Early identification of postoperative remission for thyrotropin-secreting adenomas.

OBJECTIVE: Thyrotropin-secreting adenoma (TSHoma) is a rare type of pituitary adenoma, occurring in one per million people. Little is known about TSHoma. We summarized the demographic, clinical and hormonal characteristics of TSHoma based on a single-centre experience. Moreover, we explored the predictive value of postoperative thyroid function for long-term remission. DESIGN, PATIENTS AND MEASUREMENTS: We retrospectively analysed 63 patients who were diagnosed as TSHoma and surgically treated at our hospital from January 2015 to June 2021. The preoperative clinical characteristics were analysed and compared between remission and nonremission groups. Thyroid function was measured at 1 day, 1 month, 3 months, 6 months, 12 months and over 12 months after surgery to determine whether they could predict long-term remission. RESULTS: The male to female ratio for TSHoma was 1.25. The mean age at diagnosis was 45 ± 12 years. Clinical presentation was varied, presenting with hyperthyroidism (68.25%), space-occupying effect (15.87%), amenorrhea (7.14% of female patients) and nonsymptoms (22.22%). 88.14% of patients achieved postoperative endocrinological remission. Larger tumour size and tumour invasion into cavernous sinus and suprasellar with chiasmal compression were strong predictors of lower rates of endocrinological remission. Postoperative thyroid function at 3 months was a viable diagnostic predictor for postoperative remission, especially for FT4 level with a 20.65 pmol/L cutoff. CONCLUSIONS: Tumour size and extent are major prognostic factors for remission. Postoperative thyroid function at 3 months could be used as a clinical prediction tool for long-term endocrinological remission.

Association of IGF-1 Level with Low Bone Mass in Young Patients with Cushing's Disease.

Purpose: Few related factors of low bone mass in Cushing's disease (CD) have been identified so far, and relevant sufficient powered studies in CD patients are rare. On account of the scarcity of data, we performed a well-powered study to identify related factors associated with low bone mass in young CD patients. Methods: This retrospective study included 153 CD patients (33 males and 120 females, under the age of 50 for men and premenopausal women). Bone mineral density (BMD) of the left hip and lumbar spine was measured by dual energy X-ray absorptiometry (DEXA). In this study, low bone mass was defined when the Z score was -2.0 or lower. Results: Among those CD patients, low bone mass occurred in 74 patients (48.37%). Compared to patients with normal BMD, those patients with low bone mass had a higher level of serum cortisol at midnight (22.31 (17.95-29.62) vs. 17.80 (13.75-22.77), p=0.0006), testosterone in women (2.10 (1.33-2.89) vs. 1.54 (0.97-2.05), p=0.0012), higher portion of male (32.43% vs. 11.54%, p=0.0016) as well as hypertension (76.12% vs. 51.67%, p=0.0075), and lower IGF-1 index (0.59 (0.43-0.76) vs. 0.79 (0.60-1.02), p=0.0001). The Z score was positively associated with the IGF-1 index in both the lumbar spine (r = 0.35153, p < 0.0001) and the femoral neck (r = 0.24418, p=0.0057). The Z score in the femoral neck was negatively associated with osteocalcin (r = -0.22744, p=0.0229). Compared to the lowest tertile of the IGF-1 index (<0.5563), the patients with the highest tertile of the IGF-1 index (≥0.7993) had a lower prevalence of low bone mass (95% CI 0.02 (0.001-0.50), p=0.0002), even after adjusting for confounders such as age, gender, duration, BMI, hypertension, serum cortisol at midnight, PTH, and osteocalcin. Conclusions: The higher IGF-1 index was independently associated with lower prevalence of low bone mass in young CD patients, and IGF-1 might play an important role in the pathogenesis of CD-caused low bone mass.

The recovery time of hypothalamic-pituitary-adrenal axis after curative surgery in Cushing's disease and its related factor.

PURPOSE: Patients with Cushing's disease (CD) experienced transient central adrenal insufficiency (CAI) after successful surgery. However, the reported recovery time of hypothalamic-pituitary-adrenal (HPA) axis varied and the related factors which could affect recovery time of HPA axis had not been extensively studied. This study aimed to analyze the duration of CAI and explore the factors affecting HPA axis recovery in post-operative CD patients with biochemical remission. METHODS: Medical records of diagnosis with CD in Huashan Hospital were reviewed between 2014 and 2020. 140 patients with biochemical remission and regular follow-up after surgery were enrolled in this retrospective cohort study according to the criteria. Demographic details, clinical and biochemical information at baseline and each follow-up (within 2 years) were collected and analyzed. RESULTS: Overall, 103 patients (73.6%) recovered from transient CAI within 2 years follow-up and the median recovery time was 12 months [95% confidence intervals (CI): 10-14]. The age was younger and midnight ACTH at baseline was significantly lower, while the TT3 and FT3 levels were significantly higher in patients with recovered HPA compared to patients with persistent CAI at 2-year follow-up (p < 0.05). In persistent CAI group, more patients underwent partial hypophysectomy. TT3 at diagnosis was an independent related factor of the recovery of HPA axis, even after adjusting for gender, age, duration, surgical history, maximum tumor diameter, surgical strategy, and postoperative nadir serum cortisol level (p = 0.04, OR: 6.03, 95% CI: 1.085, 22.508). Among patients with unrecovered HPA axis at 2-year follow-up, 23 CAI patients (62%) were accompanied by multiple pituitary axis dysfunction besides HPA axis, including hypothyroidism, hypogonadism, or central diabetes insipidus. CONCLUSION: HPA axis recovered in 73.6% of CD patients within 2 years after successful surgery, and the median recovery time was 12 months. TT3 level at diagnosis was an independent related factor of postoperative recovery of HPA axis in CD patients. Moreover, patients coexisted with other hypopituitarism at 2-year follow-up had a high probability of unrecovered HPA axis.

Combined therapy of GABA and sitagliptin prevents high-fat diet impairment of beta-cell function.

We recently demonstrated that combined therapy of GABA and sitagliptin promoted beta-cell proliferation, and decreased beta-cell apoptosis in a multiple low-dose streptozotocin (STZ)-induced beta-cell injury mouse model. In this study, we examined whether this combined therapy is effective in ameliorating the impairment of beta-cell function caused by high-fat diet (HFD) feeding in mice. Male C57BL/6J mice were fed normal chow diet, HFD, or HFD combined with GABA, sitagliptin, or both drugs. Oral drug daily administration was initiated one week before HFD and maintained for two weeks. After two weeks of intervention, we found that GABA or sitagliptin administration ameliorated the impairment of glucose tolerance induced by HFD. This was associated with improved insulin secretion in vivo. Notably, combined administration of GABA and sitagliptin significantly enhanced these effects as compared to each of the monotherapies. Combined GABA and sitagliptin was superior at increasing beta-cell mass, and associated Ki67+ and PDX-1+ beta-cell counts. In addition, we found that HFD-induced compensatory beta-cell proliferation was associated with increased activation of unfolded protein response (UPR), as indicated by BiP expression. This could be an important mechanism of compensatory beta-cell proliferation, and beta cells treated with GABA and sitagliptin showed greater UPR activation. Our results suggest that the combined use of these agents produces superior therapeutic outcomes.

The hypothalamic-pituitary-gonad axis in male Cushing's disease before and after curative surgery.

OBJECTIVE: Gonadal and sexual disturbances are commonly encountered in patients with Cushing's disease. Nevertheless, the prevalence of hypogonadism in male Cushing's disease, the risk factors as well as the recovery time have been scarcely reported. Therefore, we aimed to explore the prevalence of hypogonadism at baseline and its determinants. In addition, the recovery time of hypogonadism and risk factors for unrecovered gonadal axis in male Cushing's disease with biochemical remission were investigated. METHODS: We reviewed medical records of males with Cushing's disease managed between 2010 and 2020. Fifty-two male patients were enrolled according to the criteria. Each case attained biochemical remission after transsphenoidal surgery. Demographic details, clinical features, 24-hour UFC, hormonal profile [serum PRL, FSH, LH, TT, ACTH, cortisol, TT4/FT4, TT3/ FT3, TSH and IGF-1] were measured at baseline and during follow-up. The maximal tumor diameter on MRI was recorded at diagnosis. RESULTS: Hypogonadotropic hypogonadism was observed in thirty-nine patients (75%) at diagnosis. Total testosterone was negatively correlated with ACTH and 24-hour UFC. Midnight serum ACTH level at diagnosis was significantly associated with hypogonadism after adjusting for confounding factors. Thirty-two (80%) patients achieved eugonadism within 12 months after the surgery, of which twenty-eight (87.5%) achieved eugonadism within 3 months. Seven patients were persistently hypogonadal during the follow-up (≥1 year), mainly due to the hypopituitarism as a complication of the therapies such as surgery. CONCLUSION: Hypogonadotropic hypogonadism is frequent in male Cushing's disease, but it is reversible in most cases within one-year follow-up after remission.

Novel GLP-1 analog supaglutide improves glucose homeostasis in diabetic monkeys.

Glucagon-like peptide 1 (GLP-1) is an insulinotropic hormone and plays an important role in regulating glucose homeostasis. GLP-1 has a short half-life (t1/2 < 2 min) due to degrading enzyme dipeptidyl peptidase-IV and rapid kidney clearance, which limits its clinical application as a therapeutic reagent. We demonstrated recently that supaglutide, a novel GLP-1 mimetic generated by recombinant fusion protein techniques, exerted hypoglycemic and ß-cell trophic effects in type 2 diabetes db/db mice. In the present study, we examined supaglutide's therapeutic efficacy and pharmacokinetics in diabetic rhesus monkeys. We found that a single subcutaneous injection of supaglutide of tested doses transiently and significantly reduced blood glucose levels in a dose-dependent fashion in the diabetic monkeys. During a 4-week intervention period, treatment of supaglutide of weekly dosing dose-dependently decreased fasting and random blood glucose levels. This was associated with significantly declined plasma fructosamine levels. The repeated administration of supaglutide remarkably also decreased body weight in a dose-dependent fashion accompanied by decreased food intake. Intravenous glucose tolerance test results showed that supaglutide improved glucose tolerance. The intervention also showed enhanced glucose-stimulated insulin secretion and improved lipid profile in diabetic rhesus monkeys. These results reveal that supaglutide exerts beneficial effects in regulating blood glucose and lipid homeostasis in diabetic rhesus monkeys.

Novel GLP-1 Analog Supaglutide Stimulates Insulin Secretion in Mouse and Human Islet Beta-Cells and Improves Glucose Homeostasis in Diabetic Mice.

Glucagon-like peptide-1 (GLP-1), an incretin hormone plays an important role in regulating glucose homeostasis. The therapeutic use of native GLP-1 is inadequate due to its short in vivo half-life. We recently developed a novel GLP-1 mimetics supaglutide, and demonstrated that this formulation retained native GLP-1 biological activities and possessed long-lasting GLP-1 actions. In this study, we further examined its abilities in regulating blood glucose in diabetic mice. We found that supaglutide stimulated insulin secretion in both mouse and human islets in a dose-dependent fashion. Oral glucose tolerance test conducted in normal ICR mice showed that supaglutide significantly decreased postprandial glucose excursions in a dose-dependent fashion. In type 2 diabetic db/db mice, a single-dose injection of supaglutide significantly decreased blood glucose levels, and this efficacy was lasted for at least 72 h in a dose-dependent fashion. During a 4-weeks intervention course supaglutide (twice injections per week) dose-dependently and significantly decreased fasting and random blood glucose levels in hyperglycemic db/db mice. Supaglutide, at a dose of 1.2 mg/kg, significantly reduced serum fructosamine levels. This was associated with significant enlargement of beta-cell mass, increased pancreatic insulin content, and increased plasma insulin level. Notably, during the intervention course supaglutide significantly reduced body-weight gain in these obese diabetic mice, associated with reduced fat mass (but not the lean mass), improved lipid profile, i.e., declined serum triglyceride, and free fatty acid levels compared to the placebo control. These finding reveals that supaglutide exerts beneficial effects in regulating blood glucose and lipid homeostasis in diabetic db/db mice.

Novel GLP-1 Analog Supaglutide Reduces HFD-Induced Obesity Associated with Increased Ucp-1 in White Adipose Tissue in Mice.

GLP-1, an important incretin hormone plays an important role in the regulation of glucose homeostasis. However, the therapeutic use of native GLP-1 is limited due to its short half-life. We recently developed a novel GLP-1 mimetics (supaglutide) by genetically engineering recombinant fusion protein production techniques. We demonstrated that this formulation possessed long-lasting GLP-1 actions and was effective in glycemic control in both type 1 and type 2 diabetes rodent models. Here, we investigated the effects of supaglutide in regulating energy homeostasis in obese mice. Mice were fed with high-fat diet (HFD) for 6 months to induce obesity and then subjected to supaglutide treatment (300 µg/kg, bi-weekly for 4 weeks), and placebo as control. Metabolic conditions were monitored and energy expenditure was assessed by indirect calorimetry (CLAMS). Cold tolerance test was performed to evaluate brown-adipose tissue (BAT) activities in response to cold challenge. Glucose tolerance and insulin resistance were evaluated by intraperitoneal glucose tolerance test and insulin tolerance tests. Liver and adipose tissues were collected for histology analysis. Expression of uncoupling protein 1(Ucp1) in adipose tissues was evaluated by Western blotting. We found that supaglutide treatment reduced body weight, which was associated with reduced food intake. Compared to the placebo control, supaglutide treatment improved lipid profile, i.e., significantly decreased circulating total cholesterol levels, declined serum triglyceride, and free fatty acid levels. Importantly, the intervention significantly reduced fatty liver, decreased liver triglyceride content, and concomitantly ameliorated liver injury exemplified by declined hepatic alanine aminotransferase (ALT) and aspartic transaminase (AST) content. Remarkably, supaglutide reduced hepatic lipid accumulation and altered morphometry in favor of small adipocytes in fat. This is consistent with the observation that supaglutide increased tolerance of the mice to cold environment associated with up-regulation of Ucp1 in the inguinal fat. Furthermore, supaglutide improved glucose tolerance, and insulin sensitivity in the obese mice suggesting improved glucose and energy homeostasis. Our findings suggest that supaglutide exerts beneficial effect on established obesity through reducing energy intake and is associated with brown remodeling of white adipose tissue.