Clinical investigation of glucokinase activators for the restoration of glucose homeostasis in diabetes.

As a sensor, glucokinase (GK) controls glucose homeostasis, which progressively declines in patients with diabetes. GK maintains the equilibrium of glucose levels and regulates the homeostatic system set points. Endocrine and hepatic cells can both respond to glucose cooperatively when GK is activated. GK has been under study as a therapeutic target for decades due to the possibility that cellular GK expression and function can be recovered, hence restoring glucose homeostasis in patients with type 2 diabetes. Five therapeutic compounds targeting GK are being investigated globally at the moment. They all have distinctive molecular structures and have been clinically shown to have strong antihyperglycemia effects. The mechanics, classification, and clinical development of GK activators are illustrated in this review. With the recent approval and marketing of the first GK activator (GKA), dorzagliatin, GKA's critical role in treating glucose homeostasis disorder and its long-term benefits in diabetes will eventually become clear.

Insulin Degludec in People with Type 2 Diabetes in China: A Non-interventional, Retrospective Chart Review Study (CN-TREAT).

INTRODUCTION: Insulin degludec (degludec), an ultra-long-acting basal insulin analogue, provides equivalent glycemic control to other basal insulin analogues, with lower risk of hypoglycemia and flexible dosing. Chinese TREsiba AudiT (CN-TREAT) investigated outcomes with degludec in people with type 2 diabetes (T2D) in routine clinical practice in China. METHODS: This was a retrospective chart review study in adults with T2D initiating or switching to degludec at 50 sites in China between January 2020 and July 2021. The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline to end of study (EOS; week 20). Secondary endpoints included change from baseline to EOS in fasting plasma glucose (FPG), self-measured plasma glucose (SMPG), daily insulin dose, and rate of hypoglycemia. RESULTS: Data from 936 participants were included (499 insulin-naïve; 437 insulin-experienced). Mean (95% confidence interval [CI]) HbA1c change from baseline to EOS was - 1.48%-points (- 1.57; - 1.38; P < 0.0001) overall: - 1.95%-points (- 2.08; - 1.81; P < 0.0001) in insulin-naïve participants and - 0.95%-points (- 1.08; - 0.82; P < 0.0001) in insulin-experienced participants. Mean (95% CI) changes in FPG and SMPG were - 2.27 mmol/L (- 2.69; - 1.85; P < 0.0001) and - 2.89 mmol/L (- 3.52; - 2.25; P < 0.0001), respectively, with similar reductions in insulin-naïve and insulin-experienced subgroups. Rate of hypoglycemia did not change statistically significantly from baseline to EOS overall, or in insulin-experienced participants, except when adjusted for baseline hypoglycemia. Basal insulin dose did not change statistically significantly in insulin-experienced participants. CONCLUSION: In routine clinical practice in China, initiation or switching to degludec was associated with improvements in glycemic control in people with T2D, with no increased risk of hypoglycemia. TRIAL REGISTRATION: ClinialTrials.gov, NCT04227431.

Finerenone in Patients with Chronic Kidney Disease and Type 2 Diabetes: The FIDELIO-DKD Subgroup from China.

Background: This prespecified subgroup analysis of the FIDELIO-DKD trial aimed to evaluate the efficacy and safety of finerenone in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM) in China. Methods: 372 participants were recruited from 67 centers in China and randomized 1:1 to oral finerenone or placebo with standard therapy for T2DM. The primary composite outcome included kidney failure, sustained decrease of estimated glomerular filtration rate ≥40% from baseline over at least 4 weeks, or renal death. The key secondary composite outcome included death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Results: After a median follow-up of 30 months, the finerenone group showed a relative risk reduction (RRR) of 41% (hazard ratio [HR] = 0.59, 95% confidence interval [CI], 0.39-0.88; p = 0.009) for the primary composite outcome compared with placebo, consistent across its components with treatment benefits with finerenone. Based on an absolute between-group difference of 12.2% after 30 months, the number of patients who needed to be treated with finerenone to prevent one primary outcome event was eight (95% CI: 4-84). For the key secondary composite outcome, the finerenone group showed a RRR of 25% (HR = 0.75, 95% CI, 0.38-1.48; p = 0.408). Adverse events were similar between the two groups. The effects of finerenone on blood pressure were modest. No gynecomastia events were reported in the study. Hyperkalemia leading to discontinuation occurred in eight (4.3%) and two (1.1%) participants in the finerenone and control groups, respectively. The incidence of acute kidney injury was comparable between the two groups (1.6% vs. 1.6%). Conclusions: Finerenone resulted in lower risks of CKD progression than placebo and a balanced safety profile in Chinese patients with CKD and T2DM.

Efficacy and safety of adding once-weekly dulaglutide to basal insulin for inadequately controlled type 2 diabetes in Chinese patients (AWARD-CHN3): A randomized, double-blind, placebo-controlled, phase III trial.

AIM: To determine the efficacy and safety of once-weekly dulaglutide added to basal insulin in Chinese patients with type 2 diabetes mellitus (T2DM) with inadequate glycaemic control. MATERIALS AND METHODS: In the phase III, double-blind AWARD-CHN3 study, Chinese patients with T2DM (N = 291) and glycated haemoglobin (HbA1c) ≥7.0% and ≤11.0% receiving stable doses of basal insulin glargine with metformin and/or acarbose were randomized (1:1) to receive add-on dulaglutide 1.5 mg once weekly or placebo once weekly. The primary endpoint was the superiority of dulaglutide/glargine to placebo/glargine for change from baseline in HbA1c at Week 28. RESULTS: The least squares (LS) mean ± standard error change in HbA1c from baseline to Week 28 was -2.0 ± 0.08% with dulaglutide/glargine and -1.1 ± 0.07% with placebo/glargine (LS mean difference: -1.0%, 95% confidence interval [CI] -1.1 to -0.8; P < 0.001), and more patients receiving dulaglutide/glargine achieved HbA1c levels <7.0% (75.9% vs. 33.8%; P < 0.001 vs. placebo/glargine). Body weight decreased with dulaglutide/glargine and increased with placebo/glargine (LS mean difference: -1.2 kg, 95% CI -1.8 to - 0.6; P < 0.001). Reductions in fasting serum glucose were greater with dulaglutide/glargine than with placebo/glargine (LS mean difference: -0.8 mmol/L, 95% CI -1.1 to - 0.5; P < 0.001). The incidence of hypoglycaemia was similar with dulaglutide/glargine and placebo/glargine (29.2% vs. 31.3%; P = 0.704); no patient in either group had severe hypoglycaemia. The most common treatment-emergent adverse events with dulaglutide/glargine were decreased appetite (22.2%), diarrhoea (13.2%) and nausea (10.4%). CONCLUSIONS: Dulaglutide added to basal insulin was efficacious and well tolerated in Chinese patients with T2DM.

Weight loss and metabolic benefits of bariatric surgery in China: A multicenter study.

BACKGROUND: This retrospective multicenter study evaluated the efficacy and safety of bariatric surgery in Chinese patients with obesity. METHODS: Patients with obesity who underwent laparoscopic sleeve gastrectomy or laparoscopic Roux-en-Y gastric bypass and completed a 12-month follow-up between February 2011 and November 2019 were enrolled. Weight loss, glycemic and metabolic control, insulin resistance, cardiovascular risk, and surgery-related complications at 12 months were analyzed. RESULTS: We enrolled 356 patients aged 34.3 ± 0.6 years with a mean body mass index of 39.4 ± 0.4 kg/m2 . Successful weight loss occurred in 54.6%, 86.8%, and 92.7% of patients at 3, 6, and 12 months, respectively, with no difference in percent excess weight loss between the laparoscopic sleeve gastrectomy and laparoscopic Roux-en-Y gastric bypass surgery groups. The average percentage of total weight loss was 29.5% ± 0.6% at 12 months; 99.4%, 86.8%, and 43.5% of patients achieved at least 10%, 20%, and 30% weight loss, respectively, at 12 months. Significant improvements in metabolic indices, insulin resistance, and inflammation biomarkers were observed at 12 months. CONCLUSIONS: Bariatric surgery resulted in successful weight loss and improved metabolic control, insulin resistance, and cardiovascular risk in Chinese patients with obesity. Both laparoscopic sleeve gastrectomy and laparoscopic Roux-en-Y gastric bypass are suitable approaches for such patients.

Prevalence and risk factors of diabetic peripheral neuropathy: A population-based cross-sectional study in China.

AIMS: To assess the prevalence of diabetic peripheral neuropathy (DPN) and its risk factors in the type 2 diabetes mellitus (T2DM) population. METHODS: This cross-sectional study enroled patients with T2DM between July and December 2017 from 24 provinces in China. Diabetic peripheral neuropathy and its severity were assessed by the Toronto clinical scoring system, neuropathy symptoms score (NSS) and neuropathy disability score. The prevalence of DPN and its risk factors were analysed. RESULTS: A total of 14,908 patients with T2DM were enroled. The prevalence of DPN was 67.6%. Among 10,084 patients with DPN, 4808 (47.7%), 3325 (33.0%), and 1951 (19.3%) had mild, moderate, and severe DPN, respectively. The prevalence of DPN in females was higher than in males (69.0% vs. 66.6%, P = 0.002). The prevalence of DPN increased with age and course of diabetes and decreased with body mass index (BMI) and education level (all P for trend <0.05). The comorbidities and complications in patients with DPN were higher than in those without DPN, including hypertension, myocardial infarction, diabetic retinopathy, and diabetic nephropathy (all P < 0.001). Age, hypertension, duration of diabetes, diabetic retinopathy, diabetic nephropathy, glycated haemoglobin, high-density lipoprotein cholesterol, and lower estimated glomerular filtration rate were positively associated with DPN, while BMI, education level, fasting C-peptide, and uric acid were negatively associated with DPN. CONCLUSIONS: Among patients with T2DM in China, the prevalence of DPN is high, especially in the elderly, low-income, and undereducated patients.

Prevalence of diabetic retinopathy and vision-threatening diabetic retinopathy in adults with diabetes in China.

The current epidemic status of diabetic retinopathy in China is unclear. A national prevalence survey of diabetic complications was conducted. 50,564 participants with gradable non-mydriatic fundus photographs were enrolled. The prevalence rates (95% confidence intervals) of diabetic retinopathy and vision-threatening diabetic retinopathy were 16.3% (15.3%-17.2%) and 3.2% (2.9%-3.5%), significantly higher in the northern than in the southern regions. The differences in prevalence between those who had not attained a given metabolic goal and those who had were more pronounced for Hemoglobin A1c than for blood pressure and low-density lipoprotein cholesterol. The participants with vision-threatening diabetic retinopathy had significantly higher proportions of visual impairment and blindness than those with non-vision-threatening diabetic retinopathy. The likelihoods of diabetic retinopathy and vision-threatening diabetic retinopathy were also associated with education levels, household income, and multiple dietary intakes. Here, we show multi-level factors associated with the presence and the severity of diabetic retinopathy.

Association of the triglyceride-glucose index with subclinical left ventricular dysfunction in type 2 diabetes mellitus patients: A retrospective cross-sectional study.

AIMS/INTRODUCTION: The triglyceride-glucose (TyG) index is a simple and reliable indicator of insulin resistance, and is associated with the development and poor outcomes of cardiovascular disease. Subclinical left ventricular dysfunction (SLVD) is frequently detected in approximately one-third of diabetes patients, but it has not been established whether the TyG index correlates with SLVD. We carried out this research to evaluate the relationship between the TyG index and SLVD in type 2 diabetes mellitus patients. MATERIALS AND METHODS: This was a cross-sectional and observational study of 183 type 2 diabetes mellitus inpatients at Nanjing Drum Tower Hospital, Nanjing, China. The TyG index and homeostasis model assessment 2 estimates for insulin resistance (HOMA2-IR) were calculated from biochemical measurements, and speckle-tracking echocardiography was carried out. According to global longitudinal strain (GLS) by echocardiography, participants were categorized into the SLVD (GLS <18%) group or the non-SLVD (GLS ≥18%) group. RESULTS: In comparison with non-SLVD participants, SLVD participants had higher insulin resistance, as reflected by elevated TyG and HOMA2-IR indices, as well as a higher body mass index, waist circumference and triglyceride level (P < 0.05 for each). When grouped by TyG index tertiles, an elevated TyG index was correlated with other cardiometabolic risk factors, as well as a decrease in GLS. In the multivariate logistic regression analyses, the TyG index was an independent risk factor for SLVD in type 2 diabetes mellitus patients (odds ratio 2.047, 95% confidence interval 1.07-3.914, P = 0.03), whereas HOMA2-IR was not. CONCLUSIONS: The TyG index is independently associated with SLVD in type 2 diabetes mellitus patients and is a more reliable indicator of SLVD than HOMA2-IR.

Fat Mass is Associated with Subclinical Left Ventricular Systolic Dysfunction in Patients with Type 2 Diabetes Mellitus Without Established Cardiovascular Diseases.

INTRODUCTION: Left ventricular global longitudinal strain (GLS) is considered to be the first marker of diabetes mellitus-related subclinical cardiac dysfunction, but whether it is attributable to fat mass and distribution remains uncertain. In this study, we explored whether fat mass, especially fat mass in the android area, is associated with subclinical systolic dysfunction before the onset of cardiac disease. METHODS: We conducted a single-center prospective cross-sectional study between November 2021 and August 2022 on inpatients of the Department of Endocrinology, Nanjing Drum Tower Hospital. We included 150 patients aged 18-70 years with no signs, symptoms, or history of clinical cardiac disease. Patients were evaluated with speckle tracking echocardiography and dual energy X-ray absorptiometry. The cutoff values for subclinical systolic dysfunction were set at a global longitudinal strain (GLS) < 18%. RESULTS: After adjusting for sex and age, patients with GLS < 18% had a higher mean (± standard deviation) fat mass index (8.06 ± 2.39 vs. 7.10 ± 2.09 kg/m2, p = 0.02), higher mean trunk fat mass (14.9 ± 4.9 vs. 12.8 ± 4.3 kg, p = 0.01), and higher android fat mass (2.57 ± 1.02 vs. 2.18 ± 0.86 kg, p = 0.02) than those in the GLS ≥ 18%. Partial correlation analysis showed that the fat mass index, truck fat mass, and android fat mass were negatively correlated with GLS after adjusting for sex and age (all p < 0.05). Adjusted for traditional cardiovascular metabolic factors, fat mass index (odds ratio [OR] 1.27, 95% confidence interval [CI] 1.05-1.55, p = 0.02), trunk fat mass (OR 1.13, 95% CI 1.03-1.24, p = 0.01), and android fat mass (OR 1.77, 95% CI 1.16-2.82, p = 0.01) were independent risk factors for GLS < 18%. CONCLUSION: Among patients with type 2 diabetes mellitus without established clinical cardiac disease, fat mass, especially android fat mass, was associated with subclinical systolic dysfunction independently of age and sex.

Prevalence of painful diabetic peripheral neuropathy in type 2 diabetes mellitus and diabetic peripheral neuropathy: A nationwide cross-sectional study in mainland China.

AIM: The study aimed to assess the prevalence and risk factors of painful diabetic peripheral neuropathy (PDPN) in patients with type 2 diabetes mellitus (T2DM) and diabetic peripheral neuropathy (DPN) in mainland China. METHODS: This nationwide cross-sectional study enrolled T2DM patients with DPN from 25 provinces in China between July 2017 and December 2017. The prevalence, characteristics, and risk factors of PDPN were analyzed. RESULTS: Among 25,710 patients with T2DM and DPN, 14,699 (57.2%) had PDPN. The median age was 63 years old. Age over 40 years old, education level, hypertension, myocardial infarction, duration of diabetes of over five years, diabetic retinopathy and nephropathy, moderate total cholesterol, moderate and higher low-density lipoprotein (LDL) increased uric acid (UA) and decreased estimated glomerular filtration rate (eGFR) were independently associated with PDPN (all P < 0.05). Compared with low levels of C-peptide, moderate levels were independently associated with a higher risk of PDPN, while high levels were associated with a lower risk (all P < 0.001). CONCLUSIONS: In mainland China, more than half of the patients with DPN have neuropathic pain. Patients with older age, lower education level, longer duration of diabetes, lower LDL, increased UA, decreased eGFR, and comorbidities had an increased risk of PDPN.

Clinical expert consensus on the assessment and protection of pancreatic islet ß-cell function in type 2 diabetes mellitus.

Islet ß-cell dysfunction is a basic pathophysiological characteristic of type 2 diabetes mellitus (T2DM). Appropriate assessment of islet ß-cell function is beneficial to better management of T2DM. Protecting islet ß-cell function is vital to delay the progress of type 2 diabetes mellitus. Therefore, the Pancreatic Islet ß-cell Expert Panel of the Chinese Diabetes Society and Endocrinology Society of Jiangsu Medical Association organized experts to draft the "Clinical expert consensus on the assessment and protection of pancreatic islet ß-cell function in type 2 diabetes mellitus." This consensus suggests that ß-cell function can be clinically assessed using blood glucose-based methods or methods that combine blood glucose and endogenous insulin or C-peptide levels. Some measures, including weight loss and early and sustained euglycemia control, could effectively protect islet ß-cell function, and some newly developed drugs, such as Sodium-glucose cotransporter-2 inhibitor and Glucagon-like peptide-1 receptor agonists, could improve islet ß-cell function, independent of glycemic control.

Amelioration of diabetic kidney injury with dapagliflozin is associated with suppressing renal HMGB1 expression and restoring autophagy in obese mice.

Diabetic kidney disease (DKD) is a major cause of chronic and end-stage renal disease in diabetic patients. Here, we investigated protective effects and possible mechanisms of dapagliflozin on renal injury in diabetic mice. DKD mice were established by high fat diet (HFD) feeding. Half of DKD mice were randomly assigned to receive dapagliflozin treatment (200 µg/day) for 8 weeks. Renal lipid droplets, fibrosis, oxidative and endoplasmic reticulum stress were evaluated. Glomerular injury was assessed by immunohistochemistry and transmission electron microscopy. Dapagliflozin led to marked inhibition of ROS levels and endoplasmic reticulum stress in diabetic mice. HFD-induced loss of Podocin and Nephrin, and impaired podocytes were also improved with the treatment. Importantly, overexpression of HMGB1 and suppressed autophagy in the kidney were partly reversed by dapagliflozin. Therefore, we speculate that protective effects of dapagliflozin on DKD may be associated with suppression of HMGB1 expression and restoration of autophagy in the kidney.

Th1 bias of liver mucosal-associated invariant T cells promotes hepatic gluconeogenesis in type 2 diabetes mellitus.

AIMS: It is acknowledged that aberrant liver immunity contributes to the development of type 2 diabetes mellitus (T2DM). Mucosal-associated invariant T (MAIT) cells, an innate-like T-cell subset, are enriched in the human liver. Nevertheless, the characterisation and potential role of hepatic MAIT cells in T2DM remain unclear. MATERIALS AND METHODS: Fourteen newly diagnosed T2DM subjects and 15 controls received liver biopsy. The frequency and cytokine production of MAIT cells were analysed by flow cytometry. The expression of genes involved in glucose metabolism was determined in HepG2 cells co-cultured with hepatic MAIT cells. RESULTS: Compared with controls, hepatic MAIT cell frequency was significantly increased in T2DM patients (24.66% vs. 14.61%, p = 0.001). There were more MAIT cells producing interferon-γ (IFN-γ, 60.49% vs. 33.33%, p = 0.021) and tumour necrosis factor-α (TNF-α, 46.84% vs. 5.91%, p = 0.021) in T2DM than in controls, whereas their production of interleukin 17 (IL-17) was comparable (15.25% vs. 4.55%, p = 0.054). Notably, an IFN-γ+ TNF-α+ IL-17+/- producing MAIT cell subset was focussed, which showed an elevated proportion in T2DM (42.66% vs. 5.85%, p = 0.021) and positively correlated with plasma glucose levels. A co-culture experiment further indicated that hepatic MAIT cells from T2DM upregulated the gene expression of pyruvate carboxylase, a key molecule involved in gluconeogenesis, in HepG2 cells, and this response was blocked with neutralising antibodies against IFN-γ and TNF-α. CONCLUSIONS: Our data implicate an increased Th1-like MAIT cell subset in the liver of newly diagnosed T2DM subjects, which induces hyperglycaemia by promoting hepatic gluconeogenesis. It provides novel insights into the immune regulation of metabolic homoeostasis. CLINICAL TRIAL REGISTRATION NUMBER: NCT03296605 (registered at www. CLINICALTRIALS: gov on 12 October 2018).

Consensus of Chinese experts on strengthening personalized prevention and treatment of type 2 diabetes.

Up to now, there has not yet been guidance or consensus from Chinese experts in the field of personalized prevention and treatment of type 2 diabetes. In view of the above, the endocrinology diabetes Professional Committee of Chinese Non-government Medical Institutions Association, the integrated endocrinology diabetes Professional Committee of the integrated medicine branch of Chinese Medical Doctor Association, and the diabetes education and microvascular complications group of the diabetes branch of the Chinese Medical Association organized relevant experts to discuss and reach the "Chinese expert consensus on strengthening personalized prevention and treatment of type 2 diabetes" for reference in clinical practice.

Carotid atherosclerosis: An independent risk factor for small fiber nerve dysfunction in patients with type 2 diabetes mellitus.

AIMS/INTRODUCTION: To explore whether carotid atherosclerosis is an independent risk factor for small fiber nerve dysfunction in type 2 diabetes mellitus patients. MATERIALS AND METHODS: A total of 247 type 2 diabetes patients from Nanjing Drum Tower Hospital received carotid ultrasonography and quantitative sensory testing, including cold and warm detection thresholds, and some patients received cold and heat pain detection thresholds, respectively. According to the results of quantitative sensory testing, patients were divided into normal small fiber nerve function (NSF) and small fiber nerve dysfunction (SFD) group. Meanwhile, patients were divided into the non-carotid atherosclerosis group, carotid intimal thickening, unilateral carotid atherosclerosis and bilateral carotid atherosclerosis group. The correlation between carotid ultrasonography with quantitative sensory testing parameters was analyzed by SPSS 26.0. RESULTS: First, the incidence rate of SFD increased significantly in patients with carotid atherosclerosis (72.2%, P < 0.001) especially in bilateral carotid atherosclerosis (81.7%, P < 0.001). Second, compared with the NS group, the carotid intima-media thickness in SFD was thicker (P = 0.018) and the size of atherosclerotic plaque was larger (P < 0.001). In addition, the cold detection threshold decreased (P < 0.001), whereas the warm detection threshold (P < 0.001) and heat pain detection threshold (P < 0.001) increased as aggravation of carotid atherosclerosis. In the correlation analysis, the size of atherosclerotic plaque presented a positive correlation with the warm detection threshold (r = 0.476, P < 0.001) and heat pain detection threshold (r = 0.213, P < 0.001), but presented a negative correlation with the cold detection threshold (r = -0.239, P < 0.01). Furthermore, carotid atherosclerosis (odds ratio 2.326, P = 0.017), especially bilateral carotid atherosclerosis (odds ratio 5.042, P = 0.001), was an independent risk factor for SFD (P < 0.05). CONCLUSIONS: Carotid atherosclerosis was significantly associated with quantitative sensory testing and found to be an independent risk factor for small fiber nerve dysfunction in type 2 diabetes patients.

Altered brain spontaneous and synchronization activity in latent autoimmune diabetes in adults: A resting-state functional MRI study.

AIMS: This study aimed to explore the clinical features and spontaneous brain activity among patients with latent autoimmune diabetes in adults (LADA) and to investigate the relationship among these characteristics. METHODS: We conducted a cross-sectional study using cognitive assessments and resting-state functional magnetic resonance imaging (rs-fMRI) to evaluate the cognitive function and brain activities of healthy controls (HCs) and patients with LADA. Functional connectivity (FC) analysis was performed on the brain regions that showed significantly different activation in regional homogeneity (ReHo) analysis between the two groups. Furthermore, a linear regression model was conducted for the association between metabolism and cognition. RESULTS: This study enrolled patients with LADA (and age-, sex-, and education-matched HCs). Patients with LADA had worse cognitive status at the general level and poorer memory than controls. Rs-fMRI analysis among patients with LADA showed decreased ReHo values in the right occipital lobe and temporal lobe and decreased seed-based FC in the right parietal lobe compared to those of controls. The seed-based FC values in the right parietal lobe were positively associated with word fluency and processing speed in patients with LADA. Furthermore, low-density lipoprotein cholesterol was negatively correlated with Montreal Cognitive Assessment scores in patients with LADA. CONCLUSIONS: Patients with LADA had worse cognitive function and decreased spontaneous brain activity in the temporal lobe and occipital lobe compared to controls. Moreover, glycolipid metabolism was closely related to brain structure and function in patients with LADA.

Impaired Cognitive Function in Patients With Autonomous Cortisol Secretion in Adrenal Incidentalomas.

CONTEXT: Glucocorticoids have potent effects on the central nervous system. However, while patients with Cushing syndrome frequently report impairments in cognitive function, studies investigating cognitive function in patients with autonomous cortisol secretion (ACS) in adrenal incidentalomas (AIs) are scarce. OBJECTIVE: The aim of the present study was to evaluate neurocognitive function in patients with ACS. METHODS: We prospectively recruited 63 patients with AI, 36 patients with nonfunctional adrenal adenoma (NFA) (46.5 ± 10.5 years), and 27 patients with ACS (48.6 ± 9.1 years); these patients underwent a battery of validated neuropsychological tests. ACS was diagnosed when serum cortisol levels after a 1-mg dexamethasone suppression test (cortisol1 mg DST) ≥ 50 nmol/L. RESULTS: Patients with ACS had higher frequency of subjective memory complaints (40.7% vs 13.9%, P < 0.05) and higher proportion of mild cognitive impairment (22.2% vs 2.8%, P < 0.05) than patients with NFA. Furthermore, patients with ACS had worse performance on working memory and the visuospatial/constructional domain than patients with NFA (all P < 0.05). Serum cortisol1 mg DST was negatively correlated with working memory and visuospatial/constructional domains (r = -0.307 and -0.306, respectively, all P < 0.05). Performance on working memory and visuospatial/constructional domains gradually deteriorated with increases in serum cortisol1 mg DST (all P values for trend < 0.05). Multivariate linear regression analysis showed that serum cortisol1 mg DST was a significant risk factor for impairment of working memory and visuospatial/constructional domains (B = -0.006 and -0.043, respectively, all P < 0.05). CONCLUSION: This study is the first to report that ACS is accompanied by impaired cognitive function. Consequently, cognitive function assessment should be incorporated into the clinical evaluation of patients with ACS. CLINICAL TRIAL REGISTRATION NUMBER: NCT05357456.

Placenta-derived exosomes exacerbate beta cell dysfunction in gestational diabetes mellitus through delivery of miR-320b.

Recent studies have shown placenta-derived exosome (pdE) acts as an important mediator of organ-to-organ interplay regulating maternal metabolic alterations, however, the function and mechanisms of placental exosomes on pancreatic ß-cell maladaptation in gestational diabetes mellitus (GDM) remain unclear. The purpose of this investigation was to ascertain how placental exosomes affected the ß-cell dysfunction associated with the onset of GDM. Exosomes were isolated from chorionic villi explants of pregnant mice and humans with normal glucose tolerance (NGT) and GDM. The effects of pdE from GDM on glucose tolerance in vivo and islets function in vitro were determined. Isolated islets from mice fed on the chow diet displayed an increase in apoptosis and observed their glucose-stimulated insulin secretion (GSIS) greatly diminished by PdE from GDM mice. Mice that accepted PdE from mice with GDM possessed glucose intolerance.Based on miRNA microarray assay and bioinformatics analysis from human placental exosomes, we identified miR-320b selectively enriched in PdE secreted in GDM compared with NGT. Importantly, the level of placental miR-320b was positively correlated with the 1h-glucose and 2-h glucose of a 75 g oral glucose tolerance test (OGTT) during human pregnancies. Furthermore, miR-320 overexpression attributed to impaired insulin secretion and increased apoptosis in MIN6 cells and islets obtained from mice with normal insulin sensitivity. This study firstly proposed that altered miRNAs in pdE contribute to defective adaptation of ß cells during pregnancy, which expands the knowledge of GDM pathogenesis. Exosomes from the placenta may be an emerging therapeutic target for GDM.