The usefulness of the combined high-dose dexamethasone suppression test and desmopressin stimulation test in establishing the source of ACTH secretion in ACTH-dependent Cushing's syndrome.

Bilateral inferior petrosal sinus sampling (BIPSS) is the current gold standard test for differentially diagnosing ACTH-dependent Cushing's syndrome (CS). However, BIPSS is an invasive procedure, and its availability is limited. We retrospectively analysed the 24-hour urinary free cortisol (UFC) level during the high-dose dexamethasone suppression test (HDDST) and plasma ACTH/cortisol levels after the desmopressin stimulation test (DDAVP test) in subjects with confirmed Cushing's disease (CD) (n = 92) and ectopic ACTH-dependent CS (EAS) (n = 16), and evaluated the positive predictive value (PPV) of the two combined-tests in the aetiological diagnosis of ACTH-dependent CS. The percent changes in UFC levels after the HDDST and in ACTH/cortisol levels after DDAVP administration relative to the corresponding basal levels and the area under the receiver operating characteristic (ROC) curve (AUC) were analysed. UFC suppression below 62.7% suggested a pituitary origin with a sensitivity (SE) of 80% (95% CI: 70-88) and a specificity (SP) of 80% (95% CI: 52-96). A threshold increase in the ACTH level after DDAVP stimulation of 44.6% identified CD with an SE of 91% (95% CI: 83-97) and an SP of 75% (95% CI: 48-93). The combination of both tests yielded an SE of 95.5% and PPV of 98.4% for CD, and significantly improved the efficiency of the differential diagnosis between CD and EAS. These dual non-invasive endocrine tests may substantially reduce the need for BIPSS in the etiological investigation of ACTH-dependent CS.

Corrigendum: Screening and identification of hub genes in the development of early diabetic kidney disease based on weighted gene co-expression network analysis.

[This corrects the article DOI: 10.3389/fendo.2022.883658.].

Secondary analysis of newly diagnosed type 2 diabetes subgroups and treatment responses in the MARCH cohort.

OBJECTIVE: To incorporate new clusters in the MARCH (Metformin and AcaRbose in Chinese patients as the initial Hypoglycemic treatment) cohort of newly diagnosed type 2 diabetes (T2D) patients and compare the anti-glycemic effects of metformin and acarbose across different clusters. METHODS: K-means cluster analysis was performed based on six clinical indicators. The diabetic clusters in the MARCH cohort were retrospectively associated with the response to metformin and acarbose. RESULTS: A total of 590 newly diagnosed T2D patients were classified by data-driven clusters into the MARD (mild obesity-related diabetes) (34.1 %), MOD (mild obesity-related diabetes) (34.1 %), SIDD (severe insulin-deficient diabetes) (20.3 %) and SIRD (severe insulin-resistant diabetes) (11.5 %) subgroups at baseline. At 24 and 48 weeks, 346 participants had finished the follow-up. After the adjustment of age, gender, weight, baseline HbA1c, baseline fasting glucose and 2-h postprandial blood glucose (2hPG), metformin mainly decreased the fasting glucose (0.07 ± 0.89 vs -0.26 ± 0.83, P = 0.043) in the MARD subgroup presented with OGTT (oral glucose tolerance test) results compared with acarbose group at 24 weeks. Acarbose led to a greater decrease in 2hPG in the MOD subgroup compared with metformin group (0.08 ± 0.86 vs -0.24 ± 0.92, P = 0.037) at 24 weeks. There was a also significant interaction between cluster and treatment efficacy in HbA1c (glycated hemoglobin) reduction in metformin and acarbose groups at 24 and 48 weeks (pinteraction<0.001). CONCLUSIONS: Metformin and acarbose affected different metabolic variables depending on the diabetes subtype.

Evaluating the long-term cost-effectiveness of fixed-ratio combination insulin degludec/liraglutide (IDegLira) versus other treatment regimens in the chinese type 2 diabetes patients.

BACKGROUND AND AIMS: To assess the cost-effectiveness of utilizing IDegLira in comparison to other treatment regimens ( liraglutide and degludec) in managing type 2 diabetes, taking into account the Chinese healthcare system's perspective. METHODS: The clinical data were obtained from the randomized controlled trials (RCTs) of the DUAL I and DUAL II evidence studies that took place in China. To estimate the lifetime quality-adjusted life-years (QALYs) and direct medical costs of patients receiving different treatment strategies from a long-term perspective, the IQVIA CORE Diabetes Model version 9.0 (IQVIA, Basel, Switzerland) was utilized. The costs were evaluated from the perspective of the China National Health System. Future costs and clinical benefits were discounted annually at 5%, and sensitivity analyses were conducted. RESULTS: IDegLira was projected to reduce the incidence of diabetes-related complications and improve quality-adjusted life expectancy (QALE) versus liraglutide and degludec. A survival benefit was observed with IDegLira over Liraglutide (0.073 years). Lifetime costs were lower by Chinese yuan (CNY) 27,945 on IDegLira than on Liraglutide therapy. A similar survival benefit was observed with IDegLira over degludec (0.068 years). Lifetime costs were lower by CNY 1196 on IDegLira than on degludec therapy. Therefore, IDegLira was found to be cost-effective versus liraglutide and degludec with incremental cost-effectiveness ratios of Dominant per QALY gained, respectively, under the threshold of three times the gross domestic product (GDP) per capita in China. CONCLUSION: IDegLira is a cost-effective hypoglycemic treatment option that delivers positive clinical outcomes while also reducing costs for Chinese patients living with type 2 diabetes.

Long-Term Cost-Effectiveness of Subcutaneous Once-Weekly Semaglutide Versus Polyethylene Glycol Loxenatide for Treatment of Type 2 Diabetes Mellitus in China.

OBJECTIVE: This study aimed to evaluate the long-term cost-effectiveness of once-weekly subcutaneous semaglutide versus polyethylene glycol loxenatide (PEG-loxenatide) in patients with type 2 diabetes uncontrolled on metformin, from a Chinese healthcare systems perspective. METHODS: The study applied the Swedish Institute of Health Economics Diabetes Cohort Model to evaluate the long-term clinical and economic outcomes of once-weekly treatment of semaglutide at 0.5 mg and 1.0 mg, respectively, versus PEG-loxenatide 0.2 mg, over a 40-year time horizon. Baseline cohort characteristics were collected from the SUSTAIN China trial. A network meta-analysis was conducted to obtain comparative treatment effects of once-weekly semaglutide and PEG-loxenatide based on two phase 3a clinical trials. Drug costs were sourced from the national bidding price of China. Outcomes were discounted at 5.0% per annum. One-way sensitivity analysis and probabilistic sensitivity analysis were conducted to assess the uncertainty of the base-case results. RESULTS: When compared with PEG-loxenatide 0.2 mg, the projections of outcomes over the 40-year time horizon in patients with type 2 diabetes uncontrolled on metformin showed that treatment with once-weekly semaglutide 0.5 mg and 1.0 mg were associated with improved discounted life expectancy by 0.08 and 0.12 years, and improved discounted quality-adjusted life expectancy by 0.16 and 0.22 quality-adjusted life-years, respectively. Once-weekly semaglutide 0.5 mg and 1.0 mg were achieved at lifetime cost savings of 19,309 China Yuan (CNY) and 10,179 CNY, respectively. Sensitivity analyses verified the robustness of the results. CONCLUSION: From the perspective of Chinese healthcare systems, treatment with once-weekly subcutaneous semaglutide represents a dominant option versus PEG-loxenatide for patients with type 2 diabetes uncontrolled on metformin.

Data-driven subgroups of newly diagnosed type 2 diabetes and the relationship with cardiovascular diseases at genetic and clinical levels in Chinese adults.

BACKGROUND: To subgroup Chinese patients with newly diagnosed type 2 diabetes (T2D) by K-means cluster analysis on clinical indicators, and to explore whether these subgroups represent different genetic features and calculated cardiovascular risks. METHODS: The K-means clustering analysis was performed on two cohorts (n = 590 and 392), both consisting of Chinese participants with newly diagnosed T2D. To assess genetic risks, multiple polygenic risk scores (PRSs) and mitochondrial DNA copy numbers (mtDNA-CN) were calculated for all participants. Furthermore, Framingham risk scores (FRS) of cardiovascular diseases in two cohorts were also calculated to verify the genetic risks. RESULTS: Four clusters were identified including the mild age-related diabetes (MARD)(35.08%), mild obesity-related diabetes (MOD) (34.41%), severe autoimmune diabetes (SAID) 19.15%, and severe insulin-resistant diabetes (SIRD) 11.36% subgroups in the MARCH (metformin, and acarbose in Chinese patients as the initial hypoglycemic treatment) cohort. There was a significant difference in PRS for cardiovascular diseases (CVD) across four subgroups in the MARCH cohort (p < 0.05). Compared with the SIDD and SIRD subgroups, patients in the MOD subgroup had a relatively lower PRS for CVD (p < 0.05) in the MARCH cohort. Females had a higher PRS compared to males, with no significant difference in FRS across the four clusters. The MOD subgroup had a significantly lower FRS which was consistent with the results of PRS. Similar results of PRS and FRS were also replicated in the CONFIDENCE (comparison of glycemic control and b-cell function among newly diagnosed patients with type 2 diabetes treated with exenatide, insulin or pioglitazone) cohort. CONCLUSION: There are different CVD risks in diabetic subgroups based on clinical and genetic evidence which may promote precision medicine.

Screening and Identification of Hub Genes in the Development of Early Diabetic Kidney Disease Based on Weighted Gene Co-Expression Network Analysis.

Objective: The study aimed to screen key genes in early diabetic kidney disease (DKD) and predict their biological functions and signaling pathways using bioinformatics analysis of gene chips interrelated to early DKD in the Gene Expression Omnibus database. Methods: Gene chip data for early DKD was obtained from the Gene Expression Omnibus expression profile database. We analyzed differentially expressed genes (DEGs) between patients with early DKD and healthy controls using the R language. For the screened DEGs, we predicted the biological functions and relevant signaling pathways by enrichment analysis of Gene Ontology (GO) biological functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways. Using the STRING database and Cytoscape software, we constructed a protein interaction network to screen hub pathogenic genes. Finally, we performed immunohistochemistry on kidney specimens from the Beijing Hospital to verify the above findings. Results: A total of 267 differential genes were obtained using GSE142025, namely, 176 upregulated and 91 downregulated genes. GO functional annotation enrichment analysis indicated that the DEGs were mainly involved in immune inflammatory response and cytokine effects. KEGG pathway analysis indicated that C-C receptor interactions and the IL-17 signaling pathway are essential for early DKD. We identified FOS, EGR1, ATF3, and JUN as hub sites of protein interactions using a protein-protein interaction network and module analysis. We performed immunohistochemistry (IHC) on five samples of early DKD and three normal samples from the Beijing Hospital to label the proteins. This demonstrated that FOS, EGR1, ATF3, and JUN in the early DKD group were significantly downregulated. Conclusion: The four hub genes FOS, EGR1, ATF3, and JUN were strongly associated with the infiltration of monocytes, M2 macrophages, and T regulatory cells in early DKD samples. We revealed that the expression of immune response or inflammatory genes was suppressed in early DKD. Meanwhile, the FOS group of low-expression genes showed that the activated biological functions included mRNA methylation, insulin receptor binding, and protein kinase A binding. These genes and pathways may serve as potential targets for treating early DKD.

Effects of Unsuppressed Endogenous Insulin on Pharmacokinetics and/or Pharmacodynamics of Study Insulin in the Healthy: A Retrospective Study.

C-peptide, a marker of endogenous insulin, should be consistently inhibited during euglycemic clamping, while an elevated postdosing C-peptide (CPpostdosing ) is not an occasional phenomenon. This was a retrospective study that included 33 men who underwent a manual euglycemic clamp with a subcutaneous injection of insulin aspart (IAsp) aiming to describe the effects of insufficient suppression of endogenous insulin on estimates of the pharmacokinetics and pharmacodynamics of injected insulin. The time profiles of whole blood glucose, human insulin, glucose infusion rate (GIR), and C-peptide were recorded. The subjects were divided into 2 groups at a ratio of 2:1: group A ([CPpostdosing ]max >baseline CP [CPbaseline ]), group B ([CPpostdosing ]max ≤ CPbaseline ). The endogenous insulin was approximately equal to the measured value of human insulin or calculated from the C-peptide. The basal glucose, CPbaseline , basal human insulin, homeostatic model assessment of insulin resistance, IAsp dose, and demographic statistics were all comparable between the 2 groups except the "clamped" glucose. The average clamped glucose was 99.7% (group A) and 94.9% (group B) of baseline. After correction for clamped glucose, GIR area under the concentration-time curve from time 0 to 8 hours was higher in group A (P < .05) under comparable IAsp exposure. Endogenous insulin area under the concentration-time curve from time 0 to 8 hours calculated from C-peptide was different from that measured from human insulin in group A (P < .05), whereas no statistical difference between these measures was observed in group B. Hence, blood glucose should be controlled below the baseline to ensure the inhibition of endogenous insulin. Unsuppressed endogenous insulin may contribute to observed GIR, and the endogenous insulin-corrected pharmacokinetics estimated by C-peptide may be inaccurate with insufficient endogenous insulin suppression.

Medications and medical costs for diabetes patients with or without chronic respiratory disease in Beijing, China: A retrospective study.

Aims: The cost of drug regimens prescribed to Chinese patients has not been evaluated. This study aims to evaluate the medical costs and hypoglycemic agents for diabetes mellitus patients with or without chronic respiratory disease in Beijing, and to investigate the changes in the costs and number of antidiabetic medications used for diabetes patients with chronic respiratory disease from 2016 to 2018. Methods: This observational, retrospective study included diabetes patients with outpatient medication records from Beijing Medical Insurance between 2016 and 2018. The medications, including hypoglycemic and nonhypoglycemic drugs, insulin dosage, comorbidities, diabetes-related complications, treatment strategies, and annual medical costs, were recorded. Results: This study included 2,853,036 diabetes patients from 2016 to 2018. About 18.95%-20.53% of patients with chronic respiratory disease were predominantly distributed among those aged 45-84 years (88.7%-89.1%). Diabetes patients with chronic respiratory disease used more medications (4.48 ± 2.41 vs. 3.76 ± 2.33) and had higher total annual drug costs (¥12,286 ± 10,385 vs. ¥9700 ± 9202) to treat more comorbidities (2.52 ± 1.53 vs. 2.05 ± 1.85) than those without chronic respiratory disease (p <.0001, respectively). From 2016 to 2018, diabetes patients with chronic respiratory disease had a 4.2% increase in medication, a 1.9% decrease in comorbidities, and a 5.4% decrease in total annual drug costs. Conclusions: In summary, diabetes patients with chronic respiratory disease had more comorbidities, required more hypoglycemic drugs, and had higher medical costs. During 2016-2018, diabetes patients with chronic respiratory disease used more medications and spent less money on medical care.

Interindividual Variability in the Pharmacodynamic and Pharmacokinetic Characteristics of Recombinant Human Insulin and Insulin Aspart.

PURPOSE: The present study compared the interindividual variability in the pharmacodynamic (PD) and pharmacokinetic (PK) properties of a short-acting recombinant human insulin to those of insulin aspart through manual euglycemic glucose clamp tests. METHODS: Sixty healthy Chinese male volunteers were randomly assigned to receive human insulin or insulin aspart, administered via SC injection (0.2 U/kg). For the evaluation of interindividual variability in PD and PK properties (glucose infusion rate [GIR], insulin concentration [INS]) through euglycemic clamp studies, %CVs were calculated, and PK/PD interindividual variability was compared between the 2 groups. FINDINGS: The differences between the human insulin and insulin aspart groups in interindividual variabilities in total AUCs of the GIR (19% vs 21%) and INS (14% vs 17%) were not significant. The interindividual variabilities in AUCgir0-120min, early Tmax50%, and AUCins0-120min were lower in the insulin aspart group than in the human insulin group (22% vs 44%, 21% vs 35%, and 22% vs 28%, respectively; all, P ˂ 0.05), while the interindividual variabilities in the AUCs of GIR120-600min and INS120-600min were higher with insulin aspart than with human insulin (29% vs 20%, 51% vs 30%; both, P ˂ 0.05). IMPLICATIONS: The overall interindividual variability with insulin aspart was similar to that with recombinant human insulin. Yet insulin concentration and metabolic effect during the declining period were more variable with insulin aspart compared to human insulin in these healthy male subjects.

Oscillations of C-peptide in the euglycemic clamp and their effect on the pharmacodynamic assessment of insulin preparations.

C-peptide should be continuously suppressed. However, increased postdosing C-peptide is not an uncommon phenomenon in euglycemic clamp studies involving healthy participants. This study aimed to determine the extent to which the postdosing C-peptide increases from the baseline that could affect the accuracy of glucodynamics in euglycemic clamp studies involving healthy subjects. First, 10 healthy males underwent a 10-h euglycemic clamp without exogenous insulin administration to obtain a reference interval (RI) for the ratio of C-peptide after 0 min (CPt ) to baseline C-peptide (CP0 ). Then, the data from a pharmacokinetic and pharmacodynamic study of insulin aspart (IAsp) were analyzed, and 70 eligible clamps were grouped by CPt /CP0 : group A ([CPt /CP0 ]max   > upper limit of RI), group B (1<[CPt /CP0 ]max  ≤ upper limit of RI), and group C ([CPt /CP0 ]max  ≤ 1). The differences in basal and clamped blood glucose, CPt /CP0 , and the pharmacokinetics and pharmacodynamics of IAsp were compared, and the relationship between elevated CPt and the accuracy of pharmacodynamics was analyzed. The RI of CPt /CP0 was 22.7%-152.1%; 1.5 × baseline might be a ceiling for the increase in CPt under stable conditions. The maximum glucose infusion rate (GIR) in group A tended to be higher than that in group B or C (Pfor trend  = 0.033). The AUCGIR,0-10h in groups A, B, and C was 1983 ± 650,1682 ± 454, and 1479 ± 440 mg/kg (P = 0.047), respectively, under comparable IAsp exposure. No intergroup difference was detected in clamped glucose, IAsp dose, or body mass index. In conclusion, postdosing C-peptide over 1.5× baseline indicates insufficient inhibition of endogenous insulin secretion, which could compromise the pharmacodynamics of insulin preparations.

Spontaneous Remission After a Hypercalcemic Crisis Caused by an Intracystic Hemorrhage of Bilateral Parathyroid Adenomas: A Case Report and Literature Review.

Background: Hyperparathyroidism is a common cause of hypercalcemia; however, spontaneous remission after a hypercalcemic crisis caused by an intracystic hemorrhage of parathyroid adenomas is very rare. The question, then, is "What is the best treatment strategy for this type of case?" Method: A 47-year-old male patient with primary hyperparathyroidism and a hypercalcemic crisis is reported. Hypercalcemia was spontaneously relieved thereafter. Postoperative paraffin pathology results indicated an intracystic hemorrhage of bilateral parathyroid adenomas. Results: After the case report, a literature review is also included to summarize the clinical features of this patient and to provide special reference for clinical diagnosis and treatment of similar cases. Conclusions: The choice of surgical timing for such cases can be made based on the comprehensive consideration of clinical symptoms and changes in parathyroid function.

Similar pharmacokinetics and pharmacodynamics of a new biosimilar and reference insulin aspart in healthy Chinese males.

Insulin aspart (IAsp) is one of the main therapies used to control blood glucose after a meal. This study aimed to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of 2 rapid-acting IAsp products: a new IAsp biosimilar (RD10046) and NovoRapid. In a single-center, randomized, single-dose, 2-period, crossover, euglycemic clamp study (registry number: CTR20180517, registration date: 2018-05-30), healthy Chinese males were randomized to receive 0.2 U/kg of the IAsp biosimilar RD10046 and NovoRapid under fasted conditions on two separate occasions. PK and PD were assessed for up to 10 h. Of the 30 randomized subjects, all 30 completed both treatment periods. The PK (area under the curve [AUC] of total IAsp; maximum observed IAsp concentration [Cmax]) and PD (maximum glucose infusion rate [GIRmax]; total glucose infusion during the clamp [AUCGIR,0-10h]) were similar between the new IAsp biosimilar RD10046 and NovoRapid. In all cases, the 90% CIs for the ratios of the geometric means were completely contained in the prespecified acceptance limits of 0.80-1.25. No hypoglycemic events, allergic reactions, or local injection adverse reactions occurred in this trial. We concluded that the studied IAsp biosimilar (RD10046) was bioequivalent to NovoRapid.

Mineralocorticoid receptor excessive activation involved in glucocorticoid-related brain injury.

The mechanisms involved in brain damage during chronic glucocorticoid exposure are poorly understood. Since mineralocorticoid receptor (MR) activation has been proven to be important in the pathophysiology of vascular damage and MRs are highly expressed in many brain regions, we hypothesized that the cerebral injury observed in subjects with Cushing syndrome is in part associated with the overactivation of MR. The aim of this study was to determine whether the cerebral injury observed in chronic hyperglucocorticoidemia animal models is related to excessive MR activation. Male SD rats were divided into five groups: vehicle, hydrocortisone (HC, 5 mg/kg/day, i.g.), HC + spironolactone (SL, 20 mg/kg/d in chow), dexamethasone (DXM, 0.25 mg/kg/day, i.g.), and DXM + SL (20 mg/kg/d in chow). Compared to the vehicle-treated group, HC-treated rats had higher blood pressure and higher levels of cerebral vascular fibrosis, cortical/hippocampal atrophy, reactive oxygen species (ROS) production and proinflammatory gene expression. However, in HC-treated animals, treatment with SL markedly alleviated ROS production, cerebral and cerebrovascular morphological changes and inflammation but failed to reduce blood pressure. In contrast, DXM induced no cerebral morphological changes except fibrosis in cerebral vessels, an effect that was not ameliorated by SL treatment. These findings demonstrate that the excessive MR activation observed following chronic hyperglucocorticoidemia exposure contributes to cerebrovascular fibrosis and remodeling and promotes neural apoptosis in the cerebral cortex/hippocampus.