectin levels. High prolactin levels may directly stimulate insulin secretion from pancreas and directly cause hepatic and whole-body insulin resistance.

Alteration of insulin sensitivity by sex hormones during the menstrual cycle.

It is well established that insulin resistance and impaired insulin secretion are two major prerequisites in the development of type 2 diabetes. Given the growing global epidemic of obesity, it is expected that the number of people with insulin resistance will expand exponentially. To maintain glucose homeostasis, insulin action, reflected by insulin sensitivity measured in vivo, is regulated by a well organized, but complicated, hierarchical mechanism. In this regard, many studies have shown that environmental factors might have a great influence on insulin sensitivity and these issues are further complicated when interaction between genes and the environment is taken into consideration1. Additionally, a number of studies have shown that the degree of insulin sensitivity is also influenced by many biological factors, in particular, hormone alterations, which might account for the diurnal changes of insulin sensitivity in normal and diabetic individuals or involve the occurrence of the dawn phenomenon. Extensive studies were carried out to determine how sex hormones harness insulin sensitivity or predispose humans to the development of diabetes2. In a recent article, obtained from The BioCycle Study, Yeung et al.3 reported that, in a group of relatively healthy premenopausal women, insulin resistance, expressed by homeostasis model assessment for insulin resistance (HOMA‐IR), changed slightly, but significantly, during the normal menstrual cycle. Specifically, HOMA‐IR rose from 1.35 in the midfollicular phase to 1.59 (with a magnitude of increase of 17.8%) during the early luteal phase and decreased to 1.55 (by 14.8%) in the late luteal phase. These changes were positively associated with levels of estradiol and progesterone, but negatively associated with follicle stimulating hormone (FSH) and sex hormone binding globin (SHBG). In addition to findings from previous studies showing the impact of menstrual cycle variability on insulin sensitivity, this BioCycle Study enrolled the greatest number of healthy women (n = 257) and had the most frequent visits (eight visits during a cycle period), designed to monitor women at peak fertility. Thus, the findings from this study, which has overcome the shortages of previous inconsistent reports, should be reliable. However, concerns were raised as to how accurate HOMA‐IR is in capturing the degree of insulin resistance4. It will be of great value, although difficult, to use more precise measures of insulin resistance, such as the glucose clamp study, in those studied participants. The physiological effects of circulating estradiol and progesterone levels on insulin resistance in premenopausal women might be distinct from pharmacological applications in postmenopausal women. The present author and others have shown that oral contraceptive pills might decrease insulin resistance and increase cardiovascular risk in young women, whereas transdermal use of estrogen might prevent these untoward effects5. It is postulated that estrogen‐induced increases in glucocorticoid activity might account for these unwanted effects. In addition, the influence of long‐term use of estrogen might be different from that of short‐term use, with the former preserving insulin secretion and maintaining glucose homeostasis. In this article, the finding that alterations of HOMA‐IR primarily reflected changes in fasting insulin levels and not fasting glucose levels3 is not unexpected, given the tight regulation of insulin secretion during alterations of insulin sensitivity in healthy individuals. One of the limitations of the study by Yeung et al.3 was the lack of measurement of testosterone, which was reported to be associated with insulin resistance, although the use of SHBG in this study might partially reflect the bioavailability and action of testosterone. In addition, the association between HOMA‐IR and SHBG became insignificant after adjustment of body mass index (BMI), showing that these associations might be mediated through adiposity in the studied population. Finally, although the alterations of insulin resistance during the menstrual cycle might be considered as minor, caution should be taken when recruiting premenopausal women to serve as study volunteers, especially when comparing changes of insulin resistance before and after certain interventional trials.

Effect of Fenretinide and Low-Dose Tamoxifen on Insulin Sensitivity in Premenopausal Women at High Risk for Breast Cancer

The prevalence of metabolic syndrome is increasing along with breast cancer incidence worldwide. Because fenretinide improves insulin action and glucose tolerance in insulin-resistant obese mice and because tamoxifen has shown to regulate several markers involved in metabolic syndrome, we sought to investigate the effect of fenretinide or tamoxifen at low dose on features linked to insulin resistance in premenopausal women at risk for breast cancer. We randomized 235 women to low-dose tamoxifen (5 mg/daily), fenretinide (200 mg/daily), or their combination or placebo for 2 years. We used the homeostasis model assessment (HOMA; fasting insulin x glucose/22.5) to estimate insulin sensitivity. Women were considered to improve insulin sensitivity when they shifted from a HOMA >/=2.8 to <2.8. There was no effect of fenretinide or tamoxifen on HOMA overall, but overweight women (body mass index, >or=25 kg/m(2)) had a 7-fold greater probability to normalize HOMA after 2 years of fenretinide treatment [odds ratio (OR), 7.0; 95% confidence interval (95% CI), 1.2-40.5], with 25% of women improving their insulin sensitivity, whereas tamoxifen decreased insulin sensitivity by almost 7 times compared with subjects not taking tamoxifen (OR, 0.15; 95% CI, 0.03-0.88). In this group only, 5% improved their insulin sensitivity. Interestingly, women with intraepithelial or microinvasive neoplasia had higher HOMA (3.0) than unaffected subjects (2.8; P = 0.07). Fenretinide can positively balance the metabolic profile in overweight premenopausal women and this may favorably affect breast cancer risk. Furthermore, features of the metabolic syndrome should be taken into consideration before proposing tamoxifen for breast cancer prevention. The clinical implications of these results require further investigations.

Abdominal obesity, muscle composition, and insulin resistance in premenopausal women.

The independent relationships between visceral and abdominal sc adipose tissue (AT) depots, muscle composition, and insulin sensitivity were examined in 40 abdominally obese, premenopausal women. Measurements included glucose disposal by euglycemic clamp, muscle composition by computed tomography, abdominal and nonabdominal (e.g. leg) AT by magnetic resonance imaging and cardiovascular fitness. Glucose disposal rates were negatively related to visceral AT mass (r = -0.42, P < 0.01). These observations remained significant (P < 0.01) after control for nonabdominal and abdominal sc AT, muscle attenuation, and peak oxygen uptake. Total, abdominal, or leg sc AT or muscle attenuation was not significantly (P > 0.10) related to glucose disposal. Subdivision of abdominal sc AT into anterior and posterior depots did not alter the observed relationships. Further analysis matched two groups of women for abdominal sc AT but with low and high visceral AT. Women with high visceral AT had lower glucose disposal rates compared with those with low visceral AT (P < 0.05). A similar analysis performed on two groups of women matched for visceral AT but high and low abdominal sc AT revealed no statistically different values for insulin sensitivity (P > 0.10). In conclusion, visceral AT alone is a strong correlate of insulin resistance independent of nonabdominal, abdominal sc AT, muscle composition, and cardiovascular fitness. Subdivision of abdominal sc AT did not provide additional insight into the relationship between abdominal obesity and metabolic risk.