Energy Expenditure Regulation via Macrophage Migration Inhibitory Factor in Obesity and in Vitro Anti-Macrophage Migration Inhibitory Factor Effect of Alpinia Officinarum Hance Extraction

ObjectiveTo compare the resting energy expenditure in different macrophage migration inhibitory factor (MIF) genotypes and to identify the in vitro effects of Alpinia officinarum Hance extract (AOHE) on MIF expression in obese and nonobese persons.MethodsIn the fasting state, obese and nonobese persons were assessed for the measurement of resting energy expenditure rate (REE) by indirect calorimetry. We compared it with the expected amount ([REE measured by indirect calorimetry / predicted REE according to Harris Benedict equations] × 100). Participants were classified into those with normal REE (≥ 100) vs those with impaired REE (< 100). Body composition was analyzed. Real-time polymerase chain reaction was performed using specific primer pairs for MIF messenger RNA, and β-actin was used as the internal control.ResultsThe study included 69 obese and 103 non- obese participants. The proportions of MIF genotypes were slightly different in obese and nonobese participants. However, the proportions of MIF genotypes weresignificantly different in participants with normal REE and those with low REE. The MIF gene was highly expressed in the obese group compared with MIF expression in the nonobese group. Body fat mass and MIF expression were higher in participants with the GG genotype than in the other genotype groups. MIF expression was inversely associated with REE in both groups (r = − 0.36, P = .04). After treatment of peripheral blood mononuclear cells with AOHE, MIF expression differed according to MIF genotype.ConclusionsOur results indicate that AOHE is a major modulator of MIF-dependent pathologic conditions in obesity and are consistent with mounting evidence that defines a regulating role for MIF in cytokine production in an inflammatory state in in vitro studies. (Endocr Pract. 2012;18:39-48)     

Levothyroxine Replacement In Obese Hypothyroid Females After Total Thyroidectomy

Objective: Levothyroxine (LT4) replacement in hypothyroid obese patients is poorly understood. We assessed whether the LT4 regimen required to achieve euthyroidism differs between nonobese and obese hypothyroid females.Methods: We retrospectively identified nonobese and obese females who received LT4 starting with a standard dose of 1.6 μg/kg after total thyroidectomy for preoperative diagnosis of benign goiter. We examined the association between LT4 dosage required to achieve euthyroid state (thyroid-stimulating hormone [TSH] 0.4–2.5 mIU/L) and patient characteristics using linear regression models with and without adjustment for age, ethnicity, medication use, and postoperative hypoparathyroidism.Results: We identified 32 females (15 nonobese/17 obese) who achieved euthyroid state. Obese patients weighed more (104.1 ± 22.5 vs. 64.9 ± 10.0 kg, P<.0001) and required a higher final LT4 than nonobese (146 ± 38 vs. 102 ± 12 μg, P = .0002) but LT4 requirements per kg total body weight (TBW) were similar (1.60 ± 0.29 vs. 1.42 ± 0.38 μg/kg, P = .15). LT4 dose per kg ideal body weight (IBW) was higher in obese than in nonobese females (2.62 ± 0.67 vs. 1.88 ± 0.28 μg/kg, P = .0004) and this difference persisted after adjustments (P<.05). During LT4 titration, 47% and 20% of obese and nonobese patients had subnormal TSH episodes, respectively (P = .11). After taking LT4 compliance, malabsorption, and competing medication use into consideration, we found marked LT4 dose variability in obese patients. Patients who needed a mean daily LT4 dose ≤150 mg (124 ± 16 μg/day) compared with >150 μg (198 ± 4 μg/day) demonstrated lower LT4 per TBW (1.25 ± 0.18 vs. 1.84 ± 0.43 μg/kg, P = .03) and IBW (2.28 ± 0.47 vs. 3.44 ± 0.18 μg/kg, P<.0001), respectively.Conclusion: The standard approach to LT4 replacement in obese and nonobese females after thyroidectomy is imprecise. Mean daily LT4 doses in obese and nonobese patients were similar if expressed per kg TBW, though there was variability in the final LT4 among obese patients. We suggest initiating LT4 at a dose lower than that routinely recommended in obese females.Abbreviations:AACE = American Association of Clinical EndocrinologistsATA = American Thyroid AssociationBMI = body mass indexIBW = ideal body weightLT4 = levothyroxineTBW = total body weightTSH = thyroid-stimulating hormone     

High-Dose Glucocorticoid Treatment Does Not Induce Severe Hyperglycemia in Young Patients with Autoimmune Diseases by Cgms

Objective: High-dose glucocorticoids (HDG) are used in the treatment of autoimmune diseases. Glucocorticoids-induced hyperglycemia (GIH) is often described in elderly patients. In young patients with autoimmune diseases, however, the risk for GIH has not been well characterized.Methods: We recruited 24 inpatients (median age, 32 years; interquartile range, 25–42) with exacerbations of autoimmune diseases, receiving 1 to 2 mg/kg/day prednisone or equivalent methylprednisone. Fourteen subjects were naïve to glucocorticoids (group 1) and 10 subjects were on glucocorticoid maintenance (≤15 mg/day prednisone at least 3 months) (group 2) prior to HDG. All subjects were monitored by continuous glucose monitoring system (CGMS) for 3 days.Results: GIH developed in 21 (91%) subjects, 11/13 in group 1 and 10/10 in group 2. The main peak of glucose excursion (128.7 ± 6.4 mg/dL, group 1; 143.9 ± 10.0 mg/dL, group 2) occurred at 2 to 3 pm. Another peak occurred before sleep. Two-hour mean postprandial glucose levels were normal in both groups: breakfast, 105.0 ± 28.4 versus 125.6 ± 24.4 mg/dL, P = .065; lunch, 115.7 ± 21.1 versus 135.9 ± 29.0 mg/dL, P = .082; dinner, 122.8 ± 18.5 versus 137.8 ± 26.4 mg/dL, P = .144 in groups 1 and 2, respectively. There was a positive association between pretreatment hemoglobin A1C and peak glucose levels (P<.0001). Notably, 35% of our subjects experienced early morning hypoglycemia (65.2 ± 2.8 mg/dL).Conclusion: In hospitalized young patients with auto-immune diseases, CGMS data revealed that short-term consistent HDG treatment induced mild hyperglycemia, peaking in the early afternoon and before sleep. Early morning hypoglycemia was found in 35%.Abbreviations: A1C = hemoglobin A1C; AUC = the area under the curve; BG = blood glucose; BMI = body mass index; CGMS = continuous glucose monitoring system; DM = diabetes mellitus; FBG = fasting blood glucose; GA = glycated albumin; GCs = glucocorticoids; GIH = glucocorticoids-induced hyperglycemia; HDG = high-dose glucocorticoids; HOMA-IR = Homeostasis Model Assessment-Insulin Resistance; IG = interstitial glucose; IQR = interquartile range; PUMCH = Peking Union Medical College Hospital; SLE = systemic lupus erythematosus     

The Classic and Nonclassic Concenital Adrenal Hyperplasias

Objective: The American Association of Clinical Endocrinologists Adrenal Scientific Committee has developed a series of articles to update members on the genetics of adrenal diseases.Methods: Case presentation, discussion of literature, table, and bullet point conclusions.Results: The congenital adrenal hyperplasia (CAH) syndromes are autosomal recessive defects in cortisol biosynthesis. The phenotype of each CAH patient depends on the defective enzyme and the severity of the defect. Clinical manifestations derive from both failure to synthesize hormones distal to the enzymatic block, as well as consequences from cortisol precursor accumulation proximal to the block, often with diversion to other biologically active steroids. The most common form of CAH is 21-hydroxylase deficiency, which occurs in the classic form in 1 in 16,000 newborns and in a milder or nonclassic form in at least 1 in 1,000 people.Conclusion: This article reviews the various forms of CAH and pitfalls in the diagnosis and treatment of these conditions.Abbreviations: 11OHD = 11-hydroxylase deficiency 17OHD = 17-hydroxylase deficiency 17OHP = 17-hydroxyprogesterone 21OHD = 21-hydroxylase deficiency 3βHSD = 3β-hydroxysteroid dehydrogenase CAH = congenital adrenal hyperplasia CST = cosyntropin stimulation test CYP17A1 = cytochrome P450 17A1 (steroid 17-hydroxylase/17,20-lyase) DHEAS = dehydroepiandrosterone sulfate DSD = disorder of sex development LCAH = lipoid congenital adrenal hyperplasia NBS = newborn screening NCAH = nonclassic CAH PCOS = polycystic ovary syndrome PORD = P450-oxidoreductase deficiency     

Aromatase Inhibitor Increases the Height of Patients with Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

Objective: Patients with 21-hydroxylase deficiency (21OHD) typically suffer from short stature due to early exposure to adrenal-derived androgen. The aim of this study was to investigate whether adding aromatase inhibitor (AI) to gonadotropin-releasing hormone (GnRH) analogue (GnRHa) and recombinant human growth hormone (rhGH) therapy would increase the height of patients with 21OHD.Methods: This retrospective study included 15 patients with 21OHD. The AI/GnRHa/rhGH group consisted of 9 patients, who were treated with AI for at least 12 months in addition to GnRHa/rhGH therapy. The other 6 patients, who received GnRHa/rhGH therapy only, were defined as the GnRHa/rhGH group.Results: Patients were 6.3 ± 1.7 years old, and 7/15 of patients were male. Among them, 12 patients exhibited simple virilization type, and 3 patients were salt-wasting type. In the AI/GnRHa/rhGH group, patients were 6.6 ± 2.0 years old when AI therapy was initiated. Their bone age was 5.9 ± 2.2 years ahead of their chronological age. They received the AI letrizole for an average of 25.1 months (range, 12 to 37 months). In the GnRHa/rhGH group, the patients were 5.9 ± 0.9 years old when they started GnRHa/rhGH therapy, and their bone age was 6.2 ± 1.7 years ahead of their chronological age. Patients received GnRHa/rhGH therapy for an average of 24.5 months (range, 12 to 41 months). The predicted final height increased from 145.9 ± 7.9 to 158.0 ± 8.4 cm in the AI/GnRHa/rhGH group (P = .001, compared with the baseline) and from 141.7 ± 2.7 to 150.7 ± 4.7 cm in the GnRHa/rhGH group (P = .001, compared with the baseline). Bone age progression was 0.15 ± 0.05 per year versus 0.44 ± 0.13 per year in the two groups, respectively (P = .032).Conclusion: Addition of letrizole to GnRHa/rhGH therapy significantly delays bone maturation and may increase the final height.     

Markedly Delayed Insulin Secretion and a High Rate of Undetected Overt Diabetes Characterize Glucose Metabolism in Adult Patients with Cystic Fibrosis After Lung Transplantation

Objective: Cystic fibrosis–related diabetes (CFRD) is associated with adverse clinical outcomes and should be screened for by an annual oral glucose tolerance test (OGTT). Since pathophysiologic studies have mainly been performed in a pediatric/adolescent, nontransplanted collective, we aimed to assess parameters of insulin secretion and sensitivity in adult cystic fibrosis (CF) patients after lung transplantation (LT).Methods: Twelve adult CF patients after LT without known diabetes (33.3 ± 11.5 years; body mass index &lsqb;BMI] 21.5 ± 3.3 kg/m²) and 8 control subjects matched by age (36.0 ± 6.6 years; P>.05), BMI (22.3 ± 1.5 kg/m²; P>.05), and gender (CON group) underwent a 3-hour OGTT with glucose, insulin, and C-peptide measurements. Parameters of insulin secretion and sensitivity as well as lipid profiles were assessed.Results: In the CF group, 4 patients were diagnosed with overt diabetes (CFRD) compared to CF patients without diabetes (CF-noDM), of whom 6 had indeterminate glycemia with 1-h glucose values >200 mg/dL. The insulin peak after glucose load occurred after 30 minutes in CON, after 90 minutes in CF-noDM, and was missing in CFRD. Insulin sensitivity was comparable between the groups. Beta-cell glucose sensitivity was markedly reduced in CFRD (10.7 ± 5.8 pmol/min*m²*mM), higher in CF-noDM (39.9 ± 23.4 pmol/min*m²*mM), but still significantly lower compared to CON (108.3 ± 53.9 pmol/min*m²*mM; P = .0008). CFRD patients exhibited increased triglyceride levels and decreased high-density lipoprotein levels.Conclusion: Adult CF patients after LT have profound disturbances in glucose metabolism, with a high rate of undetected diabetes and markedly delayed insulin secretion. Curbed beta-cell glucose sensitivity rather than insulin resistance explains postprandial hyperglycemia and is accompanied by abnormalities in lipid metabolism.Abbreviations: AUC = area under the curve; BMI = body mass index; CF = cystic fibrosis; CFRD = cystic fibrosis–related diabetes; CFTR = cystic fibrosis transmembrane-conductance regulator; CF-TX = cystic fibrosis patients who underwent lung transplantation; CGM = continuous glucose monitoring; HbA1c = glycated hemoglobin; HDL = high-density lipoprotein; INDET = indeterminate glycemia; LDL = low-density lipoprotein; LT = lung transplantation; OGIS = oral glucose sensitivity index; OGTT = oral glucose tolerance test; QUICKI = quantitative insulin sensitivity check index     

Gender Determines Serum Free Cortisol: Higher Levels in Men

Objective: Because only the free fraction of serum cortisol can readily access glucocorticoid receptors, we investigated whether or not a gender-related difference in serum free cortisol (FC) exists in the basal and adrenocorticotropic hormone (ACTH)-stimulated state.Methods: Serum total cortisol (TC) and FC were measured in 323 subjects (175 men; 148 women). Additionally, the low-dose 1-μg ACTH test was performed in 56 subjects (30 women, 26 men). Subjects were healthy volunteers, recruited in a preventive medicine screening program and an outpatient clinic.Results: Overall, basal serum TC and FC level were ~18 and ~33%, respectively, higher in men than in women (TC, 14.5 ± 0.33 μg/dL vs. 12.3 ± 0.33 μg/dL; P<.0001; FC, 0.68 ± 0.02 μg/dL vs. 0.51 ± 0.02 μg/dL; P<.0001). The higher FC in men relative to women was apparent across a wide age range (17 to 86 years) and persisted after adjustment for age and body mass index. The FC fraction (%FC, out of TC) was concordantly higher in men (5.4 ± 0.09% vs. 4.8 ± 0.3%; P = .046). FC was not related to the estimated menopausal status (women age below and above 47, 50, or 53 years). ACTH-stimulated FC levels were significantly higher in men compared to women, as reflected by the area under the response curve (49.4 ± 3.4 μg × min vs. 39.6 ± 2.2 μg × min; P = .0014).Conclusion: Gender is an unrecognized determinant of serum FC in humans. The possibility of lifelong exposure to the higher bioactive fraction of cortisol under basal conditions or daily stress involving ACTH stimulation should be further investigated in the context of gender-related phenotypic features such as “android” (visceral) fat deposition and longevity.Abbreviations:ACTH = adrenocorticotropic hormoneBMI = body mass indexCBG = cortisol-binding globulinFC = free cortisolHPA = hypothalamic-pituitary-adrenalTC = total cortisol     

Evaluation of Para- and Perirenal Fat Thickness and its Association with Metabolic Disorders in Polycystic Ovary Syndrome

Objective: The aim of this study was to compare para- and perirenal fat (PFT) and subcutaneous abdominal fat (SFT) measurements between patients with polycystic ovary syndrome (PCOS) and control subjects and to assess the possible relation with metabolic disorders.Methods: This study included 68 patients with PCOS and 40 age- and body mass index (BMI)-matched healthy controls. We evaluated anthropometric, hormonal, and metabolic parameters, and abdominal ultrasonography was performed to measure PFT and SFT.Results: The mean PFT values were 6.1 ± 2.9 mm in patients with PCOS and 4.3 ± 2.3 mm in healthy controls (P = .002). SFT values were also higher in the patient group (9.6 ± 5 mm) compared to healthy subjects (3.5 ± 0.5 mm) (P = .017). A significant positive correlation was found between PFT and BMI (r = 0.368), waist circumference (WC) (r = 0.441), Ferriman-Gallwey (FG) score (r = 0.313), blood pressure (systolic, SBP, r = 0.213; diastolic, DBP, r = 0.215), plasma glucose (r = 0.195), homeostasis model assessment-insulin resistance (HOMA-IR, r = 0.273), SFT (r = 0.555). Conversely, negative correlations were found between PFT and estradiol (r = -0.218) and sex hormone-binding globulin (SHBG, r = -0.304). Nonobese PCOS patients (6.1 ± 3.07 mm) had higher PFT values than nonobese controls (3.47 ± 1.5 mm); however, SFT measurements did not differ (P = .086). In multiple linear regression analysis, SFT (P = .006) was a significant and independent predictor for PFT, along with WC (P = .023). In a stepwise model, SFT was the predictor of PFT (P = .001).Conclusion: PFT values were higher particularly in nonobese PCOS patients compared to nonobese control subjects. There was a significant interaction between PCOS and obesity on PFT.Abbreviations: BMI = body mass index; CT = computed tomography; DBP = diastolic blood pressure; FPG = fasting plasma glucose;; HDL-cholesterol = high-density lipoprotein cholesterol; HOMA-IR = homeostasis model assessment-insulin resistance; hsCRP = high-sensitivity C-reactive protein; LDL-cholesterol = low-density lipoprotein cholesterol; LH = luteinizing hormone; NCAH = nonclassic congenital adrenal hyperplasia; 17-OHP = 17-hydroxyprogesterone; PCOS = polycystic ovary syndrome; PFT = para- and perirenal fat; SAT = subcutaneous abdominal adipose tissue; SBP = systolic blood pressure; SFT = abdominal subcutaneous fat thickness; TG = triglyceride; US = ultrasound; VAT = visceral abdominal adipose tissue; WC = waist circumference     

Evaluation of Treatment of Central Hypothyroidism Versus Primary Hypothyroidism in Relation to Levothyroxine Replacement Dose

Objective: The aim of this study was to evaluate levothyroxine (LT4) replacement daily doses in patients with central hypothyroidism (CeH) and compare them with those adequate for patients with primary hypothyroidism (P-HYPO).Methods: We included 53 patients with CeH and 57 with P-HYPO, matched by sex, age, weight, and body mass index, in the period of 1 year. At the time of inclusion, all presented a stable and adequate dose of LT4 for at least 3 months, considering as adequate the dose associated with normal thyroid-stimulating hormone (TSH) levels and free thyroxine (T4) in P-HYPO patients, and free T4 levels in CeH patients.Results: The absolute daily dose of LT4 differed significantly between the two groups, 103.0 ± 27.1 μg (CeH) and 89.3 ± 32.0 μg (P-HYPO) (P = .017), even after adjustment for age, gender, and free T4 (P = .04). The LT4 dose adjusted to weight was also higher after adjustment for age, gender and free T4 (P = .04), with an average of 1.3 ± 0.4 μg/kg (CeH) and 1.2 ± 0.4 μg/kg (P-HYPO). Sheehan syndrome patients had a lower absolute daily dose of LT4 (P = .001), and patients who underwent pituitary radiotherapy required higher doses (P = .008). There was no difference in the daily dose of LT4 according to other pituitary hormone deficiencies.Conclusion: The results reinforce the relevance of a careful individualization of LT4 replacement in CeH management and the need for new markers for proper LT4 replacement therapy in such cases.Abbreviations: BMI = body mass index; CeH = central hypothyroidism; GH = growth hormone; LT4 = levothyroxine; P-HYPO = primary hypothyroidism; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone     

Low Free (But Not Total) 25-Hydroxyvitamin D Levels in Subjects with Normocalcemic Hyperparathyroidism

Objective: Normocalcemic primary hyperparathyroidism (NPHPT) is characterized by elevated parathyroid hormone (PTH) levels with persistently normal calcium levels. The diagnosis of NPHPT assumes the absence of secondary causes of elevated PTH levels. The objective of the current study was to examine levels of free 25-hydroxyvitamin D (25&lsqb;OH]D) in NPHPT subjects and healthy controls.Methods: Ten NPHPT subjects and 20 controls who were age, sex, race, and body mass index (BMI) matched were examined. The diagnosis of NPHPT was made if subjects had (1) a serum calcium level of 8.6 to 10.4 mg/dL, total 25(OH)D 30 to 40 ng/mL, and intact PTH (iPTH) ≥66 pg/mL; and (2) normal renal and liver function. Serum total 25(OH)D levels were measured by radioimmunoassay, and free 25(OH)D levels were determined using an enzyme-linked immunoassay.Results: Mean age of NPHPT subjects was 59.9 ± 5.4 years, and mean BMI was 28.4 ± 2.3 kg/m², which was not significantly different from the mean age and BMI of the control subjects. Mean total 25(OH)D level was 31.9 ± 1.7 ng/mL in NPHPT subjects and did not differ from that of the controls (32.7 ± 3.3 ng/mL; P = .52). However, mean free 25(OH)D was 5.0 ± 0.9 pg/mL in NPHPT subjects, which was 20% lower compared to the mean of the controls (6.2 ± 1.3 pg/mL; P = .013). Serum iPTH levels were inversely correlated with levels of measured free 25(OH)D (r = -0.42; P<.05) but did not correlate with levels of total 25(OH)D (r = -0.14; P>.10).Conclusion: Measured free 25(OH)D levels are lower in NPHPT subjects than in healthy control subjects. We suggest that some NPHPT subjects may actually have secondary hyperparathyroidism based on their free 25(OH) D levels.Abbreviations: 25(OH)D = 25-hydroxyvitamin D; BMI = body mass index; CV = coefficient of variation; DBP = vitamin D–binding protein; iPTH = intact parathyroid hormone; NPHPT = normocalcemic primary hyperparathyroidism     

Vitamin D-Binding Protein in Healthy Pre- and Postmenopausal Women: Relationship with Estradiol Concentrations

Objective: To examine the relationship between endogenous serum estradiol and vitamin D–binding protein (DBP) and total, free, and bioavailable 25-hydroxyvitamin D (25OHD) concentrations in pre- and postmenopausal women.Methods: In 165 healthy women (ages, 26 to 75 years) not taking any form of exogenous estrogen, the serum concentrations of estradiol, 25OHD, DBP, parathyroid hormone, and albumin were measured. Free and bioavailable 25OHD (free + albumin-bound) levels were calculated from total 25OHD, DBP, and serum albumin levels.Results: Premenopausal women had higher serum 25OHD (31.5 ± 7.9 ng/mL), DBP (45.3 ± 6.2 mg/dL), and estradiol (52.8 ± 35.0 pg/mL) levels than postmenopausal women (26.5 ± 4.9 ng/mL, 41.7 ± 5.7 mg/dL, and 12.9 ± 4.9 pg/mL), respectively. In addition, the calculated free and bioavailable 25OHD levels were higher in prethan postmenopausal women (P<.05). Serum estradiol correlated with DBP (r = 0.22; P<.01) and total 25OHD (r = 0.27; P<.01). In multivariate regression models (with or without serum 25OHD), estradiol was independently associated with DBP (P<.05).Conclusion: Lower estradiol level is one of the factors that contribute to lower DBP levels in older women. Our data indicate that besides well-known factors such as age, gender, and race, serum estradiol concentrations are also a physiologic predictor of DBP concentration.Abbreviations: 25OHD = 25-hydroxyvitamin D BMI = body mass index CV = coefficient of variation DBP = vitamin D–binding protein PTH = parathyroid hormone SHBG = sex hormone–binding globulin     

Nonfunctioning Adrenal Incidentalomas are not Clinically Silent: A Longitudinal Cohort Study

Objective: The association between nonfunctioning adrenal incidentalomas (NFAIs) and cardiometabolic diseases remains controversial. This retrospective cohort study investigated whether NFAIs are related with prevalent and incident cardiometabolic diseases.Methods: This study included 154 patients with biochemically confirmed NFAIs and 1:3 age and sex-matched controls without adrenal incidentalomas (n = 462) among subjects who underwent abdominal computed tomography at a single healthcare center in 2003–2012. Electronic medical records were reviewed for comorbidities at baseline and during a mean follow-up of 7.5 years. The logistic regression analysis for prevalent cardiometabolic diseases and the survival analysis for incident cardiometabolic diseases were performed.Results: The subjects were 55.7 ± 8.8 years of age and predominantly male (73.1%). The NFAI group had a higher body mass index compared to the age and sex-matched control group (25.1 ± 2.8 vs. 24.0 ± 2.8 kg/m²; P<.001). In a cross-sectional design, covariate-adjusted logistic regression showed significantly higher odds ratios (ORs) for diabetes mellitus and hypertension in the NFAI group (adjusted OR [95% confidence interval [CI]], 1.89 [1.17 to 3.06] and 2.26 [1.47 to 3.50], respectively). The NFAI group had a 2-fold higher risk of insulin resistance (adjusted ORs [95% CI], 2.03 [1.06 to 3.90]). Moreover, NFAI subjects with diabetes mellitus had a greater increase in size of adrenal lesions than those without diabetes mellitus (3.4 ± 5.5 vs. 1.4 ± 5.5 mm; P =.048). However, in the survival analysis, the incidence of any cardiometabolic diseases did not differ between the NFAI and control groups.Conclusion: NFAIs are related to prevalent diabetes mellitus or hypertension in our cross-sectional study. However, the presence of NFAIs did not affect the development of cardiometabolic diseases.Abbreviations: ACTH = adrenocorticotropic hormone; AI = adrenal incidentaloma; BMI = body mass index; CI = confidence interval; CT = computed tomography; HbA1c = hemoglobin A1c; HOMA-IR = homeostasis model assessment of insulin resistance; HU = Hounsfield units; MACE = mild autonomous cortisol excess; NFAI = nonfunctioning adrenal incidentaloma; OR = odds ratio     

Visceral and Subcutaneous Fat Increased after Treatment of Graves Disease

Objective: Patients with Graves disease (GD) tend to gain weight after treatment, but it remains unknown if weight gain is associated with an increase in the visceral and/or subcutaneous fat areas (VFA, SFA).Methods: We enrolled 25 newly diagnosed GD patients (22 females, median age 33.0 years) and studied their clinical parameters, and VFA and SFA measured by a dual bioelectric impedance analysis. We divided them into 2 groups based on the rates of change in the VFA and SFA, and we compared clinical parameters at the baseline between the groups to evaluate factors that influence increases in the VFA and/or SFA with treatment.Results: The patients' body weight (BW), VFA, and SFA were significantly increased after a 6-month treatment (BW: from 54.3 ± 10.3 kg to 58.0 ± 11.2 kg; P<.001; VFA: from 47.1 ± 21.3 cm² to 54.7 ± 23.4 cm²; P = .004; SFA: from 159.8 ± 85.9 cm² to 182.2 ± 82.9 cm²; P = .008). The percent changes of BW correlated with the SFA (ρ = .591, P = .002), but not with the VFA. The patients with larger VFA increases had significantly less VFA at the baseline compared to those with smaller increases, expressed as median and interquartile range (33.9 cm² [22.7 to 47.5 cm²] versus 54.5 cm² [45.2 to 64.0], respectively; P = .011). A larger increase in the SFA was negatively associated with serum alkaline phosphatase. An increase in the SFA was associated with free triiodothyronine (T3) in a multivariate logistic analysis (odds ratio: 0.80 [0.59 to 0.97]; P = .013).Conclusion: The patients' BW, VFA, and SFA were increased after GD treatment. The increase in SFA seemed to contribute to weight gain and was associated with a low baseline level of free T3.Abbreviations: ALP = alkaline phosphatase; BMI = body mass index; BW = body weight; GD = Graves disease; SFA = subcutaneous fat area; T3 = triiodothyronine; T4 = thyroxine; TG = triglycerides; VFA = visceral fat areas     

ACTN3 Gene R577X Polymorphism Associated with High-Density Lipoprotein Cholesterol and Adiponectin in Rugby Players

Objective: To determine the relationship between the R577X polymorphism of the α-actinin-3 (ACTN3), which may play a role in the individual differences observed in the effects of exercise on health benefits and antiatherogenic markers (i.e., high-density lipoprotein cholesterol [HDL-C] and adiponectin) in athletes.Methods: Seventy-six male rugby players (mean age 19.8 years) were enrolled in this study. Genomic DNA was extracted from peripheral blood samples, and restriction fragment length polymorphism-polymerase chain reactions were conducted to assess ACTN3 genotypes. Body mass index (BMI), waist circumference, serum lipids including HDL-C, and adiponectin levels were measured. Current smoking and alcohol intake habits were evaluated with a questionnaire. All of the parameters were compared between 2 groups displaying frequently observed genotypes: one group consisting of patients having either the R/R or R/X genotype and a second group with the X/X genotype.Results: The frequency of the X allele was 0.55 and the distribution of the genotypes was 35.5% (n = 27) for X/X, 39.5% (n = 30) for R/X, and 25.0% (n = 19) for R/R. Serum HDL-C and adiponectin levels were significantly higher in X/X genotype compared to the R/R or R/X genotype (HDL-C 1.6 ± 0.3 [SD] vs. 1.4 ± 0.2 mmol/L; P<.01, adiponectin 8.8 ± 2.6 vs. 6.9 ± 2.3 μg/mL; P<.01), even after adjustments for confounders (P<.01).Conclusion: There may be a relationship between the ACTN3 genotype and HDL-C and adiponectin levels in rugby players. This may be useful information when determining the individual responses of antiatherogenic markers to exercise.Abbreviations:ACTN3 = α-actinin-3BMI = body mass indexCVD = cardiovascular diseaseHDL-C = high-density lipoprotein cholesterolLDL-C = low-density lipoprotein cholesterolR = arginine (R) at amino acid position 577 of the ACTN3 proteinTC = total cholesterolTG = triglycerideX = truncation at amino acid position 577 of the ACTN3 protein     

The Potential Clinical Application of a Lower Bilateral Adrenal LIMB Width Ratio (L/RW) in Patients with Bilateral Primary Hyperaldosteronism

Objective: This study investigated the characteristics of the adrenal limbs of primary aldosteronism (PA) patients and evaluated the value of the adrenal limb width measurement for the differentiation of unilateral PA from bilateral PA.Methods: A total of 122 PA patients (93 unilateral PA, ages ranged from 23 to 72 years; 29 bilateral PA, ages ranged from 30 to 68 years) who had undergone successful adrenal venous sampling (AVS) and adrenal gland computed tomography (CT) scan were retrospectively included. The maximum width of each adrenal gland limb (normal area on CT images) was measured, the left adrenal limb width to right adrenal limb width ratio (L/Rw) was calculated, and its potential value in the differentiation of unilateral PA and bilateral PA was analyzed.Results: The mean widths of the left adrenal limbs and the right adrenal limbs were 0.52 ± 0.10 cm and 0.43 ± 0.09 cm in unilateral PA patients, versus 0.52 ± 0.10 cm and 0.49 ± 0.12 cm in bilateral PA patients. The L/Rw ratio was 1.22 ± 0.24 in unilateral PA patients and 1.11 ± 0.23 in bilateral PA patients (P<.05). In the subgroup of PA patients over 55 years of age, compared with AVS, the sensitivity and specificity of the L/Rw ratio at 1.06 for subtype classification were 75% and 82%, respectively.Conclusion: A lower L/Rw ratio, referring to the ratio of the left adrenal limb width to the right adrenal limb width, may be a predictor of bilateral PA, especially in PA patients over 55 years of age.Abbreviations: APA = aldosterone-producing adenoma; AVS = adrenal venous sampling; BAH = bilateral adrenal hyperplasia; BMI = body mass index; CT = computed tomography; L/Rw = ratio of left adrenal limb width to right adrenal limb width; PA = primary aldosteronism     

Cardiac Structural and Functional Abnormalities in Females with Untreated Hypopituitarism due to Sheehan Syndrome: Response to Hormone Replacement Therapy

Objective: Data on cardiac abnormalities in females with untreated hypopituitarism are limited. We investigated echocardiographic abnormalities in females with untreated hypopituitarism and their response to treatment.Methods: Twenty-three females with treatment-naïve hypopituitarism and 30 matched healthy controls were evaluated for cardiac structure and function. Echocardiographic evaluation was done at presentation and after achieving a euthyroid and eucortisol state.Results: Fourteen (61%) patients had mitral regurgitation, and 11 (48%) had pericardial effusion as against none among controls. Indices of left ventricular (LV) size like LV end diastolic dimension (LVEDD; 44.5 ± 3.5 mm in cases vs. 47.6 ± 3.8 mm in controls, P = .004), and LV diastolic volume (LVEDV; 91.8 ± 18.0 mL versus 106.5 ± 20.4 mL, P = .009) were significantly lower in the SS group compared with controls. LV mass (LVM) was 70.8 ± 19.2 g in cases and 108.0 ± 33.2 g in controls (P = .02). Similarly, indices of LV systolic function like stroke volume (SV; 59.1 ± 12.0 mL in cases and 74.4 ± 15.8 mL in controls; P = .000), ejection fraction (EF; 64.3 ± 6.2 % in cases against 69.9 ± 9.2 % in controls; P = .03), and fractional shortening (FS; 34.9 ± 4.7% versus 40.1 ± 4.4%, P = .000) were significantly decreased in patients compared with controls. Cardiac abnormalities normalized with restoration of a euthyroid and eucortisol state.Conclusion: Pericardial effusion, mitral regurgitation, and diminished LVM are common in females with untreated hypopituitarism.Abbreviations:ACTH = adrenocorticotrophic hormoneBMI = body mass indexDT = deceleration timeEDV = end-diastolic volumeEF = ejection fractionFS = fractional shorteningGH = growth hormoneIGF-1 = insulin growth factor-1ITT = insulin tolerance testIVSd = interventricular septal diameterLH = luteinizing hormoneLV = left ventricularLVEDD = LV end diastolic dimensionLVEDV = LV end diastolic volumeLVM = LV massMRI = magnetic resonance imagingMVP = mitral value prolapsePPH = postpartum hemorrhagePWd = posterior wall diameterSS = Sheehan syndromeSV = stroke volumeT3 = triiodothyronineT4 = thyroxineTSH = thyroid-stimulating hormone     

Metformin-Sustained Weight Loss and Reduced Android Fat Tissue At 12 Months In Empowir (Enhance The Metabolic Profile Of Women With Insulin Resistance): A Double Blind,Placebo-Controlled,Randomized Trial of Normoglycemic Women with Midlife Weight Gain

Objective: To assess 12-month body weight (BW) and body composition changes in normoglycemic women with midlife weight gain, after dietary and pharmacologic interventions targeting hyperinsulinemia.Methods: EMPOWIR (Enhance the Metabolic Profile of Women With Insulin Resistance; NCT00618072) was a double-blind, placebo-controlled, 12-month trial of women with >20-pound weight gain, normal glucose tolerance test, and increased area-under-the-curve insulin. Subjects (mean ± SD, 46.7 ± 6.5 years of age; body mass index, 30.8 ± 2.8 kg/m²; 50% white) attended 4 nutrition workshops to introduce a novel carbohydrate-modified diet (CMD) and were then randomized to one of three arms for 6 months (phase 1): CMD alone (D), or in combination with metformin (M), or metformin + rosiglitazone (MR), with rerandomization of the D group to one of the active treatment arms (phase 2, months 7 through 12). Repeated measure analysis of variance was used to assess BW at baseline, 6 months, and 12 months in 32 subjects with 12-month data; paired t tests compared baseline and 12-month dual-energy X-ray absorptiometry–derived body composition.Results: Mean (±SD) BW decreased significantly at 12 months in the M arm: 85.1 ± 8.5 kg to 79.8 ± 9.0 kg (P = .0003), with 54% of variance in weight over time explained by M treatment. Mean (±SD) percent android fat decreased significantly in the M and D arms: 53.5 ± 4.8% to 49.3 ± 7.6% (P = .010) and 52.9 ± 6.2% to 48.1 ± 8.7% (P = .021).Conclusion: In combination with a novel carbohydrate modified diet, metformin enhanced 12-month weight loss and improved body composition in ethnically diverse normoglycemic, hyperinsulinemic women with midlife weight gain. These findings suggest that EMPOWIR's easily implemented dietary interventions, alone and in combination with pharmacotherapies that target hyperinsulinemia, merit additional investigation in larger, long-term studies.Abbreviations:ANOVA = analysis of varianceBC = body compositionBW = body weightCMD = carbohydrate-modified dietD = diet alone groupDXA = dual-energy X-ray absorptiometryEMPOWIR = Enhance the Metabolic Profile of Women With Insulin ResistanceM = metformin groupMR = metformin + rosiglitazone group     

Axial BMD in Diabetic and Nondiabetic Southeast Asians with HIP Fractures: Do Race and Body Mass Index Matter?

Objective: Obesity is less prevalent in Asian subjects with type 2 diabetes mellitus (T2DM) in contrast to Caucasians. Whether higher axial bone mineral density (BMD) often reported in T2DM is independent of body mass index (BMI) has not been clearly shown. BMD characterization in T2DM patients with hip fractures has also not been performed. We compared the BMD of Asian diabetic and nondiabetic patients with new hip fractures and explored how BMD was influenced by BMI.Methods: We included 255 diabetic and 148 nondiabetic patients. BMD adjusted for age; BMI; race; sex; renal function; and use of statins, proton pump inhibitors, steroids, anticonvulsants, and calcium and/or vitamin D supplements were compared between the groups. We were particularly interested in the BMD comparison between underweight diabetics and nondiabetics with hip fractures.Results: The presence of T2DM was associated with higher BMD (g/cm²) at the femoral neck (0.527 ± 0.103 vs. 0.491 ± 0.102, P<.01) and lumbar spine [LS] (0.798 ± 0.147 vs. 0.723 ± 0.156, P<.01). This association persisted after adjustment for multiple confounding variables including BMI. The age-, BMI-, and sex-adjusted LS BMD was higher in underweight (BMI <18.5 kg/m²) diabetics compared to similar weight nondiabetics (0.733 ± 0.126 vs. 0.649 ± 0.131 g/cm², P = .014).Conclusion: T2DM is independently associated with higher axial BMD in patients with new hip fractures. The finding of higher BMD even in underweight diabetics with hip fractures compared to their nondiabetic counterparts suggests that higher BMD in subjects with T2DM is not due to higher BMI.Abbreviations:BMD = bone mineral densityBMI = body mass indexCV = coefficient of variationDXA = dual-energy X-ray absorptiometryHbA1c = glycated hemoglobinIGF-1 = insulin growth factor-1LS = lumbar spine25(OH)D = 25-hydroxyvitamin DT2DM = type 2 diabetes mellitus     

Synthesis,in vitro evaluation and molecular docking studies of novel amide linked triazolyl glycoconjugates as new inhibitors of α-glucosidase

A series of N-substituted amide linked triazolyl β-d-glucopyranoside derivatives (4a-l) were synthesized and their in vitro inhibitory activity against yeast α-glucosidase enzyme [EC.3.2.1.20] was assessed. Compounds 4e (IC₅₀ = 156.06 μM), 4f (IC₅₀ = 147.94 μM), 4k (IC₅₀ = 127.71 μM) and 4l (IC₅₀ = 121.33 μM) were identified as the most potent inhibitors for α-glucosidase as compared to acarbose (IC₅₀ = 130.98 μM) under the same in vitro experimental conditions. Kinetic study showed that both 4e and 4f inhibit the enzyme in a competitive manner with p-nitrophenyl α-d-glucopyranoside as substrate. Molecular docking studies of 4e, 4f, 4k and 4l were also carried out using homology model of α-glucosidase to find out the binding modes responsible for the inhibitory activity. This study revealed that the binding affinity of compounds 4e, 4f, 4k and 4l for α-glucosidase were −8.2, −8.6, −8.3 and −8.5 kcal/mol respectively, compared to that of acarbose (−8.9 kcal/mol). The results suggest that the N-substituted amide linked triazole glycoconjugates can reasonably mimic the substrates for the yeast α-glucosidase.     

Serum Free Cortisol During Glucagon Stimulation Test In Healthy Short-Statured Children And Adolescents

Objective: The total cortisol (TC) response may be measured during the glucagon stimulation test (GST) for growth hormone (GH) reserve in order to assess the integrity of the hypothalamic-pituitary-adrenal (HPA) axis. Measurements of TC are unreliable in conditions of albumin and cortisol-binding globulin (CBG) alterations (e.g., hypoproteinemia or CBG deficiency). We aimed to measure the serum free cortisol (sFC) response to the GST in children and adolescents and determine whether it could predict the GH response to glucagon stimulation.Methods: Infants and children with either short stature or growth attenuation who were referred for evaluation of GH reserve underwent the GST.Results: The study population consisted of 103 subjects (62 females), median age 3.9 years (range, 0.5–14). The mean basal and peak TC levels were 13.3 ± 6.7 μg/dL and 29.6 ± 8.8 μg/dL, respectively. The mean basal and peak sFC levels were 0.7 ± 0.8 μg/dL and 1.7 ± 1.1 μg/dL, respectively. There was a negative correlation between peak TC and age (r = -0.3, P = .007) but not between peak sFC and age (r = -0.09, P = .36). Ninety-five percent of the patients had peak TC levels >15.8 μg/dL and peak sFC levels >0.6 μg/dL.Conclusion: Our results on a cohort of healthy short-statured children can serve as reference values for the sFC response during GST. Based on these results, we propose peak TC levels >15.8 μg/dL and peak sFC levels >0.6 μg/dL for defining normalcy of the HPA axis during the GST in children and adolescents.Abbreviations:ACTH = adrenocorticotrophic hormoneBMI = body mass indexCBG = cortisol-binding globulinGH = growth hormoneGST = glucagon stimulation testHPA = hypothalamic-pituitary-adrenalSDS = standard deviation scoresFC = serum free cortisolTC = total cortisol