Regulation of circulating CTRP-2/CTRP-9 and GDF-8/GDF-15 by intralipids and insulin in healthy control and polycystic ovary syndrome women following chronic exercise training.

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with obesity, diabetes, and insulin resistance. The circulating C1Q/TNF-related proteins (CTRP-2, CTRP-9) and growth differentiation factors (GDF-8, GDF-15) contribute to glucose and lipid homeostasis. The effects of intralipids and insulin infusion on CTRP-2, CTRP-9, GDF-8 and GDF-15 in PCOS and control subjects before and after chronic exercise training were examined. METHODS: Ten PCOS and nine healthy subjects were studied at baseline status and after moderate-intensity chronic exercise training (1 h exercise, 3 times per week, 8 weeks). All participants were infused with 1.5 mL/min of saline or intralipids (20%) for 5 h, and during the last 2 h of saline or intralipids infusion hyperinsulinemic-euglycemic clamp (HIEC) was performed. CTRP-2, CTRP-9, GDF-8 and GDF-15 levels were measured at 0, 3 and 5 h. RESULTS: Intralipids dramatically increased CTRP-2 levels in PCOS (P = 0.02) and control (P = 0.004) subjects, which was not affected by insulin infusion or by exercise. Intralipids alone had no effects on CTRP-9, GDF-8, or GDF-15. Insulin increased the levels of GDF-15 in control subjects (P = 0.05) during the saline study and in PCOS subjects (P = 0.04) during the intralipid infusion. Insulin suppressed CTRP9 levels during the intralipid study in both PCOS (P = 0.04) and control (P = 0.01) subjects. Exercise significantly reduced fasting GDF-8 levels in PCOS (P = 0.03) and control (P = 0.04) subjects; however, intralipids infusion after chronic exercise training increased GDF-8 levels in both PCOS (P = 0.003) and control (P = 0.05) subjects and insulin infusion during intralipid infusion reduced the rise of GDF-8 levels. CONCLUSION: This study showed that exogenous lipids modulate CTRP-2, which might have a physiological role in lipid metabolism. Since chronic exercise training reduced fasting GDF-8 levels; GDF-8 might have a role in humoral adaptation to exercise. GDF-15 and CTRP-9 levels are responsive to insulin, and thus they may play a role in insulin responses.

Lipids and insulin regulate mitochondrial-derived peptide (MOTS-c) in PCOS and healthy subjects.

OBJECTIVE: Polycystic ovarian syndrome (PCOS) is a heterogeneous endocrine disorder associated with mitochondrial dysfunction and insulin resistance (IR). MOTS-c, a mitochondrial peptide, promotes insulin sensitivity (IS) through activating AKT and AMPK-dependent pathways. The current study was designed to examine the response of MOTS-c to lipids (intralipid) followed by insulin in PCOS and healthy subjects. METHODS: All subjects underwent 5-hour intralipid/saline infusion with a hyperinsulinemic-euglycaemic clamp in the final 2 hours. Plasma samples were collected to measure circulating MOTS-c using a commercial ELISA kit. Subsequently, this was repeated following an eight-week exercise intervention. RESULTS: Intralipid significantly increased plasma MOTS-c both in controls and PCOS subjects, whilst the insulin infusion blunted the intralipid-induced response seen for both lipids and MOT-c. Intralipid elevated plasma MOTS-c to 232 ± 124% of basal in control (P < 0.01) and to 349 ± 206% of basal in PCOS (P < 0.001) subjects. Administration of insulin suppressed intralipid-induced MOTS-c from 232 ± 124% to 165 ± 97% (NS) in control and from 349 ± 206% to 183 ± 177% (P < 0.05) in PCOS subjects, respectively. Following exercise, intralipid elevated plasma MOTS-c to 305 ± 153% of basal in control (P < 0.01) and to 215 ± 103% of basal in PCOS (P < 0.01) subjects; insulin suppressed intralipid-induced MOTS-c only in controls. CONCLUSIONS: In conclusion, this is the first study to show increased lipid enhanced circulating MOTS-c whilst insulin attenuated the MOTS-c response in human. Further, eight weeks of moderate exercise training did not show any changes in circulating MOTS-c levels in healthy controls and in women with PCOS.

The effect of lithium on the progression-free and overall survival in patients with metastatic differentiated thyroid cancer undergoing radioactive iodine therapy.

OBJECTIVE: Pretreatment with lithium (Li) is associated with an increased residence time of radioactive iodine (RAI) in differentiated thyroid cancer (DTC) metastases. There are no data translating this observation into long-term outcomes. The study goal was to compare the efficacy of three methods of preparation for RAI therapy in metastatic DTC-thyroid hormone withdrawal (THW), THW with pretreatment with Li (THW+Li), and recombinant human TSH (rhTSH). DESIGN/PATIENTS/MEASUREMENTS: We performed a cohort study comparing overall survival (OS) and progression-free survival (PFS) between the three groups: THW (n = 52), THW+Li (n = 41) and rhTSH (n = 42). Kaplan-Meier analyses were performed to compare OS and PFS between the groups. Cox proportional hazards regression model with a stepwise variable selection was performed to study the contribution of age, gender, histology, TNM status, a location of distant metastases and RAI dose. RESULTS: During the follow-up of median 5.1 (IQR = 3.0-8.1) years, 52% of patients had disease progression and 12.6% died. Although THW+Li group was characterized by the longest OS (P = 0.007), only age (HR 1.05, CI 1.01-1.09, P = 0.01) and widespread disease (HR 3.8, CI 1.2-11.8, P = 0.02) were found to affect OS in a multivariate model. There was no difference in PFS between the groups (P = 0.47). Presence of distant metastases limited to the lungs only was associated with longer PFS (PFS HR 0.35, CI 0.20-0.60, P = 0.0002). CONCLUSION: The older age is associated with shorter OS, while disease burden affects OS and PFS in patients with metastatic thyroid cancer. The method of preparation for RAI therapy does not affect the outcome.

Effects of Recombinant Human Leptin (Metreleptin) on Nocturnal Luteinizing Hormone Secretion in Lipodystrophy Patients.

BACKGROUND: Leptin replacement in patients with leptin gene mutations improves hypogonadotropic hypogonadism. The effects of leptin replacement on luteinizing hormone (LH) secretion in patients with lipodystrophy are unknown. AIM: We examined nocturnal LH secretory dynamics on and off exogenous leptin therapy using a 2-period, nonrandomized study that included leptin-naïve and leptin-treated subjects with lipodystrophy. METHODS: In period 1 (5 days) the leptin-treated group (n = 4) continued leptin; leptin was then withdrawn for the next 14 days (period 2). Leptin-naïve subjects (n = 8) were studied without leptin in period 1 and with leptin replacement in period 2. LH secretory dynamics were assessed (23:00-07:00 h, sampling every 10 min, analyzed by multiparameter deconvolution algorithm) at the end of each period. RESULTS: Mean (on vs. off: 5.0 ± 3.1 vs. 3.2 ± 1.3 IU/l, p = 0.04) and integrated LH concentrations (2,403 ± 1,495 vs. 1,534 ± 642 IU × l-1 × min-1, p = 0.04) were higher on leptin therapy. Leptin treatment increased burst mass (9.7± 15.4 vs. 7.0 ± 11.2 IU/l, p = 0.03) and tended to nonsignificantly increase LH burst frequency (0.77 ± 0.26 vs. 0.67 ± 0.24 h-1, p = 0.08). Consequently, leptin therapy increased the pulsatile production rate (64 ± 101 vs. 57 ± 73 IU × l-1 × 8 h-1, p = 0.01). On leptin, testosterone (507 ± 286 vs. 360 ± 174 ng/dl, p = 0.09) and estradiol levels (74 ± 36 vs. 29 ± 24 pg/ml, p = 0.01) were higher in males and females, respectively. CONCLUSIONS: Leptin increases spontaneous nocturnal LH secretion in patients with lipodystrophy. This is consistent with rodent and in vitro studies showing a direct stimulatory effect (hypothalamic, pituitary or both) of leptin on LH secretion. These novel findings may explicate some of the salutary effects of leptin therapy on the hypothalamic-pituitary-gonadal axis in lipodystrophy.

CDK4-E2F3 signals enhance oxidative skeletal muscle fiber numbers and function to affect myogenesis and metabolism.

Understanding how skeletal muscle fiber proportions are regulated is vital to understanding muscle function. Oxidative and glycolytic skeletal muscle fibers differ in their contractile ability, mitochondrial activity, and metabolic properties. Fiber-type proportions vary in normal physiology and disease states, although the underlying mechanisms are unclear. In human skeletal muscle, we observed that markers of oxidative fibers and mitochondria correlated positively with expression levels of PPARGC1A and CDK4 and negatively with expression levels of CDKN2A, a locus significantly associated with type 2 diabetes. Mice expressing a constitutively active Cdk4 that cannot bind its inhibitor p16INK4a, a product of the CDKN2A locus, were protected from obesity and diabetes. Their muscles exhibited increased oxidative fibers, improved mitochondrial properties, and enhanced glucose uptake. In contrast, loss of Cdk4 or skeletal muscle-specific deletion of Cdk4's target, E2F3, depleted oxidative myofibers, deteriorated mitochondrial function, and reduced exercise capacity, while increasing diabetes susceptibility. E2F3 activated the mitochondrial sensor PPARGC1A in a Cdk4-dependent manner. CDK4, E2F3, and PPARGC1A levels correlated positively with exercise and fitness and negatively with adiposity, insulin resistance, and lipid accumulation in human and rodent muscle. All together, these findings provide mechanistic insight into regulation of skeletal muscle fiber-specification that is of relevance to metabolic and muscular diseases.

Volanesorsen, an antisense oligonucleotide to apolipoprotein C-III, increases lipoprotein lipase activity and lowers triglycerides in partial lipodystrophy.

BACKGROUND: Partial lipodystrophy (PL) syndromes involve deficiency of adipose tissue, causing severe insulin resistance and hypertriglyceridemia. Apolipoprotein C-III (apoC-III) is elevated in PL and is thought to contribute to hypertriglyceridemia by inhibiting lipoprotein lipase (LPL). OBJECTIVE: We hypothesized that volanesorsen, an antisense oligonucleotide to apoC-III, would decrease apoC-III, increase LPL activity, and lower triglycerides in PL. METHODS: Five adults with PL enrolled in a 16-week placebo-controlled, randomized, double blind study of volanesorsen, 300 mg weekly, followed by 1-year open label extension. RESULTS: Within-subject effects of volanesorsen before and after 16 weeks of active drug are reported due to small sample size. From week 0 to 16, apoC-III decreased from median (25th, 75th %ile) 380 (246, 600) to 75 (26, 232) ng/mL, and triglycerides decreased from 503 (330, 1040) to 116 (86, 355) mg/dL while activation of LPL by subjects' serum increased from 21 (20, 25) to 36 (29, 42) nEq/mL*min. Although, A1c did not change, peripheral and hepatic insulin sensitivity (glucose disposal and suppression of glucose production during hyperinsulinemic clamp) increased and palmitate turnover decreased. After 32-52 weeks of volanesorsen, liver fat decreased. Common adverse events included injection site reactions and decreased platelets. CONCLUSIONS: In PL, volanesorsen decreased apoC-III and triglycerides, in part through an LPL dependent mechanism, and may improve insulin resistance and hepatic steatosis.

An intronic SNP in the thyroid hormone receptor ß gene is associated with pituitary cell-specific over-expression of a mutant thyroid hormone receptor ß2 (R338W) in the index case of pituitary-selective resistance to thyroid hormone.

BACKGROUND: The syndrome of resistance to thyroid hormone (RTH) is caused by mutations in the thyroid hormone receptor ß gene (THRB). The syndrome varies from asymptomatic to diffuse hypothyroidism, to pituitary-selective resistance with predominance of hyperthyroid signs and symptoms. The wide spectrum of clinical presentation is not completely attributable to specific THRB mutations. The THRB gene encodes two main isoforms, TR ß1 which is widely distributed, and TR ß2, whose expression is limited to the cochlea, retina, hypothalamus, and pituitary. Recent data demonstrated that in mice an intron enhancer region plays a critical role in the pituitary expression of the ß2 isoform of the receptor. We thus hypothesized that polymorphisms in the human homologous region could modulate the pituitary expression of the mutated gene contributing to the clinical presentation of RTH. METHODS: Screening and in vitro characterization of polymorphisms of the intron enhancer region of the THRB gene in the index case of pituitary-selective RTH. RESULTS: The index case of pituitary-selective resistance is characterized by the missense R338W exon 9 mutation in cis with two common SNPs, rs2596623T and rs2596622C, located in the intron enhancer region of the THRB gene. Reporter gene assay experiments in GH3 pituitary-derived cells indicate that rs2596623T generates an increased pituitary cell-specific activity of the TR ß2 promoter suggesting that rs2596623T leads to pituitary over-expression of the mutant allele. CONCLUSIONS: The combined coding mutation and non-coding SNP therefore generate a tissue-specific dominant-negative condition recapitulating the patient's peculiar phenotype. This case illustrates the role of regulatory regions in modifying the clinical presentation of genetic diseases.

Insulin sensitivity variations in apparently healthy Arab male subjects: correlation with insulin and C peptide.

INTRODUCTION: Decreased insulin sensitivity occurs early in type 2 diabetes (T2D). T2D is highly prevalent in the Middle East and North Africa regions. This study assessed the variations in insulin sensitivity in normal apparently healthy subjects and the levels of adiponectin, adipsin and inflammatory markers. RESEARCH DESIGN AND METHODS: A total of 60 participants (aged 18-45, body mass index <28) with a normal oral glucose tolerance test (OGTT) completed hyperinsulinemic-euglycemic clamp (40 mU/m2/min) and body composition test by dual-energy X-ray absorptiometry scan. Blood samples were assayed for glucose, insulin, C peptide, inflammatory markers, oxidative stress markers, adiponectin and adipsin. RESULTS: The subjects showed wide variations in the whole-body glucose disposal rate (M value) from 2 to 20 mg/kg/min and were divided into three groups: most responsive (M>12 mg/kg/min, n=17), least responsive (M≤6 mg/kg/min, n=14) and intermediate responsive (M=6.1-12 mg/kg/min, n=29). Insulin and C peptide responses to OGTT were highest among the least insulin sensitive group. Triglycerides, cholesterol, alanine transaminase (ALT) and albumin levels were higher in the least responsive group compared with the other groups. Among the inflammatory markers, C reactive protein (CRP) was highest in the least sensitivity group compared with the other groups; however, there were no differences in the level of soluble receptor for advanced glycation end products and Tumor Necrosis Factor Receptor Superfamily 1B (TNFRS1B). Plasma levels of insulin sensitivity markers, adiponectin and adipsin, and oxidative stress markers, oxidized low-density lipoprotein, total antioxidant capacity and glutathione peroxidase 1, were similar between the groups. CONCLUSIONS: A wide range in insulin sensitivity and significant differences in triglycerides, cholesterol, ALT and CRP concentrations were observed despite the fact that the study subjects were homogenous in terms of age, gender and ethnic background, and all had normal screening comprehensive chemistry and normal glucose response to OGTT. The striking differences in insulin sensitivity reflect differences in genetic predisposition and/or environmental exposure. The low insulin sensitivity status associated with increased insulin level may represent an early stage of metabolic abnormality.

Core outcomes in gestational diabetes for treatment trials: The Gestational Metabolic Group treatment set.

AIMS: With the rising number of outcomes being reported following gestational diabetes (GDM), the outcomes in existing studies vary widely making it challenging to compare and contrast the effectiveness of different interventions for GDM. The purpose of this study was to develop a core outcome and measurement set (COS) for GDM treatment trials. MATERIALS & METHODS: A Delphi study with structured consultation with stakeholders and discussion within a specialist Gestational Metabolic Group (GEM) were combined with a comprehensive systematic search across different databases (PubMed, Cochrane Library, and Embase). Several Delphi rounds over 2 years were conducted culminating in this report. RESULTS: The process resulted in a targeted set of outcomes constituting a "GEM treatment set" aligned with expert opinion. The final COS also included a measurement set for the 11 important clinical outcomes from three major domains: maternal metabolic, fetal, and pregnancy related. CONCLUSIONS: Based on the results of this study, it is recommended that future clinical trials on GDM report outcomes uniformly keeping to the recommended COS outcomes.

The pharmacodynamic equivalence of levothyroxine and liothyronine: a randomized, double blind, cross-over study in thyroidectomized patients.

CONTEXT: The substitution of liothyronine (L-T3) for levothyroxine (L-T4) is commonly employed during thyroid hormone (TH) withdrawal in preparation for diagnostic and therapeutic interventions on thyroid cancer patients. Presently, only limited data are available on the L-T3 for L-T4 therapeutic substitution. Objective To characterize the pharmcodynamic equivalence of L-T3 and L-T4. DESIGN: Randomized, double-blind, cross-over intervention study. SETTING: NIH clinical center. PATIENTS: Ten thyroidectomized patients. INTERVENTIONS: Study participants were treated with L-T3 or L-T4 with a target TSH >or= 0.5

Treatment of obesity with extension of sleep duration: a randomized, prospective, controlled trial.

BACKGROUND: The prevalence of chronic sleep deprivation is increasing in modern societies with negative health consequences. Recently, an association between short sleep and obesity has been reported. PRIMARY OBJECTIVES: To assess the feasibility of increasing sleep duration to a healthy length (approximately 7(1/2) h) and to determine the effect of sleep extension on body weight. SECONDARY OBJECTIVES: To examine the long-term effects of sleep extension on endocrine (leptin and ghrelin) and immune (cytokines) parameters, the prevalence of metabolic syndrome, body composition, psychomotor vigilance, mood, and quality of life. METHODS: One hundred-fifty obese participants who usually sleep less than 6(1/2) h, are being randomized at a 2:1 ratio to either an Intervention or to a Comparison Group. They are stratified by age (above and below 35) and the presence or absence of metabolic syndrome. During the first 12 months (Efficacy Phase) of the study, participants are evaluated at bi-monthly intervals: the Intervention Group is coached to increase sleep by at least 30-60 min/night, while the Comparison Group maintains baseline sleep duration. In the second (Effectiveness) phase, participants converge into the same group and are asked to increase (Comparison Group) or maintain (Intervention Group) sleep duration and are evaluated at 6-month intervals for an additional 3 years. Non-pharmacological and behavior-based interventions are being utilized to increase sleep duration. Endocrine, metabolic, and psychological effects are monitored. The sleep, energy expenditure, and caloric intake are assessed by activity monitors and food recall questionnaires. At yearly intervals, body composition, abdominal fat, and basal metabolic rate are measured by dual energy X-ray absorptiometry (DXA), computerized tomography (CT), and indirect calorimetry, respectively. RESULTS: As of January 2010, 109 participants had been randomized, 64 to the Intervention Group and 45 to the Comparison Group (76% women, 62% minorities, average age: 40.8 years; BMI: 38.5 kg/m(2)). Average sleep duration at screening was less than 6 h/night, 40.3 h/week. A total of 28 Intervention and 22 Comparison participants had completed the Efficacy Phase. LIMITATIONS: The study is not blinded and the sample size is relatively small. CONCLUSIONS: This proof-of-concept study on a randomized sample will assess whether sleep extension is feasible and whether it influences BMI. Clinical Trials 2010; 7: 274-285. http://ctj.sagepub.com.

Dynamic Changes in Circulating Endocrine FGF19 Subfamily and Fetuin-A in Response to Intralipid and Insulin Infusions in Healthy and PCOS Women.

Background: The fibroblast growth factors (FGF) 19 subfamily, also referred to as endocrine FGFs, includes FGF19, FGF21, and FGF23 are metabolic hormones involved in the regulation of glucose and lipid metabolism. Fetuin-A is a hepatokine involved in the regulation of beta-cell function and insulin resistance. Endocrine FGFs and fetuin-A are dysregulated in metabolic disorders including obesity, type 2 diabetes, non-alcoholic fatty liver disease and polycystic ovary syndrome (PCOS). Our study was designed to examine the response of endocrine FGFs and fetuin-A to an acute intralipid, insulin infusion and exercise in PCOS and healthy women. Subjects and Measurements: Ten healthy and 11 PCOS subjects underwent 5-h saline infusions with a hyperinsulinemic-euglycemic clamp (HIEC) performed during the final 2 h. One week later, intralipid infusions were undertaken with a HIEC performed during the final 2 h. After an 8 week of exercise intervention the saline, intralipid, and HIEC were repeated. Plasma levels of endocrine FGFs and fetuin-A were measured. Results: Baseline fetuin-A was higher in PCOS women but FGF19, FGF21, and FGF23 did not differ and were unaffected by exercise. Insulin administration elevated FGF21 in control and PCOS, suppressed FGF19 in controls, and had no effects on FGF23 and fetuin-A. Intralipid infusion suppressed FGF19 and increased FGF21. Insulin with intralipid synergistically increased FGF21 and did not have effects on lipid-mediated suppression of FGF19 in both groups. Conclusion: Our study provides evidence for insulin and lipid regulation of endocrine FGFs in healthy and PCOS women, suggesting that FGF family members play a role in lipid and glucose metabolism. Clinical Trial Registration: www.isrctn.org, Identifier: ISRCTN42448814.

Thyroid Hormone Effects on Glucose Disposal in Patients With Insulin Receptor Mutations.

CONTEXT: Patients with mutations of the insulin receptor gene (INSR) have extreme insulin resistance and are at risk for early morbidity and mortality from diabetes complications. A case report suggested that thyroid hormone could improve glycemia in INSR mutation in part by increasing brown adipose tissue (BAT) activity and volume. OBJECTIVE: To determine if thyroid hormone increases tissue glucose uptake and improves hyperglycemia in INSR mutation. DESIGN: Single-arm, open-label study of liothyronine. SETTING: National Institutes of Health. PARTICIPANTS: Patients with homozygous (n = 5) or heterozygous (n = 2) INSR mutation. INTERVENTION: Liothyronine every 8 hours for 2 weeks (n = 7); additional 6 months' treatment in those with hemoglobin A1c (HbA1c) > 7% (n = 4). OUTCOMES: Whole-body glucose uptake by isotopic tracers; tissue glucose uptake in muscle, white adipose tissue (WAT) and BAT by dynamic [18F] fluorodeoxyglucose positron emission tomography/computed tomography; HbA1c. RESULTS: There was no change in whole-body, muscle, or WAT glucose uptake from baseline to 2 weeks of liothyronine. After 6 months, there was no change in HbA1c (8.3 ± 1.2 vs 9.1 ± 3.0%, P = 0.27), but there was increased whole-body glucose disposal (22.8 ± 4.9 vs 30.1 ± 10.0 µmol/kg lean body mass/min, P = 0.02), and muscle (0.7 ± 0.1 vs 2.0 ± 0.2 µmol/min/100 mL, P < 0.0001) and WAT glucose uptake (1.2 ± 0.2 vs 2.2 ± 0.3 µmol/min/100 mL, P < 0.0001). BAT glucose uptake could not be quantified because of small volume. There were no signs or symptoms of hyperthyroidism. CONCLUSION: Liothyronine administered at well-tolerated doses did not improve HbA1c. However, the observed increases in muscle and WAT glucose uptake support the proposed mechanism that liothyronine increases tissue glucose uptake. More selective agents may be effective at increasing tissue glucose uptake without thyroid hormone-related systemic toxicity.Clinical Trial Registration Number: NCT02457897; https://clinicaltrials.gov/ct2/show/NCT02457897.

Prevalence of Hypothyroidism in Patients With Erdheim-Chester Disease.

Importance: Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis affecting multiple organs and commonly caused by somatic pathogenic variants in BRAF V600E and mitogen-activated protein kinase genes. Clinical features of ECD result from histiocytic involvement of various tissues; while endocrine involvement in ECD occurs frequently, the prevalence of central or primary hypothyroidism has not been thoroughly investigated. Objective: To assess hypothalamus-pituitary-thyroid (HPT) dysfunction in patients with ECD. Design, Setting, and Participants: This cross-sectional study included 61 patients with ECD who were enrolled in a natural history study at a tertiary care center between January 2011 and December 2018. ECD was diagnosed on the basis of clinical, genetic, and histopathological features. Data were analyzed in March 2020. Exposure: Diagnosis of ECD. Main Outcomes and Measures: Main outcome was the prevalence of thyroid dysfunction in adults with ECD compared with community estimates. Patients underwent baseline evaluation with a thyroid function test, including thyrotropin, free thyroxine (fT4), and total thyroxine (T4), and sellar imaging with magnetic resonance imaging or computed tomography scan. The association of HPT dysfunction was assessed for differences in age, sex, body mass index, BRAF V600E status, high sensitivity C-reactive protein level, sellar imaging, and pituitary hormonal dysfunction. Results: A total of 61 patients with ECD (46 [75%] men; mean [SD] age, 54.3 [10.9] years) were evaluated. Seventeen patients (28%) had hypothyroidism requiring levothyroxine therapy. The prevalence of both central and primary hypothyroidism were higher than community estimates (central hypothyroidism: 9.8% vs 0.1%; odds ratio, 109.0; 95% CI, 37.4-260.6; P < .001; primary hypothyroidism: 18.0% vs 4.7%; OR, 4.4; 95% CI, 2.1-8.7; P < .001). Patients with hypothyroidism (both primary and central), compared with patients with euthyroidism, had higher body mass index (median [interquartile range] 31.4 [28.3-38.3] vs 26.7 [24.4-31.9]; P = .004) and a higher prevalence of panhypopituitarism (7 [47%] vs 3 [7%]; P < .001). Among patients with hypothyroidism, those with central hypothyroidism, compared with patients with primary hypothyroidism, had a lower mean (SD) body mass index (28.3 [2.6] vs 36.3 [5.9]; P = .007) and higher frequencies of abnormal sellar imaging (5 [83%] vs 3 [27%]; P = .050) and panhypopituitarism (5 [83%] vs 3 [27%]; P = .050). Conclusions and Relevance: In this cohort study, a higher prevalence of central and primary hypothyroidism was identified in patients with ECD compared with the community. There should be a low threshold for testing for hypothyroidism in patients with ECD, and treatment should follow standard guidelines.

Mitochondrial-Derived Peptides Are Down Regulated in Diabetes Subjects.

Background: Mitochondrial dysfunction is implicated in the pathogenesis of Type 2 diabetes (T2D) and the development of diabetes related complications such as cardiovascular disease and stroke. Mitochondria produce several small polypeptides that may influence mitochondrial function and may impact on insulin sensitivity, such as humanin (HN) and the mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) that are mitochondrial derived proteins (MDP). The aim of this study was to determine MDP in normal, prediabetes and diabetes subjects. Subjects and Measurements: In this cross-sectional study, we analyzed the serum concentrations of MDP and adiponectin (ADP) in 225 subjects: normal (n = 68), pre-diabetes (n = 33), T2D less than (good control; n = 31), and greater than HbA1c 7% (poor control; n = 93) subjects. The relationship of serum MDP and ADP concentrations with biochemical and anthropometric measurements were performed and assessed by multilinear regression. Results: Serum HN concentrations were lower in T2D (p < 0.0001) and negatively correlated with age (p < 0.0001), HbA1c (p < 0.0001), glucose (p < 0.0001), triglycerides (p < 0.003), ALT (p < 0.004), and TG/HDL ratio (p < 0.001). Circulating HN levels were positively correlated to cholesterol (p < 0.017), LDL (p < 0.001), and HDL (p < 0.001). Linear regression analysis showed that HbA1c and ALT were two independent predictors of circulating HN. Similarly, serum MOTS-c was significantly lower in T2D subjects compared to controls (p < 0.007). Circulating MOTS-c positively correlated with BMI (p < 0.035), total cholesterol (p < 0.0001), and LDL (p < 0.001) and negatively correlated with age (p < 0.002), HbA1c (p < 0.001), and glucose (p < 0.002). Serum ADP concentrations were lower in T2D (p < 0.002) and negatively correlated with HbA1c (p < 0.001), weight (p < 0.032) TG (p < 0.0001), and ALT (p < 0.0001); and positively correlated with HDL (p < 0.0001) and HN (p < 0.003). Linear regression analysis showed that HbA1c and weight were two independent predictors of circulating ADP. Multilinear regression showed that HN and MOT-c correlated with each other, and only HN correlated with HbA1c. Conclusion: The MDPs HN and MOT-c, similar to ADP, are decreased in T2D and correlate with HbA1c. The data provide an additional evidence that mitochondrial dysfunction contributes to glycemic dysregulation and metabolic defects in T2D.

Sweet taste perception is greater in non-Hispanic black than in non-Hispanic white adults.

OBJECTIVE: Research suggests a difference in sweet taste perception between non-Hispanic black (NHB) and non-Hispanic white (NHW) adults; however, limited research has examined sweet taste perception in relation to the dietary intake of sweet products. The aim of this study was to examine sweet taste perception and the consumption of sweet foods, beverages, and sugar in NHB and NHW adults, and to evaluate whether sweet taste perception is associated with dietary intake. METHODS: This cross-sectional study examined the association between race, sweet taste perception and sweet food, beverages, and sugar consumption in healthy, NHB and NHW adults. Seven day food records were analyzed in Nutrition Data System for Research software. Intensity of sweet taste perception was tested and the general labeled magnitude scale method was used to facilitate group comparisons. Independent t tests, Mann-Whitney tests, and Pearson correlations were used to assess associations. RESULTS: Participants were NHB (n = 98) and NHW (n = 90) adults, 41 ± 1 y of age (mean ± SEM) with energy intake of 2271 ± 53 kcal. Body mass index was higher in NHBs than in NHWs (36 ± 1 versus 32 ± 1 kg/m2, P = 0.048), but no differences were observed in age, energy consumption, or total sugar intake. Sweet taste perception rating (median [interquartile range] NHB: 73.5 [63.9-83], NHW: 52.1 [46.4-57.7]; P = 0.001) and added sugar intake (NHB: 39.4 g/1000 kcal [36.3-42.4], NHW: 30 g/1000 kcal [26.7-33.4]; P < 0.001) were greater in NHB. Perceived sweet taste intensity was positively associated with consumption of servings of sweet products among NHBs (R2 = 0.057, P = 0.018) but not NHWs (R2 = -0.012, P = 0.314). CONCLUSIONS: NHBs have a higher intensity of sweet taste perception than NHWs. The positive association of sweet taste perception and sweet product consumption in NHBs suggests that a higher intensity of sweet taste perception may be associated with an increased proportion of energy consumption from added sugars.

Predictive Accuracy of Surrogate Indices for Hepatic and Skeletal Muscle Insulin Sensitivity.

CONTEXT: Surrogate indices of muscle and hepatic insulin sensitivity derived from an oral glucose tolerance test (OGTT) are frequently used in clinical studies. However, the predictive accuracy of these indices has not been validated. DESIGN: In this cross-sectional study, hyperinsulinemic-euglycemic glucose clamp with tritiated glucose infusion and a 75-g OGTT were performed in individuals (n = 659, aged 18 to 49 years, body mass index of 16 to 64 kg/m2) with varying degrees of glucose tolerance. A calibration model was used to assess the ability of OGTT-derived, tissue-specific surrogate indices [hepatic insulin resistance index (HIRI) and muscle insulin sensitivity index (MISI)] to predict insulin sensitivity/resistance indices derived from the reference glucose clamp [Hepatic-IRbasal, a product of fasting plasma insulin and hepatic glucose production (HGP), Hepatic-IRclamp, reciprocal of the percent suppression of HGP during the insulin clamp corrected for plasma insulin concentration, and Muscle-ISclamp, a measure of peripheral glucose disposal]. Predictive accuracy was assessed by root mean squared error of prediction and leave-one-out, cross-validation-type square root of the mean squared error of prediction. RESULTS: HIRI and MISI were correlated with their respective clamp-derived indices. HIRI was negatively related to Muscle-ISclamp (r = -0.62, P < 0.0001) and MISI correlated with Hepatic-IR derived from the clamp (Hepatic-IRbasal: r = -0.48, P < 0.0001 and Hepatic-IRclamp: r = -0.41, P < 0.0001). However, the accuracy of HIRI and MISI to predict Hepatic-IR (basal or during clamp) was not significantly different. Likewise, the ability of HIRI and MISI to predict Muscle-ISclamp was also similar. CONCLUSION: Our findings indicate that the surrogate indices derived from an OGTT are accurate in predicting insulin sensitivity but are not tissue specific.

Thyroid Abnormalities in Patients With Extreme Insulin Resistance Syndromes.

CONTEXT: Insulin and leptin may increase growth and proliferation of thyroid cells, underlying an association between type 2 diabetes and papillary thyroid cancer (PTC). Patients with extreme insulin resistance due to lipodystrophy or insulin receptor mutations (INSR) are treated with high-dose insulin and recombinant leptin (metreleptin), which may increase the risk of thyroid neoplasia. OBJECTIVE: The aim of this study was to analyze thyroid structural abnormalities in patients with lipodystrophy and INSR mutations and to assess whether insulin, IGF-1, and metreleptin therapy contribute to the thyroid growth and neoplasia in this population. DESIGN: Thyroid ultrasound characteristics were analyzed in 81 patients with lipodystrophy and 11 with INSR (5 homozygous; 6 heterozygous). Sixty patients were taking metreleptin. RESULTS: The prevalence of thyroid nodules in children with extreme insulin resistance (5 of 30, 16.7%) was significantly higher than published prevalence for children (64 of 3202; 2%), with no difference between lipodystrophy and INSR. Body surface area-adjusted thyroid volume was larger in INSR homozygotes vs heterozygotes or lipodystrophy (10.4 ± 5.1, 3.9 ± 1.5, and 6.2 ± 3.4 cm2, respectively. Three patients with lipodystrophy and one INSR heterozygote had PTC. There were no differences in thyroid ultrasound features in patients treated vs not treated with metreleptin. CONCLUSION: Children with extreme insulin resistance had a high prevalence of thyroid nodules, which were not associated with metreleptin treatment. Patients with homozygous INSR mutation had thyromegaly, which may be a novel phenotypic feature of this disease. Further studies are needed to determine the etiology of thyroid abnormalities in patients with extreme insulin resistance.