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Journal Cover Journal of Clinical Endocrinology & Metabolism
  [SJR: 2.94]   [H-I: 287]   [167 followers]  Follow
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   ISSN (Print) 0021-972X - ISSN (Online) 1945-7197
   Published by Endocrine Society, The Homepage  [4 journals]
  • CORRIGENDUM FOR “1,5-Anhydroglucitol in Saliva Is a Noninvasive Marker
           of Short-Term Glycemic Control”
    • Abstract: In the above-named article by Mook-Kanamori DO, El-Din Selim MM, Takiddin AH, Al-Homsi H, Al-Mahmoud KAS, Al-Obaidli A, Zirie MA, Rowe J, Yousri NA, Karoly ED, Kocher T, Gherbi WS, Chidiac OM, Mook-Kanamori MJ, Abdul Kader S, Al Muftah WA, McKeon C, Suhre K (J Clin Endocrinol Metab. 99(3):E479–E483, 2014; doi: 10.1210/jc.2013-3596), the following omission occurred in the published paper: The attached Supplemental Table 1 should have been included with the published article.
      PubDate: 2017-10-06
  • Development and Risk Factors of Type 2 Diabetes in a Nationwide Population
           of Women With Polycystic Ovary Syndrome
    • Authors: Rubin K; Glintborg D, Nybo M, et al.
      Abstract: AbstractObjectivePolycystic ovary syndrome (PCOS) is associated with insulin resistance and obesity. Prospective population-based data regarding development and possible predictors of type 2 diabetes (T2D) in PCOS are limited.DesignNational Patient Register–based study.MethodsPatients with PCOS [PCOS Denmark and embedded cohort, PCOS Odense University Hospital (OUH)] and a control population with no previous diagnosis of T2D. PCOS OUH (N = 1,162) included premenopausal women with PCOS and standardized clinical and biochemical examination. PCOS Denmark (N = 18,477) included women with PCOS in the Danish National Patient Register. Three age-matched controls were included per patient (N = 54,680).Main outcomeT2D events according to diagnosis codes and filled medicine prescriptions.ResultsThe median (quartiles) follow-up was 11.1 (6.9 to 16.0) years. The hazard ratio (HR) with 95% confidence interval (CI) for development of T2D in PCOS Denmark was HR = 4.0 (95% CI, 3.7 to 4.3; P < 0.001), and the total event rate of T2D was 8.0 per 1000 person years in PCOS Denmark vs 2.0 per 1000 person years in controls (P < 0.001). The median age at diagnosis of T2D was 31 (26 to 37) years in PCOS Denmark vs 35 (27 to 44) years in controls (P < 0.001). In multiple regression analyses, body mass index, glycated hemoglobin, fasting blood glucose, 2-hour blood glucose, homeostasis model assessment of insulin resistance, and triglycerides were positively associated with development of T2D, whereas higher number of births was negatively associated with development of T2D.ConclusionThe event rate of T2D was higher in PCOS compared with controls, and T2D was diagnosed at a younger age.
      PubDate: 2017-08-29
  • Roux-en-Y Gastric Bypass Surgery Has Unique Effects on Postprandial FGF21
           but Not FGF19 Secretion
    • Authors: Harris L; Smith G, Mittendorfer B, et al.
      Abstract: AbstractContextFibroblast growth factor (FGF)19 and FGF21 are secreted by the intestine and liver in response to macronutrient intake. Intestinal resection and reconstruction via bariatric surgery may alter their regulation.ObjectiveWe tested the hypothesis that weight loss induced by Roux-en-Y gastric bypass (RYGB) surgery, but not matched weight loss induced by laparoscopic adjustable gastric banding (LAGB), increases postprandial plasma FGF19 and FGF21 concentrations.DesignGlucose kinetics and plasma FGF19 and FGF21 responses to mixed meal ingestion and to glucose-insulin infusion during a hyperinsulinemic-euglycemic clamp procedure, with stable isotope tracer methods, were evaluated in 28 adults with obesity before and after 20% weight loss induced by RYGB (n = 16) or LAGB (n = 12).ResultsLAGB- and RYGB-induced weight loss increased postprandial plasma FGF19 concentrations (P < 0.05). However, weight loss after RYGB, but not LAGB, increased postprandial plasma FGF21 concentrations (1875 ± 330 to 2976 ± 682 vs 2150 ± 310 and 1572 ± 265 pg/mL × 6 hours, respectively). The increase in plasma FGF21 occurred ∼2 hours after the peak in delivery of ingested glucose into systemic circulation. Glucose-insulin infusion increased plasma FGF21, but not FGF19, concentrations. The increase in plasma FGF21 during glucose-insulin infusion was greater after than before weight loss in both surgery groups without a difference between groups, whereas plasma FGF19 was not affected by either procedure.ConclusionsRYGB-induced weight loss has unique effects on postprandial FGF21 metabolism, presumably due to rapid delivery of ingested macronutrients to the small intestine and delivery of glucose to the liver.
      PubDate: 2017-08-17
  • Ovarian Aging in Women With BRCA Germline Mutations
    • Authors: Lin W; Titus S, Moy F, et al.
      Abstract: AbstractContextRecent clinical and laboratory studies suggested that women with BRCA mutations have lower ovarian reserve and their primordial follicle oocytes may be more prone to DNA damage; however, direct proof is lacking.ObjectiveTo determine whether women with germline BRCA mutations have reduced primordial follicle reserve and increased oocyte DNA damage.DesignA comparative laboratory study of ovarian tissue obtained from unaffected BRCA mutation carriers (BMCs) vs age-matched organ donor cadavers.SettingTwo academic centers.Patients or Other ParticipantsOf the 230 ovarian specimens from BMCs, 18 met the study inclusion criteria. Healthy ovaries from 12 organ donor cadavers served as controls.InterventionHistology and immunohistochemical analysis on paraffin-embedded ovarian sections.Main Outcome Measure(s)Primordial follicle density and the percentage of DNA double-strand break (DSB)−positive primordial follicle oocytes.ResultsOvaries from BMCs had significantly lower primordial follicle densities than those of controls (11.2 ± 2.0 vs 44.2 ± 6.2 follicles/mm3; P = 0.0002). BRCA mutations were associated with increased DNA DSBs in primordial follicle oocytes (62% ± 5.2% vs 36% ± 3.4%; P = 0.0005). In subgroup analyses, both BRCA1 and BRCA2 mutations were associated with lower primordial follicle density (P = 0.0001 and 0.0030, respectively), and BRCA1 mutations were associated with higher DNA DSBs (P = 0.0003) than controls. The rates of follicle decline (R2 = 0.74; P = 0.0001) and DNA DSB accumulation (R2 = 0.70; P = 0.0001) appeared to be accelerated, particularly in primordial follicle oocytes of BMCs over age 30 years.ConclusionsWe provide direct evidence of diminished ovarian reserve as well as accelerated primordial follicle loss and oocyte DNA damage in women with BRCA mutations. These findings may further our understanding of ovarian aging, and be useful when counseling BMCs.
      PubDate: 2017-08-16
  • Nocturnal Urinary Excretion of FSH and LH in Children and Adolescents With
           Normal and Early Puberty
    • Authors: Kolby N; Busch A, Aksglaede L, et al.
      Abstract: AbstractContextClinical use of single serum gonadotropin measurements in children is limited by the pulsatile secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). However, first morning voided (FMV) urine may integrate the fluctuating gonadotropin serum levels.ObjectiveWe aimed to evaluate urinary and serum gonadotropin levels according to age, sex, and pubertal stage in healthy children and to assess the clinical use of FMV urinary gonadotropins in children with disordered puberty.DesignCross-sectional part of the COPENHAGEN Puberty Study and longitudinal study of patients.SettingPopulation-based and outpatient clinic.Patients or Other ParticipantsEight hundred forty-three healthy children from the COPENHAGEN Puberty Study and 25 girls evaluated for central precocious puberty (CPP).Main Outcome MeasuresClinical pubertal staging, including serum and urinary gonadotropin levels.ResultsUrinary gonadotropins increased with advancing age and pubertal development and were detectable in FMV urine before physical signs of puberty. FMV urinary LH correlated strongly with basal (r = 0.871, P < 0.001) and gonadotropin-releasing hormone (GnRH)-stimulated serum LH (r = 0.82, P < 0.001). Urinary LH was superior to urinary FSH in differentiating the pubertal stage. Receiver operating curve analysis revealed that a cut-off standard deviation (SD) score of 2 for urinary LH (IU/L) gave a sensitivity of 75% and a specificity of 92% in predicting a positive GnRH stimulation test (LHmax > 5 IU/L). Urinary concentrations of LH decreased after 3 months of GnRH treatment to levels below +2 SDs.ConclusionsUrinary gonadotropin levels increased before the onset of puberty and were elevated in girls with CPP. We suggest urinary LH as an alternative noninvasive method to improve diagnosing and therapeutic management of children with disordered puberty.
      PubDate: 2017-08-15
  • Letter to the Editor: “Type B Insulin Resistance Masquerading as
           Ovarian Hyperthecosis”
    • Authors: Azziz R.
      Abstract: Brown et al. (1) report on an interesting case of a patient who developed insulin receptor autoantibodies and whose testosterone was able to be normalized with the use of a long-acting gonadotropin-releasing hormone (GnRH) analog. Their case report suggests that although increased circulating insulin can result in ovarian hyperandrogenemia, gonadotropins, presumably luteinizing hormone (LH), are necessary for this steroidogenic effect. It is unclear from this incidental observation, however, to what degree is gonadotropin suppression necessary to negate, in part or in whole, the effect of insulin on ovarian androgen production.
      PubDate: 2017-08-14
  • Serum Insulin Bioassay Reflects Insulin Sensitivity and Requirements in
           Type 1 Diabetes
    • Authors: Janssen J; Llauradó G, Varewijck A, et al.
      Abstract: AbstractContextInsulin resistance could increase insulin requirements in type 1 diabetes (T1D). Current insulin immunoassays do not detect insulin analogs. Kinase insulin receptor (IR) activation (KIRA) bioassays specific for human IR isoforms A (IR-A) and B (IR-B) permit assessment of all circulating insulin bioactivity. We studied whether IR-A and IR-B KIRA assays are related to direct measures of insulin sensitivity or insulin doses in T1D.DesignWe evaluated 31 adult patients with T1D (age 45.7 ± 1.6 years, body mass index 28.8 ± 0.7 kg/m2). Serum IR-A and IR-B bioactivities were measured by KIRA bioassays. Insulin sensitivity of glucose production (Ra) was measured by the euglycemic hyperinsulinemic clamp technique in which a low insulin dose (0.4 mU/kg/min for 240 minutes) was combined with D-[3-3H] glucose infusion to measure rates of Ra and utilization and insulin action on antilipolysis from suppression of serum free fatty acids.ResultsBaseline circulating IR-A bioactivity was 53 ± 7 pmol/L, and IR-B bioactivity was 81 ± 11 pmol/L. Compared with baseline, insulin infusion significantly increased IR-A (P < 0.001) and IR-B (P < 0.001) bioactivities. Fasting IR-A and IR-B bioactivities were positively related to endogenous Ra (r = 0.44, P = 0.01 and r = 0.38, P < 0.05). Fasting IR-A (r = 0.43, P = 0.02) and IR-B (r = 0.47, P = 0.01) bioactivities were significantly correlated with insulin requirements and glycosylated hemoglobin (IR-A: r = 0.52, P = 0.002; IR-B: r = 0.48, P = 0.006).ConclusionsCirculating IR-A and IR-B bioactivities are associated with insulin resistance, high insulin requirements, and poor glycemic control in T1D. Measurement of IR bioactivity by KIRA assays provides a tool to assess the amount of biologically active insulin in groups of T1D patients treated with insulin analogs.
      PubDate: 2017-08-14
  • Effect of Preconception Impaired Glucose Tolerance on Pregnancy Outcomes
           in Women With Polycystic Ovary Syndrome
    • Authors: Wei D; Zhang B, Shi Y, et al.
      Abstract: AbstractContextWomen with polycystic ovary syndrome (PCOS) commonly have intrinsic insulin resistance and are recommended to undergo an oral glucose tolerance test (OGTT) for diabetes screening. However, the effect of preconception impaired glucose tolerance (IGT) on pregnancy is still unclear.ObjectiveTo prospectively assess the effect of preconception IGT on pregnancy outcomes.Design, Setting, Patients, Interventions, and Main Outcome MeasuresThis was a secondary analysis of a multicenter randomized trial in 1508 women with PCOS comparing live birth and obstetric complications between fresh and frozen embryo transfer. At baseline, fasting and 2-hour glucose and insulin levels after 75-g OGTT were measured.ResultsWomen with preconception IGT had higher risks of gestational diabetes in both singleton pregnancy [9.5% vs 3.2%; odds ratio (OR) 3.13; 95% confidence interval (CI) 1.23to 7.69] and twin pregnancy (20.0% vs 3.2%; OR 7.69; 95% CI 2.78 to 20.00) than women with normoglycemia. Preconception IGT was associated with a higher risk of large for gestational age in singleton newborns compared with normoglycemia (34.7% vs 19.8%; OR 2.13; 95% CI 1.19 to 3.85) or isolated impaired fasting glucose (i-IFG) (34.7% vs 15.4%; OR 2.94; 95% CI 1.33 to 6.25). Women with preconception IGT had a higher singleton pregnancy loss rate than women with i-IFG (31.4% vs 17.5%; OR 2.17; 95% CI 1.11 to 4.17). After adjusting for age, body mass index, duration of infertility, total testosterone level, and treatment groups (frozen vs fresh embryo transfer), these associations remained.ConclusionsPreconception IGT, independent from BMI, was associated with adverse pregnancy outcome compared with i-IFG and normoglycemia.
      PubDate: 2017-08-14
  • Prenatal Diagnosis of Resistance to Thyroid Hormone and Its Clinical
    • Authors: Pappa T; Anselmo J, Mamanasiri S, et al.
      Abstract: AbstractContextResistance to thyroid hormone-β (RTH-β) is an autosomal dominant disorder characterized by reduced sensitivity of target tissues to thyroid hormones (THs). Individuals with RTH-β have high TH levels usually due to mutations in the TH receptor-β (THRB) gene. The management of RTH-β during pregnancy is challenging, as wild-type (WT) fetuses born to RTH-β mothers have low birth weight and suppressed postnatal thyroid-stimulating hormone (TSH), due to intrauterine exposure to excess TH.ObjectiveTo determine birth weight and postnatal TSH of WT fetuses carried by mothers with RTH-β whose fT4 levels were maintained below 20% of the upper limit of normal (ULN).DesignRetrospective chart review.SettingAcademic institution in collaboration with off-site hospitals and private practices.PatientsThirteen women harboring THRB gene mutations were evaluated during 18 pregnancies.InterventionPrenatal genetic diagnosis by amniocentesis. Women carrying WT fetuses were given the option of treatment with antithyroid medication by their treating physicians with the aim to avoid serum fT4 levels above 20% of the ULN.ResultsNo significant difference was found in birth weight corrected for gestational age and in serum TSH levels at birth between WT and RTH-β infants born to RTH-β mothers.ConclusionsPrenatal diagnosis may play an important role in the management of RTH-β during pregnancy. Aiming for maternal fT4 levels not above 50% of the ULN in RTH-β mothers carrying WT fetuses seems to be a prudent approach that prevents the otherwise expected low birth weight and postnatal TSH suppression.
      PubDate: 2017-08-04
  • Bile Acid Alterations Are Associated With Insulin Resistance, but Not With
           NASH, in Obese Subjects
    • Authors: Legry V; Francque S, Haas J, et al.
      Abstract: AbstractContextBile acids (BAs) are signaling molecules controlling energy homeostasis that can be both toxic and protective for the liver. BA alterations have been reported in obesity, insulin resistance (IR), and nonalcoholic steatohepatitis (NASH). However, whether BA alterations contribute to NASH independently of the metabolic status is unclear.ObjectiveTo assess BA alterations associated with NASH independently of body mass index and IR.Design and SettingPatients visiting the obesity clinic of the Antwerp University Hospital (a tertiary referral facility) were recruited from 2006 to 2014.PatientsObese patients with biopsy-proven NASH (n = 32) and healthy livers (n = 26) were matched on body mass index and homeostasis model assessment of IR.Main Outcome MeasuresTranscriptomic analyses were performed on liver biopsies. Plasma concentrations of 21 BA species and 7α-hydroxy-4-cholesten-3-one, a marker of BA synthesis, were determined by liquid chromatography–tandem mass spectrometry. Plasma fibroblast growth factor 19 was measured by enzyme-linked immunosorbent assay.ResultsPlasma BA concentrations did not correlate with any hepatic lesions, whereas, as previously reported, primary BA strongly correlated with IR. Transcriptomic analyses showed unaltered hepatic BA metabolism in NASH patients. In line, plasma 7α-hydroxy-4-cholesten-3-one was unchanged in NASH. Moreover, no sign of hepatic BA accumulation or activation of BA receptors—farnesoid X, pregnane X, and vitamin D receptors—was found. Finally, plasma fibroblast growth factor 19, secondary-to-primary BA, and free-to-conjugated BA ratios were similar, suggesting unaltered intestinal BA metabolism and signaling.ConclusionsIn obese patients, BA alterations are related to the metabolic phenotype associated with NASH, especially IR, but not liver necroinflammation.
      PubDate: 2017-08-04
  • Long-Term Natural Course of Small Nonfunctional Pancreatic Neuroendocrine
           Tumors in MEN1—Results From the Dutch MEN1 Study Group
    • Authors: Pieterman C; de Laat J, Twisk J, et al.
      Abstract: AbstractBackgroundPancreatic neuroendocrine tumors (pNETs) are highly prevalent in patients with multiple endocrine neoplasia type 1 (MEN1), and metastatic disease is an important cause of MEN1-related mortality. Especially small nonfunctional (NF) pNETs pose a challenge to the treating physician and more information is needed regarding their natural course. We assessed long-term natural history of small NF-pNETs and its modifiers in the Dutch MEN1 population.Patients and MethodsRetrospective longitudinal observational cohort study of patients with small (<2 cm) NF-pNETs from the Dutch national MEN1 database, which includes >90% of the Dutch MEN1 population. Modifiers of long-term natural course were analyzed using linear mixed-models analysis.ResultsGrowth rate of the 115 included small NF-pNETs from 99 patients was slow (0.4 mm/y; 95% confidence interval, 0.15 to 0.59). Seventy percent of the tumors was stable and a subgroup of 30% of the tumors was growing (1.6 mm/y; 95% confidence interval, 1.1 to 2.0). No differences in clinical characteristics were identified between growing and stable tumors. Within the subgroup of growing tumors, germline missense mutations were significantly associated with accelerated growth compared with nonsense and frameshift mutations.ConclusionThe majority of small NF-pNETs are stable at long-term follow-up, irrespective of the underlying MEN1 genotype. A subgroup of tumors is slowly growing but cannot be identified on clinical grounds. In this subgroup, tumors with missense mutations exhibited faster growth. Additional events appear necessary for pNETs to progress. Future studies should be aimed at identifying these molecular driving events, which could be used as potential biomarkers.
      PubDate: 2017-08-04
  • FGF21 Is an Insulin-Dependent Postprandial Hormone in Adult Humans
    • Authors: Samms R; Lewis J, Norton L, et al.
      Abstract: AbstractContextFibroblast growth factor 21 (FGF21) secretion has been shown to respond directly to carbohydrate consumption, with glucose, fructose, and sucrose all reported to increase plasma levels of FGF21 in rodents and humans. However, carbohydrate consumption also results in secretion of insulin.ObjectiveThe aim of this study was to examine the combined and independent effects of hyperglycemia and hyperinsulinemia on total and bioactive FGF21 in the postprandial period in humans, and determine whether this effect is attenuated in conditions of altered insulin secretion and action.MethodsCirculating glucose, insulin, total and bioactive FGF21, and fibroblast activation protein were measured in adults with and without type 2 diabetes (T2D) following an oral glucose tolerance test (OGTT), and under a series of insulin and glucose clamp conditions and following high-fat diet in healthy adults.ResultsCirculating total and bioactive FGF21 levels responded acutely to OGTT, and their ratio was attenuated in T2D patients with reduced postprandial insulin response. The clamp studies revealed that insulin but not glucose accounts for the postprandial rise in FGF21. Finally, there was an attenuated rise in FGF21 in response to a high-fat dietary intervention that is known to alter insulin-stimulated substrate utilization in metabolically active tissues.ConclusionsInsulin rather than glucose per se increases total and bioactive FGF21 in the postprandial period in adult humans. Understanding the impact of T2D on bioactive FGF21 will have a significant effect upon the efficacy of therapeutic agents designed to target the FGF21 pathway.
      PubDate: 2017-08-04
  • Growth Hormone and the Epithelial-to-Mesenchymal Transition
    • Authors: Brittain A; Basu R, Qian Y, et al.
      Abstract: AbstractContextPrevious studies have implicated growth hormone (GH) in the progression of several cancers, including breast, colorectal, and pancreatic. A mechanism by which GH may play this role in cancer is through the induction of the epithelial-to-mesenchymal transition (EMT). During the EMT process, epithelial cells lose their defining phenotypes, causing loss of cellular adhesion and increased cell migration. This review aims to carefully summarize the previous two decades of research that points to GH as an initiator of EMT, in both cancerous and noncancerous tissues.Evidence AcquisitionSources were collected using PubMed and Google Scholar search engines by using specific GH- and/or EMT-related terms. Identified manuscripts were selected for further analysis based on presentation of GH-induced molecular markers of the EMT process in vivo or in vitro.Evidence SynthesisCellular mechanisms involved in GH-induced EMT are the focus of this review, both in cancerous and noncancerous epithelial cells.ConclusionsOur findings suggest that a myriad of molecular mechanisms are induced by GH that cause EMT and may point to potential therapeutic use of GH antagonists or any downregulator of GH action in EMT-related disease.
      PubDate: 2017-08-04
  • Associations Between Systemic and Local Corticosteroid Use With Metabolic
           Syndrome and Body Mass Index
    • Authors: Savas M; Muka T, Wester V, et al.
      Abstract: AbstractContextUse of systemic corticosteroids (CSs) may induce adverse cardiometabolic alterations, potentially leading to obesity and metabolic syndrome (MetS). Although evidence is accumulating that local CSs have considerable systemic effects, their effects on cardiometabolic factors in the general population remain unclear.ObjectiveTo investigate the association between overall CS use and specific CS types with MetS, body mass index (BMI), and other cardiometabolic traits.DesignCross-sectional cohort study.SettingGeneral population from the northern Netherlands.ParticipantsA total of 140,879 adult participants in the population-based Lifelines Cohort Study.Main Outcome MeasuresBMI, waist circumference, systolic and diastolic blood pressure, fasting metabolic serum parameters, and a comprehensive set of potential confounding factors.ResultsIn women, overall, systemic, and local CS use was associated with higher odds of having MetS. Among local female users, only nasal (odds ratio [OR], 1.20 [95% confidence interval (CI), 1.06 to 1.36]) and inhaled CSs [OR, 1.35 (95% CI, 1.24 to 1.49)] users were more likely to have MetS. In men, no association was found between overall and specific CS use and presence of MetS. Use of local-only CSs in women, specifically inhaled CSs in both sexes, was associated with higher BMI.ConclusionsUse of local CSs, particularly inhaled types, as well as systemic CSs, was associated with higher likelihood of having MetS, higher BMI, and other adverse cardiometabolic traits, especially among women. Because the inhaled agents are the main group of prescribed CSs, this might be a substantial risk to public health in case of a yet-to-be-proven causal relationship.
      PubDate: 2017-08-02
  • Managing Menopausal Symptoms and Associated Clinical Issues in Breast
           Cancer Survivors
    • Authors: Santen R; Stuenkel C, Davis S, et al.
      Abstract: AbstractObjectiveReview evidence to guide management of menopausal signs and symptoms in women after breast cancer and make recommendations accordingly.EvidenceRandomized controlled clinical trials, observational studies, evidence-based guidelines, and expert opinion from professional societies.BackgroundSymptoms and clinical problems associated with estrogen depletion—sleep disorders, vulvovaginal atrophy (VVA), vasomotor symptoms (VMS), mood changes, depressive symptoms, cardiovascular disease, osteopenia, and osteoporosis—confront the estimated 9.3 million breast cancer survivors globally.RecommendationsFollowing breast cancer, women should not generally be treated with menopausal hormone therapy or tibolone but should optimize lifestyle. Women with moderate to severe symptoms may benefit from mind–brain behavior or nonhormone, pharmacologic therapy. The selective serotonin/noradrenaline reuptake inhibitors and gabapentenoid agents improve VMS and quality of life. For osteoporosis, nonhormonal agents are available. Treatment of VVA remains an area of unmet need. Low-dose vaginal estrogen is absorbed in small amounts with blood levels remaining within the normal postmenopausal range but could potentially stimulate occult breast cancer cells, and although poorly studied, is not generally advised, particularly for those on aromatase inhibitors. Intravaginal dehydroepiandrosterone and oral ospemiphene have been approved to treat dyspareunia, but safety after breast cancer has not been established. Vaginal laser therapy is being used for VVA but efficacy from sham-controlled studies is lacking. Therapies undergoing development include lasofoxifene, neurokinin B inhibitors, stellate ganglion blockade, vaginal testosterone, and estetrol.ConclusionsNonhormone options and therapies are available for treatment of estrogen depletion symptoms and clinical problems after a diagnosis of breast cancer. Individualization of treatment is essential.
      PubDate: 2017-08-02
  • HbA 1c Identifies Subjects With Prediabetes and Subclinical Left
           Ventricular Diastolic Dysfunction
    • Authors: Di Pino A; Mangiafico S, Urbano F, et al.
      Abstract: AbstractContextPrediabetes is associated with subclinical cardiac changes associated with heart failure development.ObjectiveWe investigated diastolic function and its association with markers of glycation and inflammation related to cardiovascular disease in patients with prediabetes. We focused on individuals with prediabetes identified only by glycated hemoglobin A1c [HbA1c; 5.7% to 6.4% and normal fasting glucose (NFG) and normal glucose tolerance (NGT) after an oral glucose tolerance test (OGTT)].DesignCross-sectional study.SettingDepartments of Clinical and Experimental Medicine and Cardiology, University of Catania, Catania, Italy.Main Outcome MeasuresHbA1c, OGTT, Doppler echocardiography, soluble receptor for advanced glycation end products (sRAGEs), and endogenous secretory RAGE (esRAGE) were evaluated.PatientsWe recruited 167 subjects with NFG/NGT who were stratified according to HbA1c level: controls (HbA1c <5.7%) and HbA1c prediabetes (HbA1c 5.7% to 6.4%).ResultsPatients with HbA1c prediabetes (n = 106) showed a lower peak mitral inflow in early diastole (E wave) to late diastolic atrial filling velocity (A wave) ratio (E/A ratio) than controls (n = 61) (1.10 ± 0.24 vs 1.18 ± 0.23; P < 0.05). They showed a higher left atrium volume (LAV) (28.4 ± 5 vs 22.1 ± 3; P < 0.05) and sphericity index (SI) (0.6 ± 0.06 vs 0.5 ± 0.05; P < 0.05). After multiple regression analyses, HbA1c, sRAGE, and esRAGE were the major determinants of E/A ratio, LAV, and SI.ConclusionsSubjects with HbA1c prediabetes exhibited subclinical cardiac alterations associated with sRAGE, esRAGE, and HbA1c. These subjects would not have been classified as having prediabetes on the basis of fasting glycemia or post-OGTT values.
      PubDate: 2017-08-01
  • Third Trimester Estrogens and Maternal Breast Cancer: Prospective Evidence
    • Authors: Cohn B; Cirillo P, Hopper B, et al.
      Abstract: AbstractContextFull-term pregnancy is associated with a transient increase and life-time decrease in maternal breast cancer risk. Estrone (E1), estradiol (E2), and estriol (E3) are in high concentration during the third trimester. E1 and E2 metabolism produces carcinogenic intermediaries, and E3 metabolism does not.ObjectiveWe tested the hypothesis that higher E3 in pregnancy is protective while higher E1 plus E2 increases risk.DesignProspective case-cohort study (n = 620; 204 cases) nested in a 38-year follow-up of 15,528 pregnant women in the Child Health and Development Studies. We measured E1, E2, and E3 in archived third trimester serum and estimated associations with breast cancer.SettingNorthern California Kaiser members receiving obstetric care from 1959 to 1967.Main Outcome MeasureBreast cancer diagnosed through 1997.ResultsDoubling of E1+E2 was associated with greater risk [hazard ratio (HR), 1.7; 95% confidence interval (CI), 1.2 to 2.4]. In contrast, doubling of E3 or the E3/E1+E2 ratio was associated with protection (HR, 0.7; 95% CI, 0.5 to 1.0; HR, 0.6; 95% CI, 0.4 to 0.8, respectively). Associations were stronger for diagnoses within 15 years after delivery compared with 16 to 38 years (Pinteraction = 0.0002) for gravidas >27 years at delivery vs ≤27 (Pinteraction = 0.01) and for primiparas vs multiparas (Pinteraction = 0.02).ConclusionsRelatively high third trimester E3 levels might protect parous women from breast cancer and E1 and E2 might enhance the risk. If findings are confirmed, third trimester pregnancy estrogens could help explain how parity affects breast cancer.
      PubDate: 2017-07-28
  • Differential Impact of Glucose Administered Intravenously and Orally on
           Circulating miR-375 Levels in Human Subjects
    • Authors: Yan X; Wang Z, Westberg-Rasmussen S, et al.
      Abstract: AbstractBackgroundTo date, numerous nucleic acid species have been detected in the systemic circulation including microRNAs (miRNAs); however, their functional role in this compartment remains unclear.ObjectiveThe aim of this study was to determine whether systemic levels of miRNAs abundant in blood, including the neuroendocrine tissue-enriched miR-375, are altered in response to a glucose challenge.DesignTwelve healthy males were recruited for an acute crossover study that consisted of two tests each following an 8-hour fasting period. An oral glucose tolerance test (OGTT) was performed, and blood samples were collected over a 3-hour period. Following a period of at least 1 week, the same participants were administered an isoglycemic intravenous glucose infusion (IIGI) with the same blood-collection protocol.ResultsThe glucose response curve following the IIGI mimicked that obtained after the OGTT, but as expected, systemic insulin levels were lower during the IIGI compared with the OGTT (P < 0.05). miR-375 levels in circulation were increased only in response to an OGTT and not during an IIGI. In addition, the response to the OGTT also coincided with the transient increase of circulating glucagon-like peptide (GLP)-1, GLP-2, and glucose-dependent insulinotropic polypeptide.ConclusionsThe present findings show levels of miR-375 increase following administration of an OGTT and, in light of its enrichment in cells of the gut, suggest that the gastrointestinal tract may play an important role in the abundance and function of this miRNA in the blood.
      PubDate: 2017-07-28
  • Roux-en-Y Gastric Bypass Surgery in the Management of Familial Partial
           Lipodystrophy Type 1
    • Authors: Melvin A; Adams C, Flanagan C, et al.
      Abstract: AbstractContextFamilial partial lipodystrophy type 1 (FPLD1) is an extreme form of central adiposity, with peripheral lipodystrophy associated with severe manifestations of the metabolic syndrome, often poorly responsive to standard therapeutic approaches. Body mass index in FPLD1 varies but, in many cases, is below the level at which metabolic surgery is usually considered as a therapeutic option.DesignWe detailed the metabolic response to gastric bypass surgery of three patients with FPLD1, refractory to medical therapy.ResultsRoux-en-Y gastric bypass (RYGB) was associated with weight loss and substantial improvements in glycemic control and insulin sensitivity. All three patients were able to stop using insulin. Glucose tolerance testing in one patient demonstrated an increase in L-cell–derived gut hormone responses postoperatively.ConclusionRYGB surgery substantially improved glycemic control in three patients with FPLD1, two of whom had body mass indices below 30 kg/m2. RYGB should be considered in patients with partial lipodystrophy and refractory metabolic disease.
      PubDate: 2017-07-26
  • Association of Glycemic Control With Reduced Risk for Large-Vessel Disease
           After More Than 50 Years of Type 1 Diabetes
    • Authors: Tinsley L; Kupelian V, D’Eon S, et al.
      Abstract: AbstractContextPreviously we demonstrated, in individuals who have had type 1 diabetes (T1D) for 50 or more years (Medalists), that glycemic control was unrelated to diabetic complications, with the exception of cardiovascular disease (CVD), contrary to what has been documented in registry-based studies.ObjectiveThe purpose of this study is to validate these initial findings and identify contributors to mortality on an individual basis in a large cohort.DesignCross-sectional and longitudinal study.SettingJoslin Diabetes Center (JDC), Boston, Massachusetts.Patients50-year Medalists presenting to JDC for study participation.InterventionsNone.Main Outcomes MeasuresMicrovascular and macrovascular complications of diabetes and mortality.ResultsGlycemic control was not significantly associated with small-vessel complications in Medalists but was associated with CVD in the overall cohort, yet with varying effect by tertile of cohort duration. CVD was the largest contributor to mortality, whereas hemoglobin A1c was not an independent predictor of mortality either overall or substantially by diagnosis interval. Additionally, exercise mitigated mortality risk imparted by CVD.ConclusionsFew large populations with long duration of (T1D) have been available to examine the effects of long-term exposure to hyperglycemia. These data indicate that an association of glycemic control, complications, and mortality may change in an older population with T1D. These results suggest that careful control is still warranted in older populations with T1D.
      PubDate: 2017-07-26
  • Physical Activity and Improvement of Glycemia in Prediabetes by Different
           Diagnostic Criteria
    • Authors: Færch K; Witte D, Brunner E, et al.
      Abstract: AbstractContextThe effects of physical activity (PA) on improvement of glycemia may differ between prediabetic individuals defined by oral glucose tolerance test vs glycated hemoglobin (HbA1c).ObjectiveWe studied the association between PA and improvement of glycemia in individuals with prediabetes defined by glucose vs HbA1c criteria.Design, Setting, and ParticipantsFrom the Whitehall II study, 957 participants with prediabetes defined by isolated impaired fasting glucose (i-IFG), isolated impaired glucose tolerance (i-IGT), or both and 457 with prediabetes defined by HbA1c were included.Main Outcome MeasuresThe associations of PA with concomitant changes in glucose-related outcomes during 5 years of follow-up were analyzed. A recursive partitioning analysis was performed to study heterogeneity in the association between baseline PA and the probability of reversion to normoglycemia.ResultsAfter 5 years of follow-up, 405 (42%) individuals with glucose-defined prediabetes reverted to normal glucose tolerance (NGT). A 5-year increase in moderate-to-vigorous-intensity PA was associated with improvements in insulin sensitivity and β-cell function, but PA was not generally associated with reversion to NGT. Only among women ≥50 years with i-IFG or i-IGT, higher amounts of PA were associated with higher probability of reversion to NGT. In HbA1c-defined prediabetes, only 20 individuals (4.4%) reverted to normoglycemia, and PA was not associated with improvement in glycemic markers.ConclusionsPA may be particularly important for reversion to normoglycemia among older women with i-IFG or i-IGT. Individuals with prediabetes identified by HbA1c have a low probability of reversion to normoglycemia, and their changes in glycemia are not related to PA.
      PubDate: 2017-07-26
  • Bone Turnover Markers After Sleep Restriction and Circadian Disruption: A
           Mechanism for Sleep-Related Bone Loss in Humans
    • Authors: Swanson C; Shea S, Wolfe P, et al.
      Abstract: AbstractContextSleep abnormalities are associated with low bone mineral density. Underlying mechanisms are unknown.ObjectiveInvestigate the impact of sleep restriction with circadian disruption on bone biomarkers.DesignIntervention study.Participants and MethodsFour bone biomarkers [C-terminal cross-linked telopeptide of type I collagen (CTX) = bone resorption, N-terminal propeptide of type I procollagen (P1NP) = bone formation, sclerostin and fibroblast growth factor 23 = osteocyte function] were measured in bihourly serum samples over 24 hours at baseline and after ∼3 weeks of sleep restriction (5.6 hours sleep/24 hours) with concurrent circadian disruption (recurring 28-hour “day” in dim light) in 10 men (age groups: 20 to 27 years, n = 6; 55 to 65 years, n = 4). The effects of sleep/circadian disruption and age on bone biomarker levels were evaluated using maximum likelihood estimation in a mixed model for repeated measures.ResultsP1NP levels were lower after intervention compared with baseline (P < 0.001); the decrease in P1NP was greater for younger compared with older men (28.0% vs 18.2%, P < 0.001). There was no change in CTX (Δ = 0.03 ± 0.02 ng/mL, P = 0.10). Sclerostin levels were higher postintervention in the younger men only (Δ = 22.9% or 5.64 ± 1.10 pmol/L, P < 0.001).ConclusionsThese data suggest that 3 weeks of circadian disruption with concurrent sleep restriction can lead to an uncoupling of bone turnover wherein bone formation is decreased but bone resorption is unchanged. Circadian disruption and sleep restriction may be most detrimental to bone in early adulthood.
      PubDate: 2017-07-26
  • Vitamin D Stored in Fat Tissue During a 5-Year Intervention Affects Serum
           25-Hydroxyvitamin D Levels the Following Year
    • Authors: Martinaityte I; Kamycheva E, Didriksen A, et al.
      Abstract: AbstractContextVitamin D and 25-hydroxyvitamin D [25(OH)D] are stored in adipose tissue, but the clinical relevance is uncertain.ObjectiveTo evaluate changes in serum 25(OH)D and adipose tissue vitamin D levels after stopping vitamin D supplementation.DesignA prospective, double-blind cohort follow-up study.SettingClinical Research Unit at University Hospital of North Norway.PatientsSeventy-six subjects were included after participation in a 3- to 5-year prevention of type 2 diabetes study and were administered 20,000 IU of vitamin D or placebo per week.InterventionDuring the 12-month follow-up period, blood samples were drawn at the beginning and after 1, 3, 6, 9, and 12 months. Fat biopsies were taken at the start and end.Main Outcome MeasuresChanges in 25(OH)D level in serum and 25(OH)D and vitamin D levels in adipose tissue.ResultsForty-one of 42 subjects who were given vitamin D and 33 of 34 subjects who were given placebo completed the study. At the inclusion, mean serum 25(OH)D levels were 122 and 71 nmol/L in the vitamin D and placebo groups, respectively. Serum 25(OH)D levels were significantly higher in the vitamin D group than in the placebo group throughout and were 84.5 and 73.1 nmol/L, respectively, after 12 months. In the vitamin D group, adipose tissue vitamin D levels decreased by 52% over 12 months.ConclusionVitamin D and 25(OH)D stored in adipose tissue after 3 to 5 years of vitamin D supplementation may have a clinically relevant effect on serum 25(OH)D level the following year.
      PubDate: 2017-07-26
  • Association Between Gut Microbiota and Bone Health: Potential Mechanisms
           and Prospective
    • Authors: Chen Y; Greenbaum J, Shen H, et al.
      Abstract: AbstractContextIt has been well established that the human gut microbiome plays a critical role in the regulation of important biological processes and the mechanisms underlying numerous complex diseases. Although researchers have only recently begun to study the relationship between the gut microbiota and bone metabolism, early efforts have provided increased evidence to suggest an important association.Evidence AcquisitionIn this study, we attempt to comprehensively summarize the relationship between the gut microbiota and bone metabolism by detailing the regulatory effects of the microbiome on various biological processes, including nutrient absorption and the intestinal mucosal barrier, immune system functionality, the gut–brain axis, and excretion of functional byproducts. In this review, we incorporate evidence from various types of studies, including observational, in vitro and in vivo animal experiments, as well as small efficacy clinic trails.Evidence SynthesisWe review the various potential mechanisms of influence for the gut microbiota on the regulation of bone metabolism and discuss the importance of further examining the potential effects of the gut microbiota on the risk of osteoporosis in humans. Furthermore, we outline some useful tools/approaches for metagenomics research and present some prominent examples of metagenomics association studies in humans.ConclusionCurrent research efforts, although limited, clearly indicate that the gut microbiota may be implicated in bone metabolism, and therefore, further exploration of this relationship is a promising area of focus in bone health and osteoporosis research. Although most existing studies investigate this relationship using animal models, human studies are both needed and on the horizon.
      PubDate: 2017-07-26
  • Pituitary Tumor Suppression by Combination of Cabergoline and Chloroquine
    • Authors: Lin S; Wu Z, Cao L, et al.
      Abstract: AbstractContextThe dopamine agonist cabergoline (CAB) has been used widely in the treatment of prolactinomas and other types of pituitary adenomas, but its clinical use is hampered by intolerance in some patients with prolactinoma and lack of effectiveness in other pituitary tumor types. Chloroquine (CQ) is an old drug widely used to treat malaria. Recent studies, including our own, have revealed that CAB and CQ are involved in induction of autophagy and activation of autophagic cell death.ObjectiveTo test whether CAB and CQ can function cooperatively to suppress growth of pituitary adenomas as well as other cancers.ResultsIn vitro studies using the rat pituitary tumor cell lines MMQ and GH3, human pituitary tumor cell primary cultures, and several human cancer cell lines showed that CQ enhanced suppression of cell proliferation by CAB. These results were confirmed in in vivo xenograft models in nude mice and estrogen-induced rat prolactinomas. To understand the mechanism of combined CAB and CQ action, we established a low-CAB-dose condition in which CAB was able to induce autophagy but failed to suppress cell growth. Addition of CQ to low-dose CAB blocked normal autophagic cycles and induced apoptosis, evidenced by the further accumulation of p62/caspase-8/LC3-II.ConclusionThe data suggest that combined use of CAB and CQ may increase clinical effectiveness in treatment of human pituitary adenomas, as well as other cancers, making it an attractive option in tumor and cancer therapies.
      PubDate: 2017-07-20
  • Identification of Mutations in Cell-Free Circulating Tumor DNA in
           Adrenocortical Carcinoma: A Case Series
    • Authors: Creemers S; Korpershoek E, Atmodimedjo P, et al.
      Abstract: AbstractContextThe disease course of adrenocortical carcinoma (ACC) patients is heterogeneous. A marker for prognosis and treatment response would facilitate choices for diagnosis and therapy. In other cancer types, circulating cell-free tumor DNA predicted tumor dynamics.Case DescriptionsThe present pilot study included six patients. Next-generation sequencing (NGS) showed mutations in three ACC cases. From these patients, blood was drawn before (1 to 2 weeks) and after surgery and cell-free circulating DNA (cfDNA) was isolated. Tumor-specific mutations were found in the cfDNA of one of the three patients, with metastasized ACC at diagnosis. NGS of the tumor showed an NRAS mutation (c.182A>G:p.Q61R) in 78%, a TP53 mutation (c.856G>A:p.E286K) in 60%, and a TERT gene mutation (1295250C>T) in 28% of the reads. The preoperative cfDNA showed the same mutations at a frequency of 64%, 32%, and 2%, respectively. The postoperative cfDNA showed the same mutations but at lower frequencies (52%, 16%, and 3%, respectively). The patient was postoperatively treated with mitotane and chemotherapy. No mutations were detected in the corresponding leukocyte DNA or in the cfDNA from the two other patients.ConclusionsTo the best of our knowledge, we report for the first time mutations occurring at high levels in cfDNA collected before and after surgery from one of three patients, after previous identification in the tumor. However, in the cfDNA from two patients with known mutations, we were unable to reliably detect mutations in the cfDNA. Our results indicate that mutation detection in cfDNA can vary among ACC patients, and other approaches might be required to detect the tumor response and monitor progressive disease.
      PubDate: 2017-06-30
  • Plasma Leucine-Rich α -2-Glycoprotein 1 Predicts Rapid eGFR Decline and
           Albuminuria Progression in Type 2 Diabetes Mellitus
    • Authors: Liu J; Pek S, Ang K, et al.
      Abstract: AbstractContextAbnormal angiogenesis plays an important role in pathogenesis of diabetic kidney disease (DKD). Leucine-rich α-2 glycoprotein 1 (LRG1) is a newly identified angiogenic factor.ObjectiveTo study whether plasma LRG1 may independently predict progression of DKD in individuals with type 2 diabetes mellitus (T2DM).Design and SettingProspective cohort study in a regional hospital.PatientsIn total, 1226 T2DM participants were followed for a mean ± standard deviation (SD) of 3.1 ± 0.4 years.Main OutcomesAlbuminuria progression was defined as elevation in albuminuria level to a higher category. Chronic kidney disease (CKD) progression [rapid estimated glomerular filtration rate (eGFR) decline] was defined as a 40% or greater deterioration in eGFR in 3 years.ResultsBoth participants with albuminuria progression and those with CKD progression had higher plasma LRG1 levels at baseline. LRG1 independently predicted albuminuria progression above traditional risk factors, including baseline eGFR and urine albumin to creatinine ratio. A 1-SD increment in LRG1 was associated with a 1.26-fold [95% confidence interval (CI), 1.04 to 1.53, P = 0.018] higher adjusted risk for albuminuria progression. The association of LRG1 with microalbuminuria to macroalbuminuria progression was stronger than its association with normoalbuminuria to microalbuminuria progression [odds ratio (OR), 1.51; 95% CI, 1.04 to 2.18, P = 0.029 vs OR, 1.09; 95% CI, 0.86 to 1.37, P = 0.486, per 1-SD LRG1 increment]. Also, LRG1 independently predicted CKD progression above traditional risk factors. A 1-SD increment in LRG1 was associated with a 1.48-fold (95% CI, 1.04 to 2.11, P = 0.032) higher adjusted risk for CKD progression.ConclusionsPlasma LRG1 predicts both albuminuria and CKD progression beyond traditional risk factors. It may play a role in the pathologic pathway leading to progression of DKD in T2DM.
      PubDate: 2017-06-30
  • Overnight Closed-Loop Control Improves Glycemic Control in a Multicenter
           Study of Adults With Type 1 Diabetes
    • Authors: Brown S; Breton M, Anderson S, et al.
      Abstract: AbstractContextClosed-loop control (CLC) for the management of type 1 diabetes (T1D) is a novel method for optimizing glucose control, and strategies for individualized implementation are being developed.ObjectiveTo analyze glycemic control in an overnight CLC system designed to “reset” the patient to near-normal glycemic targets every morning.DesignRandomized, crossover, multicenter clinical trial.ParticipantsForty-four subjects with T1D requiring insulin pump therapy.InterventionSensor-augmented pump therapy (SAP) at home vs 5 nights of CLC (active from 23:00 to 07:00) in a supervised outpatient setting (research house or hotel), with a substudy of 5 nights of CLC subsequently at home.Main Outcome MeasureThe percentage of time spent in the target range (70 to 180 mg/dL measured using a continuous glucose monitor).ResultsForty subjects (age, 45.5 ± 9.5 years; hemoglobin A1c, 7.4% ± 0.8%) completed the study. The time in the target range (70 to 180 mg/dL) significantly improved in CLC vs SAP over 24 hours (78.3% vs 71.4%; P = 0.003) and overnight (85.7% vs 67.6%; P < 0.001). The time spent in a hypoglycemic range (<70 mg/dL) decreased significantly in the CLC vs SAP group over 24 hours (2.5% vs 4.3%; P = 0.002) and overnight (0.9% vs 3.2%; P < 0.001). The mean glucose level at 07:00 was lower with CLC than with SAP (123.7 vs 145.3 mg/dL; P < 0.001). The substudy at home, involving 10 T1D subjects, showed similar trends with an increased time in target (70 to 180 mg/dL) overnight (75.2% vs 62.2%; P = 0.07) and decreased time spent in the hypoglycemic range (<70 mg/dL) overnight in CLC vs SAP (0.6% vs 3.7%; P = 0.03).ConclusionOvernight-only CLC increased the time in the target range over 24 hours and decreased the time in hypoglycemic range over 24 hours in a supervised outpatient setting. A pilot extension study at home showed a similar nonsignificant trend.
      PubDate: 2017-06-28
  • Type 2 Diabetes and Osteoporosis: A Guide to Optimal Management
    • Authors: Paschou S; Dede A, Anagnostis P, et al.
      Abstract: AbstractContextBoth type 2 diabetes (T2D) and osteoporosis are affected by aging and quite often coexist. Furthermore, the fracture risk in patients with T2D is increased. The aim of this article is to review updated information on osteoporosis and fracture risk in patients with T2D, to discuss the effects of diabetes treatment on bone metabolism, as well as the effect of antiosteoporotic medications on the incidence and control of T2D, and to provide a personalized guide to the optimal management.Evidence AcquisitionA systematic literature search for human studies was conducted in three electronic databases (PubMed, Cochrane, and EMBASE) until March 2017. Regarding recommendations, we adopted the grading system introduced by the American College of Physicians.Evidence SynthesisThe results are presented in systematic tables. Healthy diet and physical exercise are very important for the prevention and treatment of both entities. Metformin, sulfonylureas, dipeptidyl peptidase-4 inhibitors, and glucagon-like peptide-1 receptor agonists should be preferred for the treatment of T2D in these patients, whereas strict targets should be avoided for the fear of hypoglycemia, falls, and fractures. Insulin should be used with caution and with careful measures to avoid hypoglycemia. Thiazolidinediones and canagliflozin should be avoided, whereas other sodium-dependent glucose transporter 2 inhibitors are less well-validated options. Insulin therapy is the preferred method for achieving glycemic control in hospitalized patients with T2D and fractures. The treatment and monitoring of osteoporosis should be continued without important amendments because of the presence of T2D.ConclusionsPatients with coexisting T2D and osteoporosis should be managed in an optimal way according to scientific evidence.
      PubDate: 2017-06-21
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