Serum alanine transaminase is predictive of fasting and postprandial insulin and glucagon concentrations in type 2 diabetes.

The liver plays a key role in glucose homeostasis. Serum liver enzyme levels, including alanine transaminase (ALT), aspartate transaminase (AST) and gamma-glutamyl transferase (GGT), are reportedly predictive of the risk of type 2 diabetes (T2D). However, the link between the liver enzyme profile and metabolic derangements in T2D, particularly the secretion of both insulin and glucagon, is not clear. This study evaluated its relationships with glycemia, insulin and glucagon both during fasting and after an oral glucose load or a mixed meal in T2D. 15 healthy and 43 T2D subjects ingested a 75 g glucose drink. 86 T2D subjects consumed a mixed meal. Venous blood was sampled for measurements of blood glucose and plasma insulin, C-peptide and glucagon. Blood glucose, plasma insulin, C-peptide and glucagon concentrations, both fasting and after oral glucose, correlated directly with ALT, while fewer and weaker correlations were observed with GGT or AST. Subgroup analysis in T2D subjects ascertained that plasma insulin, C-peptide and glucagon concentrations after oral glucose were higher with increasing ALT. Similar findings were observed in the T2D subjects who received a mixed meal. In conclusion, serum liver enzyme profile, particularly ALT, reflects dysregulated fasting and nutrient-stimulated plasma insulin and glucagon concentrations in T2D.

Impaired antibody response to inactivated COVID-19 vaccines in hospitalized patients with type 2 diabetes.

Patients with type 2 diabetes (T2D) are at an increased risk of morbidity and mortality of coronavirus disease 2019 (COVID-19). Data on the antibody response to COVID-19 vaccines in T2D patients are less studied. This study aimed to evaluate IgG antibody response to inactivated COVID-19 vaccines in hospitalized T2D patients. Hospitalized patients with no history of COVID-19 and received two doses of inactivated COVID-19 vaccines (Sinopharm or CoronaVac) were included in this study from March to October 2021. SARS-CoV-2 specific IgG antibodies were measured 14-60 days after the second vaccine dose. A total of 209 participants, 96 with T2D and 113 non-diabetes patients, were included. The positive rate and median titer of IgG antibody against receptor-binding domain (anti-RBD) of spike (S) protein of SARS-CoV-2 in T2D group were lower than in control group (67.7% vs 83.2%, p = .009; 12.93 vs 17.42 AU/ml, p = .014) respectively. Similarly, seropositivity and median titers of IgG antibody against the nucleocapsid (N) and S proteins of SARS-CoV-2 (anti-N/S) in T2D group were lower than in control group (68.8% vs 83.2%, p = .032; 18.81 vs 29.57 AU/mL, p = .012) respectively. After adjustment for age, sex, BMI, vaccine type, days after the second vaccine dose, hypertension, kidney disease, and heart disease, T2D was identified as an independent risk factor for negative anti-RBD and anti-N/S seropositivity, odd ratio 0.42 (95% confidence interval 0.19, 0.89) and 0.42 (95% CI 0.20, 0.91), respectively. T2D is associated with impaired antibody response to inactivated COVID-19 vaccine.

Prevalence of Gastrointestinal Symptoms in Chinese Community-Dwelling Adults with and without Diabetes.

BACKGROUND: Gastrointestinal symptoms have been reported to occur frequently in diabetes, but their prevalence in Chinese community-dwelling individuals with diabetes is unknown. The present study aimed to address this issue and explore the risk factors for gastrointestinal symptoms. METHODS: A total of 1304 community-dwelling participants (214 with diabetes, 360 with prediabetes and 730 with normoglycemia) were surveyed for gastrointestinal symptoms using the Diabetes Bowel Symptom Questionnaire. Logistic regression analyses were applied to identify risk factors for gastrointestinal symptoms. RESULTS: Of the overall study population, 18.6% reported at least one gastrointestinal symptom, without a significant difference between subjects with normoglycemia (17.7%), prediabetes (19.7%) and diabetes (20.1%). In all three groups, lower gastrointestinal symptoms, particularly diarrhea and constipation, were the most frequent. There was an interaction between age (≥65 years) and diabetes on the prevalence of at least one gastrointestinal symptom (p = 0.01) and of constipation (p = 0.004), with these being most frequent in subjects with diabetes aged ≥ 65 years. After multivariable adjustment, female gender and older age were associated with increased odds of at least one gastrointestinal symptom, specifically lower gastrointestinal symptoms. Older age was also associated with an increase in upper gastrointestinal symptoms. CONCLUSIONS: Gastrointestinal symptoms are common in Chinese community-dwelling adults with and without diabetes. Females, and the elderly with diabetes, are at an increased risk of symptoms.

Association of a novel electrolyte index, SUSPPUP, based on the measurement of fasting serum and spot urinary sodium and potassium, with prediabetes and diabetes in Chinese population.

BACKGROUND: SUSPPUP, calculated as serum sodium [Na+] to urinary Na+ divided by (serum potassium [K+]) 2 to urinary K+, is a composite electrolyte index that reflects renal Na+ retention and K+ excretion. It remains unclear whether SUSPPUP and its components including serum or urinary Na+ or K+, are associated with glucose metabolism. This study aimed to address their associations. METHODS: We conducted a cross-sectional study enrolling 5,581 Chinese adults (1,269 with prediabetes, 1,044 with diabetes, and 3,268 with normoglycemia). Fasting serum and morning spot urine were used to measure electrolytes that included Na+ and K+. RESULTS: SUSPPUP was higher in prediabetes and diabetes than normoglycemia. The odds of prediabetes and diabetes were increased by 21% and 39% for every 1-standard deviation increment of SUSPPUP after multivariable-adjustment. Multiple linear regression analysis showed that SUSPPUP correlated positively with fasting plasma glucose, 2 h plasma glucose after OGTT, and glycated hemoglobin A1c. Higher spot urinary Na+ was associated with lower odds of prediabetes and diabetes, while spot urinary K+ showed the opposite. CONCLUSION: Increases in Na+ retention and K+ excretion in the kidney, as reflected by an elevated SUSPPUP, are associated with increased prevalence of prediabetes and diabetes in Chinese community-dwellers.

Cholecystectomy is associated with dysglycaemia: Cross-sectional and prospective analyses.

Cholecystectomy has been reported to be associated with increased risk of diabetes in cross-sectional studies. In the current study, we performed both cross-sectional and prospective analyses to examine the association between cholecystectomy and dysglycaemia in Chinese community-dwelling adults. A total of 1612 participants (n = 1564 without cholecystectomy and n = 48 with cholecystectomy) were evaluated for glycaemic status (according to the World Health Organization (WHO) 1999 criteria) and then followed up over ~3.2 years. Percent changes (Δ) in fasting blood glucose and HbA1c from baseline at the follow-up visit were calculated to define glycaemic control as stable (-10% ≤ Δ < 10%), improved (Δ < -10%), or worsened (Δ ≥ 10%). The baseline cross-sectional analyses indicated that cholecystectomy was associated with an increased risk of both prediabetes and diabetes, while the prospective analysis indicated that cholecystectomy was also associated with a greater risk of deterioration in glycaemic control (ΔFPG ≥10% and ΔHbA1c ≥10%) (P < 0.05 for each, both before and after adjusting for potential confounding covariates). These observations suggest that individuals in the Chinese community-dwelling population who have undergone cholecystectomy are at increased risk of dysglycaemia. Further studies are warranted to both delineate the underlying mechanisms and to clarify whether more intense surveillance for future development of diabetes is needed in this group.

Novel clusters of newly-diagnosed type 2 diabetes and their association with diabetic retinopathy: a 3-year follow-up study.

BACKGROUND: Cluster analysis may assist in stratifying heterogeneous clinical presentations of type 2 diabetes (T2D). However, the association of cluster-based subgroups with diabetes-related outcomes such as diabetic retinopathy remains unclear. This study was aimed to address this issue with novel clusters of T2D derived from four simple parameters. METHOD: We developed a k-means clustering model in participants with newly diagnosed T2D (N = 1910) from the SENSIBLE and SENSIBLE-Addition studies, based on body mass index (BMI), waist circumference (WC), mean arterial pressure (MAP), and hemoglobin A1c (HbA1c). Diabetic retinopathy was ascertained with the protocol from the Early Treatment of Diabetic Retinopathy Study. Participants (N = 515) without diabetic retinopathy at baseline were followed-up for 3 years. Logistic regression analyses were performed to obtain the odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Three clusters were identified, with cluster 0, 1 and 2 accounting for 48.2, 8.9 and 42.9%, respectively. Participants with T2D were featured by the lowest BMI, WC, MAP, and HbA1c in cluster 0, poor glycemic condition in cluster 1, and the highest BMI, WC, and MAP in cluster 2. Compared with cluster 0, cluster 1 was associated with increased odds of diabetic retinopathy in both the cross-sectional study (OR 6.25, 95% CI: 3.19-12.23) and the cohort study (OR 9.16, 95% CI: 2.08-40.34), while cluster 2 was not. Moreover, most participants remained their clusters unchanged during follow-up. CONCLUSIONS: Our cluster-based analysis showed that participants with poor glycemic condition rather than high blood pressure and obesity had higher risk of diabetic retinopathy.

Inflammatory bowel disease and diabetes: Is there a link between them?

Patients with inflammatory bowel disease (IBD) are reported to have an increased risk of diabetes. IBD therapies may also modulate blood glucose substantially. These observations are indicative of mechanistic connection(s) between IBD and diabetes.

Compound heterozygosity of a novel Q73X mutation and a known R141X mutation in CYP11B1 resulting in 11ß-hydroxylase deficiency in a Chinese boy with congenital adrenal hyperplasia.

Steroid 11ß-hydroxylase deficiency (11ß-OHD), which is caused by mutations of the CYP11B1 gene, is the second leading cause of congenital adrenal hyperplasia (CAH), an autosomal recessive inherited disorder. Here, we report a case of classic 11ß-OHD in a Chinese boy characterized by hypertension, penile enlargement, skin pigmentation, and acne. Molecular analysis of CYP11B1 revealed that the patient was compound heterozygous for a c.217C > T (p.Q73X) mutation in exon 1 and a c.421C > T (p.R141X) mutation in exon 3. His parents carried the novel c.217C > T (p.Q73X) mutation and the prevalent c.421C > T (p.R141X) mutation. Furthermore, we identified a novel 217-bp substitution mutation (Q73X) in CYP11B1 that generates a truncated protein without biological activity, which is likely to be pathogenic. Pursuant to the phenotype of the proband and his family, the Q73X mutation is inferred to exacerbate the disease burden of the R141X mutation, a known pathogenic variant. To further explore this possibility, selecting the x-ray structure of human CYP11B2 as a template, we built three-dimensional homologous models of the normal and mutant proteins. In the mutant model, a change from a helix to terminal structure in amino acids 73 and 141 occurred that affected the binding capacity of CYP11B1 with heme and impaired 11ß-hydroxylase activity. Taken together, our findings expand the spectrum of known mutations leading to 11ß-OHD and provide evidence to study genotype-phenotype concordance, confirm early diagnosis and treatment of 11ß-OHD, and prevent most complications.

Comparison of biomarkers of endothelial dysfunction and microvascular endothelial function in patients with primary aldosteronism and essential hypertension.

INTRODUCTION: Studies have shown that primary aldosteronism (PA) has a higher risk of cardiovascular events than essential hypertension (EH). Endothelial dysfunction is an independent predictor of cardiovascular events. Whether PA and EH differ in the endothelial dysfunction is uncertain. Our study was designed to investigate the levels of biomarkers of endothelial dysfunction (Asymmetric dimethylarginine, ADMA; E-selectin, and Plasminogen activator inhibitor-1, PAI-1) and assess the microvascular endothelial function in patients with PA and EH, respectively. METHODS: The biomarkers of endothelial dysfunction were measured by enzyme-linked immunosorbent assay (ELISA). Microvascular endothelial function was evaluated by Pulse amplitude tonometry (PAT). RESULTS: Thirty-one subjects with EH and 36 subjects with PA including 22 with aldosterone-producing adenoma (APA) and 14 with idiopathic hyperaldosteronism (IHA) were enrolled in our study. The ADMA levels among the three groups were different (APA 47.83 (27.50, 87.74) ng/ml vs EH 25.08 (22.44, 39.79) ng/ml vs IHA 26.00 (22.23, 33.75) ng/ml; p = 0.04), however, when the APA group was compared with EH and IHA group, there was no statistical significance (47.83 (27.50, 87.74) ng/ml vs 25.08 (22.44, 39.79) ng/ml for EH, p = 0.11; 47.83 (27.50, 87.74) ng/ml vs IHA 26.00 (33.75) ng/ml, p = 0.07). The results of ADMA levels are presented as Median (p25, p75). Whereas, levels of PAI-1 and E-selectin, microvascular endothelial function were not significantly different between PA and EH subjects. CONCLUSIONS: Our study shows no significant differences between PA and EH in terms of biomarkers of endothelial dysfunction and microvascular endothelial function. The microvascular endothelial function of PA and EH patients is comparable.

CSN6 Promotes the Migration and Invasion of Cervical Cancer Cells by Inhibiting Autophagic Degradation of Cathepsin L.

CSN6 is one subunit of the highly conserved constitutive photomorphogenesis 9 (COP9) signalosome (CSN), which is overexpressed in many types of cancers, and has received great attention as a regulator of the degradation of cancer-related proteins, suggesting its importance in oncogenic activity. CSN6 has been shown to be overexpressed in cervical cancer (CC) and associated with CC development. CC remains to be one of the most aggressive cancers affecting women. Cathepsin L (CTSL), significantly associated with the autophagy, plays a critical role in degradation of extracellular matrix for metastasis. However, the detailed biological functions of CSN6 on CTSL in CC metastasis have not been well clarified. Our data has shown that CSN6 and CTSL are positively correlated. The overexpression of CSN6 and CTSL might be a strong indicator for CC enhanced aggressiveness. CSN6 could suppress the degradation of CTSL, then facilitated the migration and invasion of CC cells. Interestingly, our results indicated that autophagy is essential for decreasing CTSL, while CSN6 could inhibit the autophagy ability of CC cells. In addition, blocking of the mammalian target of rapamycin (mTOR) pathway reversed CSN6-mediated autophagy inhibition. We further demonstrated that CSN6 positively regulated CTSL expression through an autophagy-lysosomal system. Taken together, we concluded that CSN6 might promote the migration and invasion of cervical cancer cells by inhibiting autophagic degradation of CTSL and serve as a potential gene therapy target for the treatment of CC metastasis.

Simultaneous occurrence of primary aldosteronism due to aldosteronoma and ectopic meningioma in the adrenal gland: A case report.

RATIONALE: Primary aldosteronism due to aldosteronoma is the most common form of secondary hypertension, with an estimated prevalence of 4% of hypertensive patients in primary care and around 10% of referred patients. Diagnosis is a clinical challenge with simultaneous occurrence of primary ectopic meningioma in the adrenal gland. To our knowledge this is the first reported case of simultaneous occurrence of aldosteronomas and ectopic meningioma in the adrenal gland based on literatures. PATIENT CONCERNS: A 30-year-old man presented with resistant hypertension for one year. The computed tomographic scans were suggestive of left adrenal gland hyperplasia. INTERVENTION: The patient underwent partial unilateral laparoscopic adrenalectomy. DIAGNOSIS: The histopathological examination of the resected sample confirmed primary ectopic meningioma in adrenal gland and aldosterone producing adenoma (APA). The saline load test, captopril test, and plasma aldosterone/renin ratio were indicative of primary aldosteronism (PA). OUTCOMES: The patient had controlled blood pressure postoperatively. LESSONS: The patient was diagnosed with PA due to APA and nonfunctional primary ectopic meningioma in the adrenal gland which is very rare and dealt with unilateral laparoscopic adrenalectomy.

Suppression of Jab1 expression inhibits proliferation and promotes apoptosis of AMC-HN-8 cells.

c-Jun activation domain-binding protein-1 (Jab1) is a multifunctional protein involved in cell proliferation and apoptosis, DNA damage and repair and genome stability. In a number of types of human carcinoma, the abnormal expression of Jab1 is associated with poor prognosis, suggesting that Jab1 serves a vital function in tumorigenesis. However, the functional effects and the underlying molecular mechanisms of Jab1 in laryngeal squamous cell carcinoma (LSCC) progression remain poorly understood. The results of the present study demonstrate that downregulating Jab1 expression promotes LSCC apoptosis while inhibiting the proliferation of LSCC cells. Furthermore, Jab1 inhibition results in decreased protein kinase B phosphorylation accompanied by increased caspase-3 cleavage and p53 expression. It has been identified that the increased expression of Jab1 is markedly associated with LSCC progression, therefore Jab1 may be used as a novel target for the treatment of laryngeal cancer.

Suppression of CSN5 promotes the apoptosis of gastric cancer cells through regulating p53-related apoptotic pathways.

As one of the COP9 signalosome complex, CSN5 (also known as Jab1) has been confirmed overexpression in many human cancers and affected multiple pathways associating with cell proliferation and apoptosis. Correlation of CSN5 overexpression with poor prognosis for cancer provides evidence that it is involved in the tumorigenesis. However, little is known about the functional role and the underlying mechanism of CSN5 in gastric cancer progression. In the current study, the effect of CSN5 siRNA (small-interfering RNA) on the proliferation and apoptosis of human gastric cancer cells (AGS and MKN45) were examined. Our results showed that knockdown of CSN5 could inhibit proliferation and promote apoptosis of gastric cancer cells. Additionally, suppression of CSN5 expression contributed to the increased expression levels of p53 and Bax. In conclusion, CSN5 overexpression is significantly correlated with gastric cancer progression, and CSN5 could be a novel target in gastric cancer therapy.

[Identification analysis of eukaryotic expression plasmid Rap2a and its effect on the migration of lung cancer cells].

BACKGROUND: Rap2a, a member of the small GTPase superfamily, plays a critical role in regulating the function of integrin and cell adhesion, thereby controlling cell motility and cell/matrix interactions. However, the function of Rap2a in carcinogenesis is still poorly understood. To clone Rap2a cDNA, which belongs to human Ras-related small G protein superfamily, we constructed its eukaryotic expression vector and determined its expression in lung cancer cells. The aim of this study is to explore the role of Rap2a in carcinogenesis. METHODS: The levels of endogenous Rap2a protein in lung cancer cells were measured by Western blot. Total RNA of human osteosarcoma cells U2OS was extracted and reverse-transcribed into cDNA by RT-PCR. Then, Rap2a gene was amplified by PCR and inserted into pcDNA3.1(+). The reconstructed plasmid was identified by restricted enzyme digestion and sequencing. pcDNA3.1(+)-Rap2a was transfected into H1299 and A549 cells, the expression of Rap2a was detected by Western blot. In addition, the migratory abilities of lung cancer cells were evaluated by Transwell assay. Matrix metalloproteinase (MMP)2 enzyme activity was evaluated by gelatin zymography. RESULTS: Rap2a is significantly upregulated in lung cancer cells. The results of enzyme digestion and sequencing showed that the coding sequence of pcDNA3.1(+)-Rap2a was right and was inserted into the vector correctly. The results of Western blot showed that H1299 and A549 cells were transfected successfully. Transwell assay indicated that the ectopic expression of Rap2a promotes lung cancer cells migration. Correspondly, enzyme activity of MMP2 also increased. CONCLUSIONS: Eukaryotic expression plasmid pcDNA3.1(+)-Rap2a was constructed successfully. Rap2a could be expressed in lung cancer cells efficiently and promotes lung cancer cell migration.