Reactive Hypoglycemia: A Trigger for Nutrient-Induced Endocrine and Metabolic Responses in Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is an insulin-resistant state compensated for by the body via hyperinsulinemia. More than 50% of women with PCOS are obese and/or have metabolic syndrome. Weight loss improves both metabolic and reproductive outcomes. Energy/caloric content as well as the nutrient composition of one's diet may also be important. This article will present a series of studies from our research comparing the effects of dietary protein vs. simple carbohydrates (CHOs). The results of the acute challenge studies demonstrate that simple CHO intake causes reactive hypoglycemia in one third of women with PCOS, especially among obese and insulin-resistant individuals. Symptoms of hypoglycemia are associated with secretion of cortisol and adrenal androgens. Simple CHOs suppress the hunger signal ghrelin for a shorter period. During weight loss, women who receive protein supplementation achieve more significant weight and fat mass losses. The amino acid compositions of the protein supplements do not affect the improvements in weight and insulin resistance. It is plausible that simple CHO intake leads to weight gain, or interferes with weight loss, by causing reactive hypoglycemia, triggering adrenal steroid secretion and thus leading to snacking. Since obese women with PCOS are more susceptible to reactive hypoglycemia, a vicious cycle is established. Restriction of simple CHOs may break this cycle.

Anti-Mullerian Hormone-Based Phenotyping Identifies Subgroups of Women with Polycystic Ovary Syndrome with Differing Clinical and Biochemical Characteristics.

Even though polycystic ovary syndrome (PCOS) was originally defined as "amenorrhea associated with bilateral polycystic ovaries", women without PCO morphology can be included in this diagnosis. This may contribute to the clinical heterogeneity seen in PCOS. Serum anti-Mullerian hormone (AMH) correlates with the number of ovarian cysts. We investigated whether phenotyping based on serum AMH can distinguish subgroups of PCOS with different clinical and biochemical characteristics. The electronic medical records of 108 women with PCOS (Rotterdam criteria) were reviewed. The serum AMH value correlated inversely (0.03 < p < 0.0001) with age, weight, and BMI values and directly with serum total testosterone (T), free T, and bioavailable T values. When divided into quartiles based on serum AMH values, the women in the highest quartile (AMH: 18.5 ± 9.9 ng/mL; n = 27) had lower BMI (29.4 ± 6.9 vs. 34.0 ± 10.6-36.7 ± 7.2 kg/m2) but higher total T (51.3 ± 27.2 vs. 26.5 ± 10.4-35.1 ± 16.3 ng/dL), free T (7.7 ± 6.0 vs. 4.4 ± 2.3-5.7 ± 3.2 ng/dL), and bioavailable T (22.1 ± 17.0 vs. 12.2 ± 6.6-16.5 ± 8.7 ng/dL) values. The combination of high AMH and high testosterone values may point to the ovaries and reproductive etiology for PCOS in this subgroup. Thus, AMH-based phenotyping may provide a practical and cost-effective tool to explore the heterogeneity in PCOS.

New Biomarkers to Evaluate Hyperandrogenemic Women and Hypogonadal Men.

Androgens can have variable effects on men and women. Women may be evaluated for androgen excess for several reasons. Typically, young premenopausal women present with clinical symptoms of hirsutism, alopecia, irregular menses, and/or infertility. The most common cause of these symptoms is polycystic ovary syndrome. After menopause, even though ovaries stop producing estrogen, they continue to produce androgen, and women can have new onset of hirsutism and alopecia. Laboratory evaluation involves measurement of the major ovarian and adrenal androgens. In women, age, phase of the menstrual cycle, menopausal status, obesity, metabolic health, and sex hormone-binding proteins significantly affect total-androgen levels and complicate interpretation. This review will summarize the clinically relevant evaluation of hyperandrogenemia at different life stages in women and highlight pitfalls associated with interpretation of commonly used hormone measurements. Hypogonadism in men is a clinical syndrome characterized by low testosterone and/or low sperm count. Symptoms of hypogonadism include decreased libido, erectile dysfunction, decreased vitality, decreased muscle mass, increased adiposity, depressed mood, osteopenia, and osteoporosis. Hypogonadism is a common disorder in aging men. Hypogonadism is observed rarely in young boys and adolescent men. Based on the defects in testes, hypothalamus, and/or pituitary glands, hypogonadism can be broadly classified as primary, secondary, and mixed hypogonadism. Diagnosis of hypogonadism in men is based on symptoms and laboratory measurement. Biomarkers in use/development for hypogonadism are classified as hormonal, Leydig and Sertoli cell function, semen, genetic/RNA, metabolic, microbiome, and muscle mass-related. These biomarkers are useful for diagnosis of hypogonadism, determination of the type of hypogonadism, identification of the underlying causes, and therapeutic assessment. Measurement of serum testosterone is usually the most important single diagnostic test for male hypogonadism. Patients with primary hypogonadism have low testosterone and increased luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Patients with secondary hypogonadism have low testosterone and low or inappropriately normal LH and FSH. This review provides an overview of hypogonadism in men and a detailed discussion of biomarkers currently in use and in development for diagnosis thereof.

SELF BLOOD GLUCOSE MONITORING UNDERESTIMATES HYPERGLYCEMIA AND HYPOGLYCEMIA AS COMPARED TO CONTINUOUS GLUCOSE MONITORING IN TYPE 1 AND TYPE 2 DIABETES.

OBJECTIVE: When glucose records from self blood glucose monitoring (SBGM) do not reflect estimated average glucose from glycosylated hemoglobin (HgBA1) or when patients' clinical symptoms are not explained by their SBGM records, clinical management of diabetes becomes a challenge. Our objective was to determine the magnitude of differences in glucose values reported by SBGM versus those documented by continuous glucose monitoring (CGM). METHODS: The CGM was conducted by a clinical diabetes educator (CDE)/registered nurse by the clinic protocol, using the Medtronic iPRO2™ system. Patients continued SBGM and managed their diabetes without any change. Data from 4 full days were obtained, and relevant clinical information was recorded. De-identified data sets were provided to the investigators. RESULTS: Data from 61 patients, 27 with type 1 diabetes (T1DM) and 34 with T2DM were analyzed. The lowest, highest, and average glucose recorded by SBGM were compared to the corresponding values from CGM. The lowest glucose values reported by SBGM were approximately 25 mg/dL higher in both T1DM ( P = .0232) and T2DM ( P = .0003). The highest glucose values by SBGM were approximately 30 mg/dL lower in T1DM ( P = .0005) and 55 mg/dL lower in T2DM ( P<.0001). HgBA1c correlated with the highest and average glucose by SBGM and CGM. The lowest glucose values were seen most frequently during sleep and before breakfast; the highest were seen during the evening and postprandially. CONCLUSION: SBGM accurately estimates the average glucose but underestimates glucose excursions. CGM uncovers glucose patterns that common SBGM patterns cannot. ABBREVIATIONS: CDE = certified diabetes educator; CGM = continuous glucose monitoring; HgBA1c = glycosylated hemoglobin; MAD = mean absolute difference; SBGM = self blood glucose monitoring; T1DM = type 1 diabetes; T2DM = type 2 diabetes.

Glucose-lowering effect of whey protein depends upon clinical characteristics of patients with type 2 diabetes.

OBJECTIVE: Whey protein (WP) intake has been shown to reduce postprandial glycemia. Majority of WP research in type 2 diabetes (T2DM) involved acute challenge or weight loss studies. It is not known if WP supplementation can provide sustained glucose lowering. Our goal was to investigate the effects of WP on glycemia comprehensively by using continuous glucose monitoring (CGM) while avoiding the confounding effects of variable food intake through controlled feeding. RESEARCH DESIGN AND METHODS: This double-blinded and placebo (PL)-controlled study included 22 patients with T2DM patients (11 male, 11 female; age 57.1±12.6 years) on diet or metformin monotherapy. First, one serving (21 g) of WP was compared with PL in parallel-armed acute challenge studies. Next, in a crossover design, each patient underwent CGM twice, over 2 consecutive weeks, 3.5 days each week. Identical diets were provided by the study during both CGM periods. During the first CGM, one serving of either WP or PL was consumed before breakfast and another before dinner. During the second CGM, participants switched to the alternate supplement. Order of the supplements was randomized. RESULTS: During acute challenge studies, WP stimulated insulin and glucagon-like peptide (GLP)-1 secretion; suppressed ghrelin (all p<0.05), while PL had no effect. During CGM, glucose response to WP varied depending on the baseline characteristics of the patients. When evaluated using linear regression, the most predictive baseline variables were body mass index (BMI) (p=0.0006), triglycerides (p=8.3×10-5) and GLP-1 (p=0.006). Lower BMI, triglyceride and GLP-1 predicted decreased glucose levels on WP. Obesity, hypertriglyceridemia and high fasting GLP-1 concentrations predicted increased glucose levels. CONCLUSIONS: Effects of WP supplementation on glycemia in T2DM depend on the baseline characteristics. Lower body weight, normal triglyceride and lower GLP-1 levels predict glucose lowering. In contrast, obesity, hypertriglyceridemia and high baseline GLP-1 predict increased glucose response.

New biomarkers for diagnosis and management of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting young women. Even though the definition of PCOS has changed over the years, all diagnostic criteria include two or more of the following: oligomenorrhea/oligoovulation/anovulation, androgen excess and polycystic ovaries (PCO). Traditional method of assessing the ovarian morphology has been transvaginal pelvic ultrasound. Recent studies support that serum anti-Mullerian hormone (AMH) levels correlate with the number of ovarian follicles and cysts. Hence, measurement of AMH is adequate to make the diagnosis. Traditionally, hyperandrogenemia has been assessed by measuring total-testosterone. The literature stresses the importance of sex hormone binding globulin (SHBG) measurements and bioavailable-testosterone and free-testosterone calculations, because insulin resistance decreases SHBG, lowers total-testosterone, and leads to under-estimation of bioavailable- and free-testosterone. Since 50-60% of PCOS patients have metabolic syndrome, assessment of metabolic risk is also necessary. It is important to diagnose insulin resistance before development of glucose intolerance and diabetes. This requires measurements of not only plasma glucose but also insulin concentrations. Determination of HgBA1 can be informative as well. This review aims to present an accurate and cost-effective approach to diagnosis and management of PCOS.

Changes in plasma metabolites and glucose homeostasis during omega-3 polyunsaturated fatty acid supplementation in women with polycystic ovary syndrome.

BACKGROUND: Both fish (FO) and flaxseed oils (FLX) are n-3 polyunsaturated fatty acids (PUFA). Fish oil contains long chain while FLX contains essential n-3 PUFA. We demonstrated that FO altered insulin secretion and resistance in polycystic ovary syndrome (PCOS) women but FLX did not. Surprisingly, the effects of FO were similar to those of the n-6 PUFA-rich soybean oil (SBO). Since increased branched chain (BCAA) and aromatic amino acids (AA) affect insulin secretion and resistance, we investigated whether FO, FLX and /or SBO affect plasma metabolites, especially AA. METHODS AND FINDINGS: In this six-week, randomized, 3-parallel arm, double-blinded study, 54 women received 3.5 g/day FO, FLX or SBO. In 51 completers (17 from each arm), fasting plasma metabolites were measured at the beginning and at the end. As compared to FLX, FO and SBO increased insulin response and resistance as well as several BCAA and aromatic AA. Pathway analysis indicated that FO exerted the largest biochemical impact, affecting AA degradation and biosynthesis, amine, polyamine degradation and alanine, glycine, l-carnitine biosynthesis and TCA cycle, while FLX had minimal impact affecting only alanine biosynthesis and l-cysteine degradation. CONCLUSION: Effects of FO and SBO on plasma AA were similar and differed significantly from those of the FLX. The primary target of dietary PUFA is not known. Dietary PUFA may influence insulin secretion and resistance directly and alter plasma AA indirectly. Alternatively, as a novel concept, dietary PUFA may directly affect AA metabolism and the changes in insulin secretion and resistance may be secondary.

Whey protein supplementation does not alter plasma branched-chained amino acid profiles but results in unique metabolomics patterns in obese women enrolled in an 8-week weight loss trial.

BACKGROUND: It has been suggested that perturbations in branched-chain amino acid (BCAA) catabolism are associated with insulin resistance and contribute to elevated systemic BCAAs. Evidence in rodents suggests dietary protein rich in BCAAs can increase BCAA catabolism, but there is limited evidence in humans. OBJECTIVE: We hypothesize that a diet rich in BCAAs will increase BCAA catabolism, which will manifest in a reduction of fasting plasma BCAA concentrations. METHODS: The metabolome of 27 obese women with metabolic syndrome before and after weight loss was investigated to identify changes in BCAA metabolism using GC-time-of-flight mass spectrometry. Subjects were enrolled in an 8-wk weight-loss study including either a 20-g/d whey (whey group, n = 16) or gelatin (gelatin group, n = 11) protein supplement. When matched for total protein by weight, whey protein has 3 times the amount of BCAAs compared with gelatin protein. RESULTS: Postintervention plasma abundances of Ile (gelatin group: 637 ± 18, quantifier ion peak height ÷ 100; whey group: 744 ± 65), Leu (gelatin group: 1210 ± 33; whey group: 1380 ± 79), and Val (gelatin group: 2080 ± 59; whey group: 2510 ± 230) did not differ between treatment groups. BCAAs were significantly correlated with homeostasis model assessment of insulin resistance at baseline (r = 0.52, 0.43, and 0.49 for Leu, Ile, and Val, respectively; all, P < 0.05), but correlations were no longer significant at postintervention. Pro- and Cys-related pathways were found discriminant of whey protein vs. gelatin protein supplementation in multivariate statistical analyses. CONCLUSIONS: These findings suggest that BCAA metabolism is, at best, only modestly affected at a whey protein supplementation dose of 20 g/d. Furthermore, the loss of an association between postintervention BCAA and homeostasis model assessment suggests that factors associated with calorie restriction or protein intake affect how plasma BCAAs relate to insulin sensitivity. This trial was registered at clinicaltrials.gov as NCT00739479.

Lignan content of the flaxseed influences its biological effects in healthy men and women.

OBJECTIVE: The omega-3 polyunsaturated fatty acid (n-3 PUFA) as well as lignan components of flaxseed (FLX) can have beneficial effects. In this 6-week-long, randomized, double-blinded, placebo-controlled study, we investigated the effects of FLX lignans on cardiovascular risk factors. METHODS: Thirty-seven subjects (13 men and 24 women, age: 54±7 years, body mass index [BMI]: 29.7±1 kg/m2) consumed nutrition bars with similar macronutrient contents. The fatty acid composition and the lignan contents of the bars differed significantly. Two FLX bars both contained 3.0 g of alpha linolenic acid (ALA: 18:3 n-3) but different amount of lignans (0.15 g vs. 0.41 g). RESULTS: High-lignan FLX decreased total cholesterol (C) by 12% (p=0.044), LDL-C by 15% (p=0.022), and oxidized (Ox)-LDL by 25% (p=0.035). Regular FLX tended to increase Ox-LDL by 13% (p=0.051). The difference between the effects of high-lignan vs. regular lignan FLX on Ox-LDL was highly significant (p=0.004). CONCLUSION: High-lignan FLX has the unique property of decreasing Ox-LDL, which is an independent risk factor for cardiovascular disease.

Free fatty acid binding protein-4 and retinol binding protein-4 in polycystic ovary syndrome: response to simvastatin and metformin therapies.

Free fatty acid binding protein-4 (FABP4) and retinol binding protein-4 (RBP4) contribute to metabolic syndrome. We investigated serum FABP4 and RBP4 responses to insulin sensitizing and lipid lowering therapies in polycystic ovary syndrome (PCOS). Sixty-two healthy, untreated women with PCOS (age 25.1 ± 3.6 years, BMI: 24.0 ± 4.7 kg/m(2)) were randomized to metformin (n = 24), simvastatin (n = 20) or metformin plus simvastatin (n = 18) for 3 months. Anthropometric measures, fasting blood tests and oral glucose tolerance tests (OGTT) were obtained at the baseline and the end. At the baseline serum FABP4 correlated with obesity (BMI: r = 0.63, p < 0.001), insulin resistance (fasting insulin: r = 0.44, p = 0.0002; QUICKI: r = -0.30, p = 0.02; OGTT-insulin sensitivity index: r = -0.27, p = 0.04), dyslipidemia (HDL: r = -0.26, p = 0.03) and hyperandrogenemia (free-testosterone: r = 0.23, p = 0.03; SHBG: r = -0.28, p = 0.03); while RBP4 correlated with total-cholesterol (r = 0.33, p = 0.009). Multiple regression analysis indicated that t best predictors of serum FABP4 and RBP4 were BMI (ß = 1.02, p = 0.0003) and total cholesterol (ß = 2326, p = 0.01), respectively. Simvastatin, alone or with metformin did not affect serum FABP4 or RBP4. Serum FABP4 related to the obesity, insulin resistance and inflammation while RBP4 related to lipids. Insulin sensitizing and lipid lowering therapies did not affect FABP4 or RBP4 levels in PCOS.

Utility of hemoglobin-A1C in nondiabetic women with polycystic ovary syndrome.

OBJECTIVE: Hemoglobin A1c (A1C) ≥5.7% is now accepted as a biomarker for identifying individuals at risk for diabetes. Compared to the general population, women with polycystic ovary syndrome (PCOS) have a higher risk for diabetes. Our goal was to determine what glucose homeostasis abnormalities can be identified by A1C ≥5.7% in women with PCOS. METHODS: In a cross-sectional study, nondiabetic women with PCOS (according to the National Institutes of Health [NIH] criteria) were divided into 2 groups based on A1C (<5.7% [n = 23] and ≥5.7% [n = 25]). Oral glucose tolerance tests (OGTT) and frequently sampled intravenous glucose tolerance tests (FS-IVGTT) were conducted, and body composition, cardiovascular risk factors, and sex steroid levels were assessed. RESULTS: Compared to women with A1C <5.7%, those with A1C ≥5.7% were older (35.1 ± 1.1 years vs. 31.1 ± 1.1 years; P = .04), had higher glucose levels at fasting and during OGTT, and had a lower insulin sensitivity index (SI: 2.0 ± 0.2 vs. 4.2 ± 0.6; P = .0195) and disposition index (DI: 1,014 ± 82 vs. 1,901 ± 217; P = .011) during FS-IVGTT. They also had higher triglycerides, high-sensitivity C-reactive protein (hs-CRP), and fatty acid-binding protein 4 (FABP4) levels. There was no difference in serum androgen levels. CONCLUSION: A1C ≥5.7% identified the subgroup of PCOS patients with higher insulin resistance, inadequate compensatory insulin response, impaired glucose disposition, and increased cardiovascular risk factors. Thus, A1C represents an inexpensive and informative biomarker to identify PCOS patients at risk for metabolic abnormalities.

Lean mass and insulin resistance in women with polycystic ovary syndrome.

Insulin resistance is common in women with polycystic ovary syndrome (PCOS). Muscle is the major tissue utilizing glucose while excess adipose tissue relates to insulin resistance. Thus, body composition is likely to be an important regulator of insulin sensitivity. Thirty-nine PCOS patients (age: 29.9±1.0 years; BMI: 33.8±1.2 kg/m(2)) participated in a cross sectional study. Body composition was measured by dual energy x-ray absorptiometry (DEXA). Insulin resistance and secretion were assessed using oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FS-IVGTT). In contrast with the conventional expectations, lean mass correlated directly (P<.05) with the insulin resistance measure HOMA (r=0.440); and inversely with the insulin sensitivity index QUICKI (r=-0.522) independent of fat mass. In 11 pairs of subjects matched for fat mass (35.6±2.2 and 35.6±2.4 kg) but with discordant lean mass (52.8±1.8 vs 44.4±1.6 kg), those with higher lean mass had a higher glucose response during OGTT (AUC(Glucose); P=.034). In contrast, 17 pairs matched for lean mass (48.7±1.7 and 48.9±1.6 kg) but discordant for fat mass (43.3±2.6 vs 30.3±8.9 kg) showed no differences in insulin resistance parameters. These novel findings indicate that lean mass relates directly to insulin resistance in PCOS.

Metabolic and endocrine effects of long-chain versus essential omega-3 polyunsaturated fatty acids in polycystic ovary syndrome.

The objective of the study was to compare the effects of essential vs long-chain omega (n)-3 polyunsaturated fatty acids (PUFAs) in polycystic ovary syndrome. In this 6-week, prospective, double-blinded, placebo (soybean oil)-controlled study, 51 completers received 3.5 g n-3 PUFA per day (essential PUFA from flaxseed oil or long-chain PUFA from fish oil). Anthropometric variables, cardiovascular risk factors, and androgens were measured; oral glucose tolerance test (OGTT) and frequently sampled intravenous GTT (IVGTT) were conducted at baseline and 6 weeks. Between-group comparisons showed significant differences in serum triglyceride response (P = .0368), whereas the changes in disposition index also tended to differ (P = .0621). When within-group changes (after vs before intervention) were considered, fish oil and flaxseed oil lowered serum triglyceride (P = .0154 and P = .0176, respectively). Fish oil increased glucose at 120 minutes of OGTT (P = .0355), decreased the Matsuda index (P = .0378), and tended to decrease acute insulin response during IVGTT (P = .0871). Soybean oil increased glucose at 30 (P = .0030) and 60 minutes (P = .0121) and AUC for glucose (P = .0122) during OGTT, tended to decrease acute insulin response during IVGTT (P = .0848), reduced testosterone (P = .0216), and tended to reduce sex hormone-binding globulin (P = .0858). Fasting glucose, insulin, adiponectin, leptin, or high-sensitivity C-reactive protein did not change with any intervention. Long-chain vs essential n-3 PUFA-rich oils have distinct metabolic and endocrine effects in polycystic ovary syndrome; and therefore, they should not be used interchangeably.

The beneficial effects of α-cyclodextrin on blood lipids and weight loss in healthy humans.

α-Cyclodextrin (α-CD) is a soluble fiber derived from corn. It has previously been reported that early intervention with Mirafit fbcx, a trademarked name for α-CD, has beneficial effects on weight management in obese individuals with type 2 diabetes, and that it preferentially reduces blood levels of saturated and trans fats in the LDL receptor knockout mice. The current investigation involves overweight but not obese nondiabetic individuals and was intended to confirm the effects of α-CD on both weight management and improving blood lipid levels. Forty-one healthy adults (age: 41.4 ± 13.6 years) participated in this 2-month, double-blinded, crossover study. In 28 compliant participants (8 males and 20 females), when the active phase was compared to the control phase, there were significant decreases in body weight (-0.4 ± 0.2 kg, P < 0.05), serum total cholesterol (mean ± s.e.m., -0.295 ± 0.10 mmol/l, 5.3%, P < 0.02) and low-density lipoprotein (LDL) cholesterol (-0.23 ± 0.11 mmol/l, -6.7%, P < 0.05). Apolipoprotein B (Apo B) (-0.0404 ± 0.02 g/l, -5.6%, P = 0.06) and insulin levels also decreased by 9.5% (-0.16 ± 0.08 pmol/l, P = 0.06) while blood glucose and leptin levels did not change. These results suggest that α-CD exerts its beneficial health effects on body weight and blood lipid profile in healthy nonobese individuals, as previously reported in obese individuals with type 2 diabetes.

Determinants of impaired fasting glucose versus glucose intolerance in polycystic ovary syndrome.

OBJECTIVE: To determine insulin resistance and response in patients with polycystic ovary syndrome (PCOS) and normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance, and combined glucose intolerance (CGI). RESEARCH DESIGN AND METHODS: In this cross-sectional study, 143 patients with PCOS (diagnosed on the basis of National Institutes of Health criteria) underwent oral glucose tolerance testing (OGTT), and 68 patients also had frequently sampled intravenous glucose tolerance tests. Changes in plasma glucose, insulin, cardiovascular risk factors, and androgens were measured. RESULTS: Compared with patients with NGT, those with both IFG and CGI were significantly insulin resistant (homeostasis model assessment 3.3 +/- 0.2 vs. 6.1 +/- 0.9 and 6.4 +/- 0.5, P < 0.0001) and hyperinsulinemic (insulin area under the curve for 120 min 973 +/- 69 vs. 1,470 +/- 197 and 1,461 +/- 172 pmol/l, P < 0.0001). Insulin response was delayed in patients with CGI but not in those with IFG (2-h OGTT, insulin 1,001 +/- 40 vs. 583 +/- 45 pmol/l, P < 0.0001). Compared with the NGT group, the CGI group had a lower disposition index (1,615 +/- 236 vs. 987 +/- 296, P < 0.0234) and adiponectin level (11.1 +/- 1.1 vs. 6.2 +/- 0.8 ng/ml, P < 0.0096). Compared with the insulin-resistant tertile of the NGT group, those with IFG had a reduced insulinogenic index (421 +/- 130 vs. 268 +/- 68, P < 0.05). Compared with the insulin-sensitive tertile of the NGT group, the resistant tertile had higher triglyceride and high-sensitivity C-reactive protein (hs-CRP) and lower HDL cholesterol and sex hormone-binding globulin (SHBG). In the entire population, insulin resistance correlated directly with triglyceride, hs-CRP, and the free androgen index and inversely with SHBG. CONCLUSIONS: Patients with PCOS develop IFG and CGI despite having significant hyperinsulinemia. Patients with IFG and CGI exhibit similar insulin resistance but very different insulin response patterns. Increases in cardiac risk factors and free androgen level precede overt glucose intolerance.

In polycystic ovary syndrome, adrenal steroids are regulated differently in the morning versus in response to nutrient intake.

OBJECTIVE: To investigate adrenal steroid regulation in polycystic ovary syndrome. DESIGN: Five-hour oral glucose tolerance test (OGTT) and frequently sampled-intravenous gluclose tolerance test. SETTING: University research center. PATIENT(S): Thirty patients. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Anthropometrics, leptin, cortisol, DHEAS, glucose, insulin. RESULT(S): Morning cortisol correlated with sensitivity index (SI, r = .540), DHEAS correlated inversely with age (r = -.6359), body mass index (BMI, r = -.6199), fat mass (r = -0.630), and leptin (r = -0.5676). Between the second and fourth hour of OGTT, cortisol changes (Delta) exhibited three patterns: I, responders (n = 9, Delta: 10.7 +/- 1.0 microg/dL); II, nonresponders (n = 10, Delta: -3.5 +/- 0.6 microg/dL); III, intermediates (n = 11, Delta: 4.3 +/- 1.0 microg/dL). Compared with nonresponders, responders were more obese (BMI: 37.0 +/- 1.6 vs. 31.7 +/- 1.8 kg/m(2)); had higher leptin (28.9 +/- 1.7 vs. 24.1 +/- 1.1 ng/mL), and lower DHEAS (133 +/- 12 vs. 236 +/- 32 ng/mL), higher glucose at 1 h of OGTT (195 +/- 13 vs. 131 +/- 12 mg/dL), higher area under the curve (AUC)(Glucose) (332 +/- 20 vs. 265 +/- 17 mg/dL), higher AUC(Insulin) (244 +/- 50 vs. 125 +/- 30 muU/mL), and lower nadir glucose (61 +/- 2 vs. 70 +/- 2 mg/dL). CONCLUSION(S): Obesity and insulin resistance are associated with lower morning cortisol and DHEAS but increased cortisol and DHEA responses after glucose ingestion. Morning steroid levels may not reflect the day-long exposure.

Serum fatty acid binding protein 4, free fatty acids, and metabolic risk markers.

Fatty acid binding protein (FABP) 4 chaperones free fatty acids (FFAs) in the adipocytes during lipolysis. Serum FFA relates to metabolic syndrome, and serum FABP4 is emerging as a novel risk marker. In 36 overweight/obese women, serum FABP4 and FFA were measured hourly during 5-hour oral glucose tolerance test. Insulin resistance was determined using frequently sampled intravenous glucose tolerance test. Serum lipids and inflammation markers were measured at fasting. During oral glucose tolerance test, serum FABP4 decreased by 40%, reaching its nadir at 3 hours (from 45.3 +/- 3.1 to 31.9 +/- 1.6 ng/mL), and stayed below the baseline at 5 hours (35.9 +/- 2.2 ng/mL) (P < .0001 for both, compared with the baseline). Serum FFA decreased by 10-fold, reaching a nadir at 2 hours (from 0.611 +/- 0.033 to 0.067 +/- 0.004 mmol/L), then rebounded to 0.816 +/- 0.035 mmol/L at 5 hours (P < .001 for both, compared with baseline). Both fasting FABP4 and nadir FABP4 correlated with obesity. Nadir FABP4 correlated also with insulin resistance parameters from frequently sampled intravenous glucose tolerance test and with inflammation. Nadir FFA, but not fasting FFA, correlated with the metabolic syndrome parameters. In conclusion, fasting FABP4 related to metabolic risk markers more strongly than fasting FFA. Nadir FABP4 and nadir FFA measured after glucose loading may provide better risk assessment than the fasting values.

Effects of protein versus simple sugar intake on weight loss in polycystic ovary syndrome (according to the National Institutes of Health criteria).

OBJECTIVE: To compare the effects of protein vs. simple sugars on weight loss, body composition, and metabolic and endocrine parameters in polycystic ovary syndrome (PCOS). DESIGN: A 2-month, free-living, randomized, single-blinded study. SETTING: University PCOS clinic. PATIENT(S): Thirty-three patients with PCOS. INTERVENTION(S): To achieve a final energy reduction of 450 kcal/day, first the daily energy intake was reduced by 700 kcal; then a 240-kcal supplement containing either whey protein or simple sugars was added. MAIN OUTCOME MEASURE(S): Changes in weight, fat mass, fasting glucose and insulin, plasma lipoproteins, and sex steroids. RESULT(S): Twenty-four subjects (13 in the simple sugars group and 11 in the protein group) completed the study. The protein group lost more weight (-3.3 +/- 0.8 kg vs. -1.1 +/- 0.6 kg) and more fat mass (-3.1 +/- 0.9 kg vs. -0.5 +/- 0.6 kg) and had larger decreases in serum cholesterol (-33.0 +/- 8.4 mg/dL vs. -2.3 +/- 6.8 mg/dL), high-density lipoprotein cholesterol (-4.5 +/- 1.3 mg/dL vs. -0.4 +/- 1.3 mg/dL), and apoprotein B (-20 +/- 5 mg/dL vs. 3 +/- 5 mg/dL). CONCLUSION(S): In patients with PCOS, a hypocaloric diet supplemented with protein reduced body weight, fat mass, serum cholesterol, and apoprotein B more than the diet supplemented with simple sugars.