Subclinical thyroid dysfunction is defined by serum thyroid-stimulating hormone (TSH) levels either greater or less than the reference range with normal thyroxine (T4) concentrations, and consists of subclinical hypothyroidism (SCH) and subclinical hyperthyroidism (SCHyper). For the proper diagnosis of SCH, it is most important to be able to correctly evaluate the serum TSH levels, which have numerous unique characteristics. We also need to be versed in TSH harmonization, which was recently launched world-wide. In this review, we will attempt to determine the best clinical approaches to the treatment of subclinical thyroid dysfunction based on recent guidelines published from several countries and novel findings of several recent large-scale clinical studies.
Adipose tissue is a complex heterogeneous tissue composed of adipocytes along with several non-adipocyte populations, including blood, stromal, endothelial, and progenitor cells, as well as extracellular matrix (ECM) components. As obesity progresses, the adipose tissue expands dynamically through adipocyte hypertrophy and/or hyperplasia. This expansion requires continuous ECM remodeling to properly accommodate the size increase as well as functional changes. Upon reaching a hypertrophic threshold beyond the adipocyte buffering capacity, excess ECM components are deposited, causing fibrosis and ultimately resulting in unhealthy metabolic maladaptation. These complex ECM remodeling processes in adipose tissues are regulated by the local environment, several key mediators, and genetic factors that are closely linked to insulin sensitivity. It is crucial to understand how adipocytes interact with nonadipocyte populations and various mediators (i.e., immune cells, ECM components, and adipokines) during these processes. This mini-review provides an overview of the latest research into the biology of obesity-induced adipose tissue fibrosis and its related clinical manifestations, providing insight for further studies aimed at controlling metabolic syndrome and its comorbidities.
Dynamic remodeling of adipose tissue plays a critical role in the pathophysiology of obesity disease. In this article, Dr. Yutaka Hasegawa elegantly updates the research on the molecular mechanism whereby adipocytes interact with non-adipocytes during the course of adipose dysfunction and fibrosis in obesity. This review does provide us with invaluable perspective for endocrinology-based obesity science.
This study evaluated scar satisfaction in Arabic patients who underwent thyroidectomy surgery using validated assessment tools. We aimed to assess the relationship between scar length and scar satisfaction, and validate Arabic versions of the universally used scar satisfaction questionnaires. In this retrospective cohort study, 60 patients who underwent thyroidectomy at King Abdulaziz University Hospital were enrolled. Scars were evaluated in two stages: firstly, by a clinician, and secondly, by a naïve observer. Ratings of disfigurement were measured using the validated Patient and Observer Scar Assessment Scale (POSAS) that was translated into Arabic. Results: The Arabic version of the POSAS showed good or excellent reliability. Average POSAS scores were 12.88, 18.02, and 7.53, respectively, indicating that most patients were satisfied. Incision size and POSAS scores (but not Patient and Naïve Observer scores) were positively correlated, and larger incisions resulted in greater dissatisfaction. Fitzpatrick Skin Type score and Observer scores were positively correlated, but there were no significant correlations between Patient and Naïve Observer scores with skin type. In conclusion, this study validated the Arabic version of universally used questionnaires for scar satisfaction. Most patients were satisfied with their neck scars regardless of scar length. Our findings pave the way for further research into patient postoperative scar satisfaction in Arabic-speaking populations.
Thyroid tumors arising from follicular cells can generally be divided into malignant and benign tumors. However, some cases are difficult to clearly diagnose whether they are benign or malignant. Therefore, in the most recent version of World Health Organization (WHO) classification, some borderline lesions such as follicular tumor of uncertain malignant potential (FT-UMP), well-differentiated tumor of uncertain malignant potential (WDT-UMP), and noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) were proposed. In this study, we investigated the clinical aspects, including the prognosis, of FT-UMP patients. We investigated the clinical features of 339 patients with FT-UMP. On ultrasound, 68% of the tumors were diagnosed as intermediate, and only 5% of those tumors were diagnosed as malignant. On cytology, 40% of the tumors were diagnosed as follicular neoplasm, and only 1% of these were suspected to be or diagnosed as malignancy. The diagnosis was based on questionable capsular invasion for 332 patients, questionable vascular invasion for 2 patients, and both for 5 patients. Eighty-six percent of the tumors showed low cell proliferation activity. To date, five patients (1%) have shown distant recurrence during postoperative follow-up and underwent various treatments such as radioactive iodine therapy, orthopedic surgery, and denosumab injection. None of these patients have died due to thyroid carcinoma. Our findings suggest that FT-UMP is generally an indolent disease, but some patients show distant recurrence. Physicians should carefully follow patients, although it remains unknown how long they should be observed after surgery.
This study aimed to retrospectively compare the clinical efficacy of different types of long-acting insulin therapies—glargine U100, glargine U300, degludec, and insulin degludec/insulin aspart—among Japanese patients with type 2 diabetes after insulin use was initiated in an outpatient setting. The study consisted of 822 insulin-naïve patients in Japan who started using long-acting insulin for treatment of type 2 diabetes and continued for over 12 months. In addition, the impact of insulin type on insulin withdrawal was investigated by dividing the participants into two groups: those who achieved insulin withdrawal and those who did not, during the 12-month observation period based on a Cox proportional hazards model. As a result, HbA1c was decreased, and BMI was increased in all participants regardless of the insulin type used. A total of 185 participants succeeded in insulin withdrawal. After adjustment was made for several confounders, the positive determinant factors for withdrawal were short duration of diabetes and the choice of IDegAsp when compared with Gla100; the negative determinant factor was use of insulin secretagogues at the start of the study. In conclusion, all long-acting insulins were a powerful tool for treatment of type 2 diabetes, and patients with short duration of diabetes and/or no usage of insulin secretagogues resulted in favorable outcomes in terms of insulin withdrawal within a year in an outpatient setting. In addition, insulin degludec/insulin aspart was found to possibly be a better choice for treatment when it was compared with glargine U100 among the four types of insulin.
Our study aimed to investigate the C-peptide-releasing effect associated with the risk of elevated serum uric acid (SUA) levels in patients with type 2 diabetes mellitus (T2DM). In the cross-sectional study, 345 patients with T2DM hospitalized at the First Affiliated Hospital of Harbin Medical University were consecutively enrolled, and their baseline data were collected. The study design used two parameters for C-peptide releasing effects: the multiplication effect of 1 h postprandial C-peptide to fasting C-peptide ratio (1hCp/FCp) and 2hCp/FCp; the incremental effect of 1hCp minus FCp (1hΔCp) and 2hΔCp. The patients with T2DM in the upper quartiles of SUA had higher FCp, 1hCp, 1hΔCp, 2hCp, and 2hΔCp. Multiple linear regression analysis revealed that after adjusting all the confounding factors, the serum C-peptide including 1hCp (β = 5.14, p = 0.036), 1hΔCp (β = 7.80, p = 0.010), 2hCp (β = 4.27, p = 0.009) and 2hΔCp (β = 5.20, p = 0.005) were still positively correlated with SUA levels in patients with T2DM. In female patients, only the 2hCp (β = 4.78, p = 0.017) and 2hΔCp (β = 5.28, p = 0.019) were associated with SUA level; however, in male patients, no C-peptide parameter was associated with SUA levels in T2DM (all p > 0.05). Within a certain range, the elevated SUA levels might be associated with the better C-peptide incremental effect of islet β cell function in T2DM, especially in female patients.
Cardiovascular morbidity and mortality rates are considered to be high in patients with diabetes despite negative stress test results; however, little data are available to support this supposition. We compared the long-term cardiovascular events between patients with diabetes and those without diabetes with negative treadmill stress echocardiography and evaluated the predictors for cardiovascular events in patients with diabetes. A total of 1,243 consecutive patients (mean age, 56 ± 10 years; non-diabetics: diabetics, 975:268; mean follow-up of 5 years) with negative treadmill stress echocardiography were evaluated. Clinical data were examined, and major adverse cardiovascular events (MACEs, a composite of coronary revascularization, acute myocardial infarction, and cardiovascular death) were compared between the non-diabetic and diabetic groups. In the population matched by clinical characteristics, the diabetic and non-diabetic groups had similar occurrence of MACEs (non-diabetics vs. diabetics = 5% versus 7%; p = 0.329) and event-free survival. MACEs in the diabetic group were associated with elevated early diastolic velocity of the mitral inflow/mitral annulus (E/e') ratio, indicative of diastolic dysfunction. The absence of statin and dipeptidyl peptidase-4 inhibitor use and use of sulfonylureas were also predictors of more MACEs. In conclusion, long-term cardiovascular events in patients with diabetes and negative stress echocardiography were comparable to those in patients without diabetes. However, appropriate monitoring of diastolic dysfunction, statin use, and individualized antidiabetic drug selection are required to reduce the cardiovascular risk in patients with diabetes.
Prenatal and postnatal biphasic increases in plasma testosterone levels derived from perinatal testes are considered critical for defeminizing/masculinizing the brain mechanism that regulates sexual behavior in male rats. Hypothalamic kisspeptin neurons are indispensable for stimulating GnRH and downstream gonadotropin, as well as the consequent testicular testosterone production/release in adult male rats. However, it is unclear whether kisspeptin is responsible for the increase in plasma testosterone levels in perinatal male rats. The present study aimed to investigate the role of Kiss1/kisspeptin in generating perinatal plasma LH and the consequent testosterone increase in male rats by comparing the plasma testosterone and LH profiles of wild-type (Kiss1+/+) and Kiss1 knockout (Kiss1–/–) male rats. A biphasic pattern of plasma testosterone levels, with peaks in the prenatal and postnatal periods, was found in both Kiss1+/+ and Kiss1–/– male rats. Postnatal plasma testosterone and LH levels were significantly lower in Kiss1–/– male rats than in Kiss1+/+ male rats, whereas the levels in the prenatal embryonic period were comparable between the genotypes. Exogenous kisspeptin challenge significantly increased plasma testosterone and LH levels and the number of c-Fos-immunoreactive GnRH neurons in neonatal Kiss1–/– and Kiss1+/+ male rats. Kiss1 and Gpr54 (kisspeptin receptor gene) were found in the testes of neonatal rats, but kisspeptin treatment failed to stimulate testosterone release in the cultured testes of both genotypes. These findings suggest that postnatal, but not prenatal, testosterone increase in male rats is mainly induced by central kisspeptin-dependent stimulation of GnRH and consequent LH release.
Recent compelling evidence has shown that neck circumference (NC), as a reliable and convenient anthropometric index, has better predictive values of hyperuricemia and insulin resistance in women with polycystic ovary syndrome (PCOS) compared with traditional anthropometric measurements. Since both PCOS and metabolic syndrome (MetS) share similar characteristics and affect long-term health of women, we conducted this cross-sectional study to explore the correlation of NC with MetS and metabolic risk factors. Anthropometric parameters, blood pressure, glycemic and lipid profile of 633 PCOS and 2,172 non-PCOS women from January 2018 to June 2021 were analyzed. The results showed that the prevalence of MetS was 28.0% and 9.4% in PCOS and non-PCOS women, respectively. The prevalence of MetS, hypertention, obesity, central obesity, hyperglycemia and dyslipidaemia was also significantly higher in both PCOS and non-PCOS women with larger NC. Additionally, logistic regression analysis showed that PCOS women in the highest quartile of NC had the highest prevalence of MetS (RR = 9.94, 95%CI: 2.41–40.99) after adjusting for confounding factors, while the association between NC and MetS was much attenuated after adjusting for confounding factors in non-PCOS women. Furthermore, we also identified that the optimal NC cutoff value was 33 cm in PCOS women for the prediction of MetS. The potential mechanism could be attributed to the increased release of adipokines and excessive free fatty acids release from subcutaneous adipose tissue, which consequently precipitate the development of MetS. In conclusion, NC was found to be positively and independently correlated with the prevalence of MetS.
Exercise has beneficial effects on metabolic syndrome (MS). However, the exercise prescriptions that best support plasma glucose and lipid control remain unknown. We evaluated the effects of different combinations of aerobic and resistance training programs on plasma glucose and lipid metabolism and sleep quality in elderly MS patients. Eighty-five elderly MS patients were randomly assigned to five groups: aerobic training (AT), resistance training (RT), high aerobic with low resistance training (HALRT), high resistance with low aerobic training (HRLAT), or control. The exercise groups performed supervised moderate-intensity exercise during three 50-min sessions per week for 12 weeks. Body mass index (BMI), waist circumference (WC), systolic blood pressure (SBP), diastolic blood pressure (DBP), handgrip strength (HGS), fasting plasma glucose (FPG), 2-hour postprandial blood glucose (2hPG), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) levels and sleep quality were evaluated at baseline and after 12 weeks. All intervention groups showed significant improvements in SBP, HGS, FPG, 2hPG, and Pittsburgh Sleep Quality Index (PSQI) scores compared to baseline (all p < 0.05), while DBP, TC, TG, and LDL-C levels were significantly improved only in the HRLAT and HALRT groups (p < 0.05). The HALRT group showed the largest improvements in WC, SBP, DBP, HGS, FPG, 2hPG, and PSQI score (p < 0.001). The largest improvements in BMI, TC, and LDL-C were observed in the HRLAT group (p < 0.001). The combined exercise prescriptions were more effective than aerobic or resistance training alone at improving plasma glucose and lipid metabolism and sleep quality in elderly MS patients.
Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder that causes gonadotropin-releasing hormone (GnRH) deficiency and sexual immaturity. CHH may accompany an abnormal sense of smell (Kallmann syndrome, KS) or no such manifestation (normosmic-CHH). This unusual combination of manifestations is explained by the fact that GnRH neurons originate in the olfactory placode and migrate to the forebrain during embryogenesis. We describe the case of a 31-year-old man with normosmic-CHH, who also had obesity, type 2 diabetes and intellectual disability. He was noticed to have sexual immaturity (small testes with no pubic hair) at age 20 years, when diabetic ketoacidosis developed. Basal and GnRH-stimulated levels of LH (1.0→12.0 IU/L) and FSH (1.9→6.1 IU/L) were detectable but low. The results of the T&T olfactometer and the Alinamin test were definitely normal, with an anatomically normal olfactory system on MRI. Sequencing of 22 CHH-related genes was performed, and compound heterozygous PROKR2 variants were identified: one was a previously known loss-of-function variant (p.Trp178Ser) and the other was a nonsense variant (p.Trp212*). Through a literature review, we found 22 patients (including our patient) with CHH due to biallelic PROKR2 variants, which led us to recognize that most of the patients (86%) were diagnosed with KS. Clinical observations in this study indicate that, even though they have CHH, biallelic PROKR2 variant carriers may have a normal olfactory system as well as presumably normal migration of GnRH neurons. This suggests that the PROK2-PROKR2 pathway affects the function of GnRH neurons after their migration.
Evidence about the relationship between Helicobacter pylori (Hp) infection and type 2 diabetes mellitus (T2DM) is inconsistent and contradictory. This study attempted to investigate this association in the middle-aged and elderly Chinese population and analyze the joint effects of Hp infection and some risk factors on T2DM. Following a cross-sectional design, participants were recruited from the First Affiliated Hospital of Anhui Medical University in Hefei City, China. Hp status was measured using a 14C urea breath test. A total of 1,288 participants, including 90 diabetic patients and 1,198 nondiabetic subjects, were recruited in the current study. The participants with T2DM had a greater prevalence of Hp infection than participants without T2DM (26.67% versus 18.11%, p = 0.045). Furthermore, we found that Hp infection was closely associated with an incremental risk of T2DM [odds ratio (OR) = 1.77, 95% confidence intervals (CI): 1.04–3.00] after adjustment for potential confounders. In addition, we observed that the participants who were Hp-positive and ≥60 years old (OR = 9.16, 95% CI: 3.29–25.52), Hp-positive and obese (OR = 3.35, 95% CI: 1.57–7.14) or Hp-positive and hypertensive (OR = 6.10, 95% CI: 3.10–12.01) had a significantly higher risk for T2DM than those who were Hp-negative and ≤50 years old, Hp-negative and nonobese or Hp-negative and nonhypertensive. These findings imply that Hp infection is associated with an increased risk of T2DM in the middle-aged and elderly Chinese population. The association could be further elevated by the combination of Hp infection and some traditional risk factors.
Numerous studies have examined the role of autophagy in thyroid cancer treatment; however there are discrepancies among the reported data, with some showing the pro-survival and others the anti-survival effects of autophagy. These discrepant results appear to be at least in part due to insufficient analyses or data misinterpretation as well as improper assessments of autophagic activity. Therefore, the present study re-evaluated the regulation of autophagic activity by various anticancer modalities and examined the role of autophagy in thyroid cancer treatment in three thyroid cancer cell lines (TPC1, ACT1 and KTC1). The immunofluorescence and DalGreen findings demonstrated that cisplatin, irradiation and sorafenib were all autophagy inducers as previously reported, but, unlike previous studies using thyroid cancer cells, doxorubicin acted as an inhibitor. KTC1 cells are unique because they only responded to cisplatin. The efficacy of anticancer therapeutics was significantly higher in chloroquine or 3-methyladenine-treated autophagy-defective cells than in autophagy-competent cells, thereby indicating the pro-survival effect of autophagy induced by anticancer therapeutics, which is partly due to inhibition of apoptosis. Thus, the present findings relating to several anticancer therapeutics and three thyroid cancer cell lines demonstrate the pro-survival effect of autophagy in thyroid cancer treatment. Although the present study only involved cell lines, it provides evidence for the beneficial combination of the anticancer therapeutic modalities with autophagy inhibitors, and proposes that autophagy inhibitors may serve as a possible adjunctive therapy for thyroid cancer.
Polycystic ovary syndrome (PCOS) is a common gynecological disease accompanied by a variety of clinical features, including anovulation, hyperandrogenism, and ovarian abnormalities, resulting in infertility. PCOS affects approximately 6%–15% of all reproductive-age women worldwide. Metformin, a popular drug used to treat PCOS in patients, has beneficial effects in reducing hyperandrogenism and inducing ovulation; however, the mechanisms by which metformin ameliorates PCOS are not clear. Hence, we aimed to explore the mechanisms of metformin in treating PCOS. In the present study, we first treated a letrozole-induced PCOS rat model with metformin, detected the pathological recovery of PCOS, and then assessed the effects of metformin on H2O2-induced autophagy in ovarian granulosa cells (GCs) by detecting the level of oxidative stress and the expression of autophagy-associated proteins and key proteins in the PI3K/AKT/mTOR pathway. We demonstrated that metformin ameliorated PCOS in a rat model by downregulating autophagy in GCs, and metformin decreased the levels of oxidative stress and autophagy in H2O2-induced GCs and affected the PI3K/AKT/mTOR signaling pathway. Taken together, our results indicate that metformin ameliorates PCOS in a rat model by decreasing excessive autophagy in GCs via the PI3K/AKT/mTOR pathway, and this study provides evidence for targeted reduction of excessive autophagy of ovarian granulosa cells and improvement of PCOS.