Hypothalamic AMP-Activated Protein Kinase as a Whole-Body Energy Sensor and Regulator.

5´-Adenosine monophosphate (AMP)-activated protein kinase (AMPK), a cellular energy sensor, is an essential enzyme that helps cells maintain stable energy levels during metabolic stress. The hypothalamus is pivotal in regulating energy balance within the body. Certain neurons in the hypothalamus are sensitive to fluctuations in food availability and energy stores, triggering adaptive responses to preserve systemic energy equilibrium. AMPK, expressed in these hypothalamic neurons, is instrumental in these regulatory processes. Hypothalamic AMPK activity is modulated by key metabolic hormones. Anorexigenic hormones, including leptin, insulin, and glucagon-like peptide 1, suppress hypothalamic AMPK activity, whereas the hunger hormone ghrelin activates it. These hormonal influences on hypothalamic AMPK activity are central to their roles in controlling food consumption and energy expenditure. Additionally, hypothalamic AMPK activity responds to variations in glucose concentrations. It becomes active during hypoglycemia but is deactivated when glucose is introduced directly into the hypothalamus. These shifts in AMPK activity within hypothalamic neurons are critical for maintaining glucose balance. Considering the vital function of hypothalamic AMPK in the regulation of overall energy and glucose balance, developing chemical agents that target the hypothalamus to modulate AMPK activity presents a promising therapeutic approach for metabolic conditions such as obesity and type 2 diabetes mellitus.

Risk factor control and cardiovascular events in patients with type 2 diabetes mellitus.

BACKGROUND: Since patients with type 2 diabetes mellitus (T2DM) have an increased risk of cardiovascular events, interventions addressing risk factors reduce the incidence of cardiovascular disease (CVD) events. This study aimed to evaluate the difference in the incidence of CVD events according to risk factor control in patients with diabetes with and without cardio-renal disease. METHODS: We analyzed 113,909 patients with diabetes and 290,339 without diabetes using data released by the National Health Insurance Service (NHIS). RESULTS: Among patients with diabetes with four or five poorly controlled risk factors, hazard ratio for CVD events was 1.19 (95% confidence interval [CI], 1.06-1.34) in patients with cardio-renal disease and 2.31 (95% CI, 1.95-2.74) in patients without cardio-renal disease compared to patients with diabetes without risk factors. In subjects with diabetes and cardio-renal disease, patients with four or five poorly controlled risk factors had a higher risk of CVD mortality compared to subjects without risk factors (hazard ratio, 1.64; 95% CI, 1.18-2.30). CONCLUSION: Controlling cardiovascular risk factors reduced the incidence of CVD events in patients with diabetes, especially those without cardio-renal disease. The degree of risk control was strongly associated with CVD mortality in patients with diabetes with baseline cardio-renal disease.

Causal relationship between particulate matter 2.5 and diabetes: two sample Mendelian randomization.

Backgrounds: Many studies have shown particulate matter has emerged as one of the major environmental risk factors for diabetes; however, studies on the causal relationship between particulate matter 2.5 (PM2.5) and diabetes based on genetic approaches are scarce. The study estimated the causal relationship between diabetes and PM2.5 using two sample mendelian randomization (TSMR). Methods: We collected genetic data from European ancestry publicly available genome wide association studies (GWAS) summary data through the MR-BASE repository. The IEU GWAS information output PM2.5 from the Single nucleotide polymorphisms (SNPs) GWAS pipeline using pheasant-derived variables (Consortium = MRC-IEU, sample size: 423,796). The annual relationship of PM2.5 (2010) were modeled for each address using a Land Use Regression model developed as part of the European Study of Cohorts for Air Pollution Effects. Diabetes GWAS information (Consortium = MRC-IEU, sample size: 461,578) were used, and the genetic variants were used as the instrumental variables (IVs). We performed three representative Mendelian Randomization (MR) methods: Inverse Variance Weighted regression (IVW), Egger, and weighted median for causal relationship using genetic variants. Furthermore, we used a novel method called MR Mixture to identify outlier SNPs. Results: From the IVW method, we revealed the causal relationship between PM2.5 and diabetes (Odds ratio [OR]: 1.041, 95% CI: 1.008-1.076, P = 0.016), and the finding was substantiated by the absence of any directional horizontal pleiotropy through MR-Egger regression (ß = 0.016, P = 0.687). From the IVW fixed-effect method (i.e., one of the MR machine learning mixture methods), we excluded outlier SNP (rs1537371) and showed the best predictive model (AUC = 0.72) with a causal relationship between PM2.5 and diabetes (OR: 1.028, 95% CI: 1.006-1.049, P = 0.012). Conclusion: We identified the hypothesis that there is a causal relationship between PM2.5 and diabetes in the European population, using MR methods.

Non-alcoholic fatty liver disease is associated with hyperandrogenism in women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a highly complex reproductive metabolic disorder and women with PCOS have high prevalence of non-alcoholic fatty liver disease (NAFLD). Despite both hyperandrogenism and insulin resistance are common pathophysiologies in NAFLD and PCOS, this association is still controversial. Therefore, the aim of this study is to evaluate the relationship between hyperandrogenism and NAFLD in females diagnosed with PCOS. We recruited 667 women diagnosed with PCOS and 289 women with regular menstrual cycles as control. The PCOS diagnosis was made using National Institute of Child Health and Human Disease criteria. Total and free testosterone levels (TT and TF, respectively), and free androgen index (FAI) were used as measures of hyperandrogenism. Fatty liver index and liver fat score (FLI and LFS, respectively), and hepatic steatosis index (HSI) were used to assess NAFLD. The prevalence of NAFLD in PCOS women evaluated by LFS, FLI, and HIS were 19.9, 10.3, and 32.2%, respectively. In the control group, the incidence was 2.1, 0.7, and 4.2%, respectively. Both FT and FAI levels showed significant association with increased NAFLD-related indices, after adjusting for insulin resistance and other factors (LFS (OR 3.18 (95% CI 1.53-6.63) in FT; 1.12 (1.04-1.22) in FAI), FLI (OR 2.68 (95% CI 1.43-5.03) in FT; 1.13 (1.06-1.20) in FAI), and HSI (OR 3.29 (95% CI 2.08-5.21) in FT; 1.5 (1.09-1.21) in FAI). TT did not exhibit association with any NAFLD index. In women with PCOS, significantly higher rate of NAFLD was observed compared to the control women. The FT and FAI were independently associated with NAFLD in women with PCOS. The findings suggest the possibility of hyperandrogenism contributing to the progression and/or development of NAFLD in PCOS.

The effect of menopause on cardiovascular risk factors according to body mass index in middle-aged Korean women.

BACKGROUND: Menopausal status and obesity are associated with an increased risk for cardiovascular diseases. However, there are few studies on the effect of menopause on cardiovascular risk factors according to the degree of obesity during the menopausal transition. We aimed to evaluate the effect of menopause on cardiovascular risk factors according to body mass index (BMI) in middle-aged Korean women. METHODS: We analyzed 361 postmenopausal women and 758 premenopausal women (age: 45-55 years) without diabetes mellitus, hypertension, or dyslipidemia, using a cohort database released by the Korean National Health and Nutrition Examination Survey 2016-2018. Subjects were divided into two groups based on BMI. Women who underwent a hysterectomy or were pregnant were excluded from this study. Differences between groups adjusted for age and BMI were assessed. RESULTS: Postmenopausal women (52 ± 2 years) were older than premenopausal women (48 ± 2 years), and BMI did not differ between the two groups (22.8 ± 2.9 vs. 23.0 ± 3.1 kg/m2). After adjustment for age and BMI in total and non-obese subjects (not obese subjects), postmenopausal women exhibited higher hemoglobin A1c and total cholesterol levels than premenopausal women. Subgroup analysis for 138 postmenopausal and 138 age- and BMI-matched premenopausal women showed that postmenopausal women had higher total cholesterol levels than premenopausal women with marginal significance (201 ± 25 vs. 196 ± 27 mg/dL). CONCLUSION: Menopausal status was associated with increased glucose and cholesterol levels independent of age and BMI in middle-aged Korean women. Menopausal status showed a significant relationship with increased total cholesterol levels even after adjusting for age and BMI in non-obese women but not obese women. Therefore, intensive monitoring and treating of lipid status is necessary to prevent cardiovascular events during the menopausal transition, especially in non-obese subjects.

Relationship between age at menarche and metabolic diseases in Korean postmenopausal women: The Korea National Health and Nutrition Examination Survey 2016-2018.

BACKGROUND: Cardiovascular disease is the leading cause of morbidity and mortality in postmenopausal women. Early menarche may be associated with an increased risk of metabolic diseases such as diabetes and cardiovascular disease. This study aimed to investigate the effect of menarche age and the risk of diabetes and metabolic syndrome in Korean postmenopausal women. METHODS: We analyzed 4,933 postmenopausal women (mean age: 64.7 years) using the Korean National Health and Nutritional Examination Survey 2016-2018. Subjects were divided into three groups according to menarche age (early menarche: ≤ 12 years (n = 451), reference: 13-16 years (n = 3,421), and late menarche: ≥ 17 years (n = 1,061)). Logistic regression analysis was used to estimate the odds ratio (OR) for diabetes and metabolic syndrome. RESULTS: Women with an early menarche age were younger, more educated, and had higher income than the other groups (p-value < 0.001). There were no differences in body mass index, blood pressure, fasting glucose, HbA1c, and cholesterol levels among the three groups. After adjusting for potential confounding factors, early menarche age was significantly associated with the risk of diabetes (OR 1.435, 95% confidence interval (CI): 1.069-1.928). The prevalence of metabolic syndrome in all subjects was 41.1%. After adjusting for potential confounding factors, the OR of metabolic syndrome in the early menarche group was 1.213 (95% CI: 0.971-1.515). CONCLUSION: The risk of diabetes was 1.43 times higher in postmenopausal Korean women with early menarche. Although the risk of metabolic syndrome was not statistically significant, it showed a tendency to increase in the early menarche group. Our results suggest that age at menarche may be helpful in diabetes risk stratification and early interventions for postmenopausal women.

Body mass index and stroke risk among patients with diabetes mellitus in Korea.

BACKGROUND: Obesity and diabetes mellitus (DM) are both associated with cardiovascular disease. This study aimed to evaluate the association between body mass index (BMI) and stroke risk among patients with DM in Korea since relatively few studies have analyzed this area in detail. METHODS: We analyzed a total of 56,051 DM patients aged >30 years from the Korean National Health Insurance Service Cohort who had undergone at least one national health examination between 2002 and 2012. BMI scores were divided into six categories, while hazard ratios for stroke were calculated using Cox proportional hazard models. RESULTS: Overall stroke risk was positively associated with BMI for both men and women. For ischemic stroke, the risk was positively associated with BMI in women. However, for me, only patients with the highest BMI were at increased risk compared with patients with a BMI of 20-22.4 kg/m2. For hemorrhagic stroke, the risk was significantly associated with BMI with a U-shaped association in men. In women, only patients with the lowest BMI had an increased risk of hemorrhagic stroke compared with patients that have a BMI of 20-22.4 kg/m2. CONCLUSION: BMI was positively associated with the overall risk of stroke among DM patients in Korea. The risk of ischemic stroke was higher in obese patients compared to overweight or normal-weight patients. However, the risk of hemorrhagic stroke was higher in slimmer patients compared with overweight or obese patients.

Waist circumference and mortality or cardiovascular events in a general Korean population.

BACKGROUND: Obesity is associated with cardiovascular diseases and is a risk factor for all-cause mortality. Until now, the associations between abdominal obesity and mortality or cardiovascular disease (CVD) incidence have not been conclusive. We aimed to evaluate the associations between waist circumference (WC) and mortality or CVD incidence in a general Korean population. METHODS: We analyzed a total of 204,068 adults older than 40 years of age who had undergone a national health examination at least once from 2009 to 2018 in the Korean National Health Insurance Service Cohort. WC was divided into five categories (< 80, 80-84.9, 85-89.9, 90-94.9, ≥ 95 cm). Hazard ratios for death and CVD incidence were calculated using Cox proportional hazards models. RESULTS: In men, WC and overall mortality showed a reverse J-shaped association. In women, the association between WC and overall mortality was not significant. For both men and women, WC was not associated with the risk of cardiovascular mortality. Contrary to the mortality trend, CVD incidence was positively associated with WC in both men and women, and the risk of the CVD incidence was the lowest in subjects with a WC < 80 cm. CONCLUSIONS: WC exhibited a significant J-shaped association with overall mortality in men, where subjects who had central obesity showed a lower rate of mortality than those in the lowest or highest WC group. The risk of incident CVD showed a positive association with central obesity, where the lowest risk was observed for subjects in the lowest WC group in a general Korean population.

Association of serum creatinine levels and risk of type 2 diabetes mellitus in Korea: a case control study.

BACKGROUND: Reduced skeletal muscle has been suggested as a potential risk factor for type 2 diabetes mellitus (T2DM). Serum creatinine is the primary metabolite of creatine in skeletal muscle. Therefore, low serum creatinine levels may be associated with an increased risk of T2DM. We aimed to evaluate the association between serum creatinine levels and the risk of T2DM in Korea. METHODS: We analyzed a total of 264,832 nondiabetic adults older than 40 years of age who had undergone a national health examination at least once from 2009 to 2015 in the Korean National Health Insurance Service Cohort. Hazard ratios for T2DM were calculated. RESULTS: In men, serum creatinine levels and the risk for T2DM showed an inverse J-shaped association. This association was confirmed after adjustment for age, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), and fasting plasma glucose. In women, there was a trend that serum creatinine levels were inversely associated with the risk of T2DM among those with serum creatinine below 1.1 mg/dl. However, serum creatinine levels were not significantly associated with the risk of T2DM after adjustment for age, BMI, SBP, DBP, and fasting plasma glucose. CONCLUSIONS: Reduced levels of serum creatinine were significantly associated with an increased risk of T2DM in men with creatinine below 1.20 mg/dl. There was a trend that decreased levels of serum creatinine were associated with an increased risk of T2DM among women with serum creatinine below 1.1 mg/dl, although this result was not statistically significant.

Primary cilia mediate early life programming of adiposity through lysosomal regulation in the developing mouse hypothalamus.

Hypothalamic neurons including proopiomelanocortin (POMC)-producing neurons regulate body weights. The non-motile primary cilium is a critical sensory organelle on the cell surface. An association between ciliary defects and obesity has been suggested, but the underlying mechanisms are not fully understood. Here we show that inhibition of ciliogenesis in POMC-expressing developing hypothalamic neurons, by depleting ciliogenic genes IFT88 and KIF3A, leads to adulthood obesity in mice. In contrast, adult-onset ciliary dysgenesis in POMC neurons causes no significant change in adiposity. In developing POMC neurons, abnormal cilia formation disrupts axonal projections through impaired lysosomal protein degradation. Notably, maternal nutrition and postnatal leptin surge have a profound impact on ciliogenesis in the hypothalamus of neonatal mice; through these effects they critically modulate the organization of hypothalamic feeding circuits. Our findings reveal a mechanism of early life programming of adult adiposity, which is mediated by primary cilia in developing hypothalamic neurons.

Vitamin D receptor and binding protein polymorphisms in women with polycystic ovary syndrome: a case control study.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age, characterized by hyperandrogenism, oligomenorrhea, polycystic ovary morphology, and insulin resistance. Vitamin D deficiency and vitamin D receptor (VDR)/vitamin D binding protein (VDBP) gene variants could play an important role in susceptibility to PCOS and contribute to metabolic disturbances and menstrual dysfunction. We aimed to investigate the associations of VDR gene and VDBP gene polymorphisms with PCOS susceptibility and to elucidate the impacts of these polymorphisms on the hormonal and metabolic parameters of PCOS. METHODS: We recruited 432 women with PCOS and 927 controls. Polymorphisms in the VDR gene (VDR Fok-I, Cdx2, Apa-I, and Bsm-I) and VDBP gene (VDBP rs4588, rs7041, and rs22822679) were genotyped. A 75-g oral glucose tolerance test was performed. RESULTS: The distributions of genotypes and allele frequencies in VDR and VDBP genes did not differ between PCOS and control. In women with PCOS, compared to the VDR Fok-I GG genotype, the VDR Fok-I AG genotype was significantly associated with increased levels of total testosterone (ß = 5.537, P = 0.005). Compared to the VDR Cdx2 AC genotype, the VDR Cdx2 CC genotype was associated with increased levels of fasting insulin and HOMA-IR in women with PCOS, however, the associations were not statistically significant. CONCLUSIONS: This finding indicates that genetic variations in VDR and VDBP were not associated with increased risk for PCOS. In contrast, the VDR Fok-I polymorphism was associated with testosterone level and the Cdx2 polymorphism with insulin sensitivity in PCOS. However, the Cdx2 polymorphism was not significantly associated with increased insulin and insulin sensitivity in women with PCOS after multiple linear regression.

Insulin resistance is associated with hirsutism in unselected reproductive-aged women.

OBJECTIVE: Hirsutism affects 5%-10% of reproductive-aged women worldwide and exhibits clinical importance as a cutaneous manifestation of underlying hyperandrogenism. Racial and genetic factors play roles in manifestation of hirsutism, and the prevalence of hirsutism seems to be low in East Asians. However, the reference value of the modified Ferriman-Gallwey (mFG) score to diagnose hirsutism and the prevalence of hirsutism have not been determined in Korean populations to date. We aimed to investigate the distribution of the mFG score and establish its reference value for defining hirsutism and to examine its relationship with metabolic and reproductive traits in reproductive-aged Korean women. DESIGN, PATIENTS AND MEASUREMENTS: We enrolled 2139 female volunteers of reproductive age (15-39 years). We recorded mFG scores from 0 to 4 on 9 different body locations (upper lip, chin, chest, arm, upper abdomen, lower abdomen, upper back, lower back and thighs). Hirsutism was defined as >95th percentile of mFG score. In addition, a 75-g oral glucose tolerance test was performed, and the homoeostasis model assessment of insulin resistance (HOMA-IR) was calculated. RESULTS: The mFG values of the 50th, 75th, 90th and 95th percentiles were 0, 1, 4 and 6, respectively. Therefore, the mFG score was indicative of hirsutism when the score was 6 or greater, which represents the 95th percentile. In the correlation analysis, total testosterone, free testosterone, fasting plasma insulin and HOMA-IR were positively correlated with mFG score (all Ps <0.05). Multiple linear regression analysis revealed that HOMA-IR (ß = 0.081) was positively associated with mFG score after adjustments for age, body mass index, total testosterone and the number of menses per year (P < 0.001). CONCLUSIONS: In conclusion, setting the 95th percentile of the mFG score as normal, the reference value to define hirsutism was 6 in reproductive-aged Korean women. HOMA-IR was positively associated with the mFG score even after adjustment for biochemical hyperandrogenism.

Hypothalamic Macrophage Inducible Nitric Oxide Synthase Mediates Obesity-Associated Hypothalamic Inflammation.

Obesity-associated metabolic alterations are closely linked to low-grade inflammation in peripheral organs, in which macrophages play a central role. Using genetic labeling of myeloid lineage cells, we show that hypothalamic macrophages normally reside in the perivascular area and circumventricular organ median eminence. Chronic consumption of a high-fat diet (HFD) induces expansion of the monocyte-derived macrophage pool in the hypothalamic arcuate nucleus (ARC), which is significantly attributed to enhanced proliferation of macrophages. Notably, inducible nitric oxide synthase (iNOS) is robustly activated in ARC macrophages of HFD-fed obese mice. Hypothalamic macrophage iNOS inhibition completely abrogates macrophage accumulation and activation, proinflammatory cytokine overproduction, reactive astrogliosis, blood-brain-barrier permeability, and lipid accumulation in the ARC of obese mice. Moreover, central iNOS inhibition improves obesity-induced alterations in systemic glucose metabolism without affecting adiposity. Our findings suggest a critical role for hypothalamic macrophage-expressed iNOS in hypothalamic inflammation and abnormal glucose metabolism in cases of overnutrition-induced obesity.

Exogenous nicotinamide adenine dinucleotide regulates energy metabolism via hypothalamic connexin 43.

BACKGROUND: Nicotinamide adenine dinucleotide (NAD)-dependent deacetylase SIRT1 is an important regulator of hypothalamic neuronal function. Thus, an adequate hypothalamic NAD content is critical for maintaining normal energy homeostasis. METHODS: We investigated whether NAD supplementation increases hypothalamic NAD levels and affects energy metabolism in mice. Furthermore, we investigated the mechanisms underlying the effects of exogenous NAD on central metabolism upon entering the hypothalamus. RESULTS: Central and peripheral NAD administration suppressed fasting-induced hyperphagia and weight gain in mice. Extracellular NAD was imported into N1 hypothalamic neuronal cells in a connexin 43-dependent and CD73-independent manner. Consistent with the in vitro data, inhibition of hypothalamic connexin 43 blocked hypothalamic NAD uptake and NAD-induced anorexia. Exogenous NAD suppressed NPY and AgRP transcriptional activity, which was mediated by SIRT1 and FOXO1. CONCLUSIONS: Exogenous NAD is effectively transported to the hypothalamus via a connexin 43-dependent mechanism and increases hypothalamic NAD content. Therefore, NAD supplementation is a potential therapeutic method for metabolic disorders characterized by hypothalamic NAD depletion.

Primary Cilia as a Signaling Platform for Control of Energy Metabolism.

Obesity has become a common healthcare problem worldwide. Cilia are tiny hair-like organelles on the cell surface that are generated and anchored by the basal body. Non-motile primary cilia have been considered to be evolutionary rudiments until a few decades, but they are now considered as important signaling organelles because many receptors, channels, and signaling molecules are highly expressed in primary cilia. A potential role of primary cilia in metabolic regulation and body weight maintenance has been suspected based on rare genetic disorders termed as ciliopathy, such as Bardet-Biedl syndrome and Alström syndrome, which manifest as obesity. Recent studies have demonstrated involvement of cilia-related cellular signaling pathways in transducing metabolic information in hypothalamic neurons and in determining cellular fate during adipose tissue development. In this review, we summarize the current knowledge about cilia and cilia-associated signaling pathways in the regulation of body metabolism.

Insulin resistance according to ß-cell function in women with polycystic ovary syndrome and normal glucose tolerance.

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with insulin resistance (IR) and compensatory hyperinsulinemia. IR is recognized as a major risk factor for the development of type 2 diabetes mellitus. However, few studies have investigated IR in women with PCOS and normal glucose tolerance. The objective of this study was to evaluate IR and ß-cell function in women with PCOS and normal glucose tolerance. Additionally, we sought to evaluate the usefulness of oral glucose tolerance test (OGTT)-derived IR indices in lean women with PCOS. METHODS: We recruited 100 women with PCOS and normal glucose tolerance and 100 age- and BMI-matched women as controls. IR and insulin secretory indices, including the homeostasis-model assessment (HOMA)-IR, HOMA-M120, HOMA-F and the Stumvoll index, were calculated from an OGTT. Increased ß-cell function was defined as>75th percentile for the HOMA-F in control women. RESULTS: Women with PCOS had higher values for post-load 2-hour glucose, fasting insulin, post-load 2-hour insulin, HOMA-IR, HOMA-M120, HOMA-F and lower values for the Stumvoll index than the controls (all Ps<0.05). Women with PCOS and increased ß-cell function showed lower Stumvoll index values than the matched controls (P<0.05). The HOMA-F was significantly associated with the HOMA-M120 and Stumvoll index when adjusted for age and BMI in a multiple regression analysis (all Ps<0.05). The HOMA-M120 was positively correlated with triglycerides and free testosterone, and the Stumvoll index was negatively correlated with triglycerides and free testosterone in lean women with PCOS (all Ps<0.05). CONCLUSIONS: Women with PCOS and normal glucose tolerance showed higher IR than controls matched for age, BMI, and ß-cell function. ß-cell function was increased in women with PCOS when compared to the matched controls, but not when the lean subjects were compared to the matched controls separately. Therefore, early evaluation of IR in women with PCOS and normal glucose tolerance may be needed.

Differentiation between polycystic ovary syndrome and polycystic ovarian morphology by means of an anti-Müllerian hormone cutoff value.

BACKGROUND/AIMS: Although increased serum anti-Müllerian hormone (AMH) level has been suggested to be a surrogate marker of polycystic ovarian morphology (PCOM), its association with polycystic ovary syndrome (PCOS) is controversial, and its diagnostic value has not been determined. We aimed to observe the relationship between the AMH level and PCOS phenotypes and to determine the optimal cutoff value of AMH for the diagnosis of PCOS in young Korean women. METHODS: We recruited 207 women with PCOS (120 with PCOM and 87 without PCOM) and 220 regular cycling women with normoandrogenemia (100 with PCOM and 120 without PCOM). Subjects underwent testing at a single outpatient visit. Serum AMH level was measured. RESULTS: Women with PCOS had higher serum AMH levels than did regular cycling women with normoandrogenemia (p < 0.05). Women with PCOM had higher serum AMH levels than women without PCOM, regardless of PCOS status (p < 0.05). The optimal AMH cutoff value for the diagnosis of PCOS was 10.0 ng/mL (71% sensitivity, 93% specificity). Serum AMH was an independent determinant of total testosterone after adjustment for age, body mass index, and the number of menses/year (ß = 0.31, p < 0.01). An association between AMH and hyperandrogenism was only observed in women with PCOS, and it was independent of the presence of PCOM. CONCLUSION: The serum AMH level can be useful for the diagnosis of PCOS at any age less than 40 years, and the optimal cutoff value for the diagnosis of PCOS identified in this study of young Korean women was 10.0 ng/mL.

The Role of Serum MicroRNA-6767-5p as a Biomarker for the Diagnosis of Polycystic Ovary Syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder, and the underlying molecular mechanisms are not clear. To date, few studies have been conducted on the altered expression of serum microRNAs (miRNAs) in women with PCOS. The present study was performed to examine the role of the serum miRNA as a biomarker for the diagnosis of PCOS and its relationship with metabolic and reproductive traits. METHODS: A cross-sectional comparison was made in 21 women with PCOS and age- and body mass index (BMI)- matched 21 healthy women in an academic center laboratory between December 2008 and October 2010. We selected miRNAs that were more than 1.5-fold up-regulated or less than 0.67-fold down-regulated in women with PCOS compared with controls using the SurePrint G3 Human miRNA Microarray. Subsequently, we validated the relative expression of the miRNAs using TaqMan quantitative real-time polymerase chain reaction (RT-qPCR) assays. RESULTS: Serum miRNA-4522, miRNA-324-3p, and miRNA-6767-5p were down-regulated in women with PCOS compared with controls in the microarray analysis. Among these miRNAs, serum miRNA-6767-5p was validated (fold change in women with PCOS/controls = 0.39, P-value<0.05) by RT-qPCR. The miRNA-6767-5p was negatively associated with fasting glucose (ß = -0.370) and positively associated with the number of menses per year (ß = 0.383) after adjustment for age and BMI (Ps<0.05). Genes targeted by miRNA-6767-5p were involved in the cell cycle and the immune system. CONCLUSIONS: Serum miRNA-6767-5p may be a novel candidate as a molecular biomarker in the diagnosis of PCOS and may participate in the development of the metabolic and reproductive traits of PCOS.

Triglycerides to High-Density Lipoprotein Cholesterol Ratio Can Predict Impaired Glucose Tolerance in Young Women with Polycystic Ovary Syndrome.

PURPOSE: The triglycerides to high-density lipoprotein cholesterol (TG/HDL-C) ratio could be related to insulin resistance (IR). We previously reported that Korean women with polycystic ovary syndrome (PCOS) had a high prevalence of impaired glucose tolerance (IGT). We aimed to determine the cutoff value of the TG/HDL-C ratio for predicting IR and to examine whether the TG/HDL-C ratio is useful for identifying individuals at risk of IGT in young Korean women with PCOS. MATERIALS AND METHODS: We recruited 450 women with PCOS (24±5 yrs) and performed a 75-g oral glucose tolerance test (OGTT). IR was assessed by a homeostasis model assessment index over that of the 95th percentile of regular-cycling women who served as the controls (n=450, 24±4 yrs). RESULTS: The cutoff value of the TG/HDL-C ratio for predicting IR was 2.5 in women with PCOS. Among the women with PCOS who had normal fasting glucose (NFG), the prevalence of IGT was significantly higher in the women with PCOS who had a high TG/HDL-C ratio compared with those with a low TG/HDL-C ratio (15.6% vs. 5.6%, p<0.05). CONCLUSION: The cutoff value of the TG/HDL-C ratio for predicting IR was 2.5 in young Korean women with PCOS, and women with NFG and a high TG/HDL-C ratio had a higher prevalence of IGT. Therefore, Korean women with PCOS with a TG/HDL-C ratio >2.5 are recommended to be administered an OGTT to detect IGT even if they have NFG.

Emerging role of the brain in the homeostatic regulation of energy and glucose metabolism.

Accumulated evidence from genetic animal models suggests that the brain, particularly the hypothalamus, has a key role in the homeostatic regulation of energy and glucose metabolism. The brain integrates multiple metabolic inputs from the periphery through nutrients, gut-derived satiety signals and adiposity-related hormones. The brain modulates various aspects of metabolism, such as food intake, energy expenditure, insulin secretion, hepatic glucose production and glucose/fatty acid metabolism in adipose tissue and skeletal muscle. Highly coordinated interactions between the brain and peripheral metabolic organs are critical for the maintenance of energy and glucose homeostasis. Defective crosstalk between the brain and peripheral organs contributes to the development of obesity and type 2 diabetes. Here we comprehensively review the above topics, discussing the main findings related to the role of the brain in the homeostatic regulation of energy and glucose metabolism.