Hepatocyte nuclear factor 1B deletion, but not intragenic mutation, might be more susceptible to hypomagnesemia.

AIMS: HNF1B syndrome is caused by defects in the hepatocyte nuclear factor 1B (HNF1B) gene, which leads to maturity-onset diabetes of the young type 5 and congenital organ malformations. This study aimed to identify a gene defect in a patient presenting with diabetes and severe diarrhea, while also analyzing the prevalence of hypomagnesemia and its correlation with the HNF1B genotype. MATERIALS AND METHODS: Whole exome sequencing was used to identify responsible point mutations and small indels in the proband and their family members. Multiplex ligation-dependent probe amplification was carried out to identify HNF1B deletions. Furthermore, an analysis of published data on 539 cumulative HNF1B cases, from 29 literature sources, was carried out to determine the correlation between the HNF1B genotype and the phenotype of serum magnesium status. RESULTS: Using multiplex ligation-dependent probe amplification, we identified a de novo heterozygous HNF1B deletion in the patient, who showed dorsal pancreas agenesis and multiple kidney cysts, as detected by magnetic resonance imaging. Magnesium supplementation effectively alleviated the symptoms of diarrhea. Hypomagnesemia was highly prevalent in 192 out of 354 (54.2%) patients with HNF1B syndrome. Compared with patients with intragenic mutations, those with HNF1B deletions were more likely to suffer from hypomagnesemia, with an odds ratio of 3.1 (95% confidence interval 1.8-5.4). CONCLUSIONS: Hypomagnesemia is highly prevalent in individuals with HNF1B syndrome, and those with HNF1B deletion are more susceptible to developing hypomagnesemia compared with those with intragenic mutations. The genotype-phenotype associations in HNF1B syndrome have significant implications for endocrinologists in terms of genotype detection, treatment decisions and prognosis assessment.

Exploring the Temporal Correlation of Sarcopenia with Bone Mineral Density and the Effects of Osteoblast-Derived Exosomes on Myoblasts through an Oxidative Stress-Related Gene.

Sarcopenia is an age-related accelerated loss of muscle strength and mass. Bone and muscle are closely related as they are physically adjacent, and bone can influence muscle. However, the temporal association between bone mineral density (BMD) and muscle mass in different regions of the body after adjustment for potential indicators and the mechanisms by which bone influences muscle in sarcopenia remain unclear. Therefore, this study aimed to explore the temporal association between muscle mass and BMD in different regions of the body and mechanisms by which bone regulates muscle in sarcopenia. Here, cross-lagged models were utilized to analyze the temporal association between BMD and muscle mass. We found that low-density lipoprotein (LDL-C) positively predicted appendicular lean mass. Mean whole-body BMD (WBTOT BMD), lumbar spine BMD (LS BMD), and pelvic BMD (PELV BMD) temporally and positively predicted appendicular lean mass, and appendicular lean mass temporally and positively predicted WBTOT BMD, LS BMD, and PELV BMD. Moreover, this study revealed that primary mice femur osteoblasts, but not primary mice skull osteoblasts, induced differentiation of C2C12 myoblasts through exosomes. Furthermore, the level of long noncoding RNA (lncRNA) taurine upregulated 1 (TUG1) was decreased, and the level of lncRNA differentiation antagonizing nonprotein coding RNA (DANCR) was increased in skull osteoblast-derived exosomes, the opposite of femur osteoblast-secreted exosomes. In addition, lncRNA TUG1 enhanced and lncRNA DANCR suppressed the differentiation of myoblasts through regulating the transcription of oxidative stress-related myogenin (Myog) gene by modifying the binding of myogenic factor 5 (Myf5) to the Myog gene promoter via affecting the nuclear translocation of Myf5. The results of the present study may provide novel diagnostic biomarkers and therapeutic targets for sarcopenia.

The longitudinal associations between bone mineral density and appendicular skeletal muscle mass in Chinese community-dwelling middle aged and elderly men.

BACKGROUND: The present study aimed to investigate longitudinal associations between bone mineral densities (BMDs) and appendicular skeletal muscle (ASM) mass in different regions of the body using three different indicators, in Chinese community-dwelling middle-aged and elderly men. METHODS: A total of 1,343 men aged ≥ 40 years from a Chinese community were assessed at baseline (2014-2016), one-year follow-up (2016-2017; n = 648), two-year follow-up (2017-2018; n = 407), and three-year follow up (2018-2019; n = 208). At all the four time-points, measurements included ASM mass and BMDs for all regions of the body using dual-energy X-ray absorptiometry. A questionnaire was completed by patients and biochemical markers were assessed. We applied three different indicators to define ASM mass or lean mass respectively, including the appendicular skeletal muscle index (ASM adjusted by height, ASMI, according to the Asian Working Group for Sarcopenia), skeletal muscle index (ASM adjusted by weight, SMI, according to the International Working Group on Sarcopenia), and the appendicular skeletal muscle/body mass index (ratio of ASM and Body mass index (BMI), ASM/BMI, according to the Foundation for the National Institutes of Health). After adjusting for potential confounders, the generalized additive mixed model (GAMM) was used to analyze the trend in ASM mass over time, and to test the association between ASM mass and regional and whole-body BMDs. RESULTS: The incidence of low lean mass was 8.2% defined by ASMI, 16.3% defined by SMI, and 8.3% defined by ASM/BMI. There was a linear relationship between BMDs and ASM mass, and ASMI, ASM/BMI, and SMI gradually decreased with time. After adjusting for covariances, GAMM analysis determined longitudinal associations between BMDs and ASM mass by three indicators respectively: the skull BMD was negatively associated with ASM mass. For each unit increase in skull BMD, ASMI decreased by 0.28 kg/m2 (95% confidence interval (CI) [-0.39 to -0.16]), ASM/BMI decreased by 0.02 m2 (95% CI [-0.03 to -0.00]), and SMI decreased by 0.01% (95% CI[-0.01 to -0.00]). The remaining parameters (including whole-body mean BMD, thoracic spinal BMD, lumbar spinal BMD, hip BMD, femoral neck BMD, pelvic BMD, left arm BMD, right arm BMD, left leg BMD, right leg BMD) were positively correlated with ASM mass. The ASMI increased by 3.07 kg/m2for each unit increase in the femoral neck BMD (95% CI [2.31-3.84]). The ASM/BMI increased by 0.22 m2for each unit increase in the left arm BMD (95% CI [0.12-0.33]), and the SMI increased by 0.05% per unit increase in the left arm BMD (95% CI [0.02-0.08]). CONCLUSIONS: Compared to ASMI and ASM/BMI, SMI was more sensitive to screen for the low lean mass. Skull BMD was negatively associated with ASM mass, while BMDs throughout the rest of the body were positively correlated with ASM mass among the middle-aged and elderly Chinese men.

Dysfunction and Therapeutic Potential of Endothelial Progenitor Cells in Diabetes Mellitus.

Diabetes mellitus (DM) is a chronic, multifactorial metabolic disease whereby insulin deficiency or resistance results in hyperglycemia. Endothelial cells (ECs) form the innermost layer of the blood vessel and produce and release a variety of vasoactive substances and growth factors to regulate vascular homeostasis and angiogenesis. Hyperglycemia and insulin resistance can cause endothelial dysfunction, leading to vascular complications such as coronary artery disease, peripheral arterial disease, diabetic nephropathy, neuropathy and retinopathy. The detrimental effect exerted on ECs by hyperglycemia and insulin resistance underlines the importance of reparatory mechanisms in DM. Endothelial progenitor cells (EPCs), derived from bone marrow, have been recognized as endogenous cells involved in endothelial repair and new blood vessel formation. Initially isolated from a subset of circulating CD34+ mononuclear cells, EPCs were found to possess the ability to differentiate into ECs when cultured in vitro and incorporate into newly formed vessels upon transplantation in animal models of ischemia. Due to the low frequency of CD34+ cells in circulation, the vast majority of studies investigating EPC actions have used cells that are generated through the culture of peripheral blood mononuclear cells (PBMNCs) for 4 - 7 days in endothelial selective medium. These cells, mainly of myeloid hematopoietic cell origin, were termed "Early EPCs," of which, few expressed stem/progenitor-cell markers. Therefore, early EPCs were also termed "myeloid angiogenic cells" (MACs). When PBMNCs are cultured for over 2 weeks, early EPCs gradually diminish while so-called late EPCs appear. Late EPCs share phenotypic features with mature ECs and are therefore also termed blood-derived ECs; they will not be addressed in this review. MAC dysfunction has been observed in a variety of disease conditions including DM. In this article we review the activities and therapeutic potential of MACs in DM. We will interchangeably use "EPCs" and "MACs" to refer to the cells procured by culture of PBMNCs in EC selective medium for approximately 7 days.

Liraglutide regulates the viability of pancreatic α-cells and pancreatic ß-cells through cAMP-PKA signal pathway.

AIMS: As a glucagon-like peptide-1 receptor agonist, liraglutide could effectively increase insulin secretion from pancreatic ß-cells and suppress glucagon secretion from pancreatic α-cells in the treatment of hyperglycemia in type 2 diabetes patients. However, the mechanisms for the different regulation of pancreatic α-cells and ß-cells are still unclear. In this study, we mainly explored the different effects of liraglutide on mouse pancreatic α-cell line and ß-cell line in vitro. MAIN METHODS: Herein, mouse pancreatic α-cell line, α-TC1-6, and mouse pancreatic ß-cell line, ß-TC-tet, were used to analyze the biological effects of liraglutide in different concentrations. Cell proliferation, cell apoptosis and cell secretion ability were detected in different groups. Besides, the level of miR-375 and cAMP-PKA signal pathway were further evaluated using qPCR and western blot. KEY FINDINGS: The results indicated that liraglutide could increase the level of miR-375 and cell apoptosis in pancreatic α-cells through inhibiting the cAMP-PKA signal pathway, but activate cAMP-PKA signal pathway in pancreatic ß-cells, and further lead to the down-regulation of miR-375 and improve cell viability. Therefore, the treatment with liraglutide could down-regulate the glucagon secretion ability of α-TC1-6 cells, and the insulin secretion ability of ß-TC-tet cells was enhanced with the liraglutide treatment in a dose-dependent manner. SIGNIFICANCE: In conclusion, we mainly found that liraglutide could regulate the viability of pancreatic α-cells and pancreatic ß-cells through inhibiting and activating cAMP-PKA signal pathway respectively. The better understanding of the mechanism could help us to develop more novel therapy methods for diabetes in the future.

Relationship between glycated albumin and glycated hemoglobin according to glucose tolerance status: A multicenter study.

AIMS: To determine the relationship between glycated albumin (GA) and glycated hemoglobin (HbA1c) and to explore the association of glycated albumin/glycated hemoglobin (GA/HbA1c) ratio with glucose indices in Chinese subjects with varying glucose tolerance status. METHODS: This hospital-based, cross-sectional study involved 953 participants without known diabetes from 11 centers in China. Oral glucose tolerance test (OGTT) was used to identify three groups of subjects: normal glucose regulation (n=194), impaired glucose regulation (n=303) and newly diagnosed type 2 diabetes group (n=456). The GA, HbA1c and GA/HbA1c ratio were tested. RESULTS: GA was positively correlated with HbA1c (r=0.832, P<0.001). After correcting for age, sex and BMI, the correlations remained significant (r=0.824, P<0.001). Linear regression analysis estimated that a 1% increase of HbA1c was associated with a 2.84% increase of GA (GA=2.843×HbA1c-0.203; R(2)=0.692, P<0.001). GA would be 18.3 (16.7-19.9)% and 19.7 (18.0-21.4)% with HbA1c of 6.5% (48mmol/mol) and 7.0% (53mmol/mol). The mean GA/HbA1c ratio was 2.81±0.38, and it significantly increased with the presence of glucose intolerance (all, P<0.05). In the total study population, GA/HbA1c was correlated with BMI, glucose levels and 30-min insulin during OGTT, the homeostatic model assessment of ß-cell function (HOMA-ß), and ΔI30/ΔG30 (all, P<0.05). Increased glucose at 30min (standardized ß=0.221, P<0.001), and decreased BMI (standardized ß=-0.114, P=0.008) were associated with elevated GA/HbA1c ratio by multiple linear regression (adjusted R(2)=0.045). CONCLUSIONS: The relationship between GA and HbA1c was strong. The GA/HbA1c ratio was related to acute postprandial glucose fluctuation and BMI level.

Efficacy and Safety of 1-Hour Infusion of Recombinant Human Atrial Natriuretic Peptide in Patients With Acute Decompensated Heart Failure: A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial.

The aim of the study was to evaluate the efficacy and safety of 1-h infusion of recombinant human atrial natriuretic peptide (rhANP) in combination with standard therapy in patients with acute decompensated heart failure (ADHF). This was a phase III, randomized, double-blind, placebo-controlled, multicenter trial. Eligible patients with ADHF were randomized to receive a 1-h infusion of either rhANP or placebo at a ratio of 3:1 in combination with standard therapy. The primary endpoint was dyspnea improvement (a decrease of at least 2 grades of dyspnea severity at 12 h from baseline). Reduction in pulmonary capillary wedge pressure (PCWP) 1 h after infusion was the co-primary endpoint for catheterized patients. Overall, 477 patients were randomized: 358 (93 catheterized) patients received rhANP and 118 (28 catheterized) received placebo. The percentage of patients with dyspnea improvement at 12 h was higher, although not statistically significant, in the rhANP group than in the placebo group (32.0% vs 25.4%, odds ratio=1.382, 95% confidence interval [CI]: 0.863-2.212, P = 0.17). Reduction in PCWP at 1 h was significantly greater in patients treated with rhANP than in patients treated with placebo (-7.74 ±â€Š5.95 vs -1.82 ±â€Š4.47 mm Hg, P < 0.001). The frequencies of adverse events and renal impairment within 3 days of treatment were similar between the 2 groups. Mortality at 1 month was 3.1% in the rhANP group vs 2.5% in the placebo group (hazard ratio = 1.21, 95% CI: 0.34-4.26; P > 0.99). 1-h rhANP infusion appears to result in prompt, transient hemodynamic improvement with a small, nonsignificant, effect on dyspnea in ADHF patients receiving standard therapy. The safety of 1-h infusion of rhANP seems to be acceptable. (WHO International Clinical Trials Registry Platform [ICTRP] number, ChiCTR-IPR-14005719.).

Relationship between HbA1c and continuous glucose monitoring in Chinese population: a multicenter study.

OBJECTIVE: Since there is a paucity of reference data in the literature to indicate the relationship between HbA1c, and 24 h mean blood glucose (MBG) from continuous glucose monitoring (CGM) in Chinese populations, we described the above relationship in adult Chinese subjects with different glucose tolerance status. METHODS: Seven-hundred-and-forty-two individuals without history of diabetes were included to the study at 11 hospitals in urban areas across China from 2007-2009 and data of 673 subjects were included into the final analysis. Oral glucose tolerance test (OGTT) classified the participants as nondiabetic subjects, including those with normal glucose regulation (NGR; n = 121) and impaired glucose regulation (IGR; n = 209), or newly diagnosed type 2 diabetes (n = 343). All participants completed testing for HbA1c levels and wore a CGM system for three consecutive days. The 24 h MBG levels were calculated. Spearman correlations and linear regression analyses were applied to quantify the relationship between glucose markers. RESULTS: The levels of HbA1c and 24 h MBG significantly increased with presence of glucose intolerance (NGR

Alanine aminotransferase is associated with an adverse nocturnal blood glucose profile in individuals with normal glucose regulation.

OBJECTIVE: Although the association between alanine aminotransferase (ALT) levels and risk of type 2 diabetes is well-studied, the effects of slightly increased ALT levels within the normal range on the temporal normal glucose profile remains poorly understood. METHODS: A total of 322 Chinese subjects without impaired glucose tolerance or previous diagnoses of diabetes were recruited for study from 10 hospitals in urban areas across China. All subjects wore a continuous glucose monitoring (CGM) system for three consecutive days. The diurnal (06∶00-20∶00) and nocturnal (20∶00-06∶00) mean blood glucose (MBG) levels were calculated. Subjects were stratified by ALT quartile level and correlation analyses were performed. RESULTS: The median ALT level was 17 IU/L, and subjects with ALT ≥17 IU/L had higher nocturnal MBG level than those with ALT <17 IU/L (P<0.05). Nocturnal MBG was positively correlated with ALT levels (Pearson correlation analysis: r = 0.187, P = 0.001), and the correlation remained significant after correction for the homeostatic model assessment of insulin resistance index (HOMA-IR) (r = 0.105, P = 0.041). No correlations were found between diurnal MBG and ALT, and nocturnal or diurnal MBG and aspartate aminotransferase or gamma-glutamyltransferase (all, P>0.05). Multivariate stepwise regression analysis of elevated nocturnal MBG identified increased HOMA-IR, elevated ALT levels, and decreased homeostatic model assessment of ß-cell function as independent factors (all, P<0.05). CONCLUSIONS: Mildly elevated ALT levels, within the normal range, are associated with unfavorable nocturnal glucose profiles in Chinese subjects with normal glucose regulation.

Establishment of normal reference ranges for glycemic variability in Chinese subjects using continuous glucose monitoring.

BACKGROUND: Glycemic variability is increasingly recognized as an important issue in diabetes management. However, the lack of normative values may limit its applicability in the clinical setting. The objective of this study was to establish preliminary normal reference ranges for glycemic variability by analyzing continuous glucose monitoring (CGM) data obtained from healthy Chinese adults. MATERIAL/METHODS: Three-day CGM data were obtained from 434 healthy adults at 10 academic hospitals throughout China. Glycemic variability was calculated as the 24-hour mean amplitude of glycemic excursions (MAGE) and standard deviations (SD) of blood glucose readings. RESULTS: 434 healthy subjects (male 213, female 221; age 43 ± 14, 20-69 years old; BMI 21.8 ± 1.7 kg/m2, 18.5-24.9 kg/m2) completed the study. MAGE and SD values for the 434 healthy subjects were 1.73 (1.08) mmol/L and 0.75 (0.42) mmol/L [median (interquartile range)], respectively. In both men and women, MAGE and SD tended to increase with age. Neither MAGE nor SD showed a significant difference between men and women. Values for both parameters were non-normally distributed within the population. The 95th percentiles of MAGE and SD were 3.86 and 1.40 mmol/L, respectively. These values were adopted as the upper limits of normal.< CONCLUSIONS: MAGE <3.9 mmol/L and SD <1.4 mmol/L are recommended as the normal reference ranges for glycemic variability in Chinese adults. The values established in this study may facilitate the adoption of glycemic variability as a metric of overall glycemic control in diabetes.

[A multi-center clinical study of the reference value of serum glycated albumin].

OBJECTIVE: To set up the reference value of serum glycated albumin (GA) in Chinese for using in clinical practice through a multi-center clinical trial. METHODS: Three hundred and eighty individuals with normal weight and normal glucose regulation, including 183 males and 197 females ranging from 20 to 69 years, were recruited from 10 hospitals in China Serum GA levels were measured with liquid enzymatic method. RESULTS: (1) The GA level of the 380 subjects was (14.5 +/- 1.9)%. When dividing these subjects by age into 3 subgroups, there was no difference in the GA levels among the 3 subgroups (P > 0.05). Compared with the women, the men had higher GA level in the first subgroup aging from 20 to 39 (P = 0.028). However, no significant difference was detected after adjusting with BMI as confounder. (2) When dividing those subjects by BMI into 3 subgroups, with BMI ranging from 18.5-20.9 kg/m2 21.0-22.9 kg/m2 and 23.0-24.9 kg/m2 respectively, we came to the following results: for men, there was no difference in the GA levels among the 3 subgroups (P > 0.05), but for women, the GA level of the first subgroup was higher than that of the second subgroup (P = 0.024). (3) The level of GA in the 2.5th to 97.5th percentile was 10.8%-17.1%. (4) Sixty normal subjects were chosen to repeat evaluation of GA levels after 2-3 weeks and the GA levels were of no difference (P > 0.05). CONCLUSION: The normal range of serum GA for the Chinese population could be suggested at 11%-17%.

Reference values for continuous glucose monitoring in Chinese subjects.

OBJECTIVE: The widespread clinical application of continuous glucose monitoring (CGM) is limited by the lack of generally accepted reference values. This multicenter study aims to establish preliminary normal reference values for CGM parameters in a sample of healthy Chinese subjects. RESEARCH DESIGN AND METHODS: A total of 434 healthy individuals with normal glucose regulation completed a 3-day period of glucose monitoring using a CGM system. The 24-h mean blood glucose (24-h MBG) and the percentage of time that subjects' blood glucose levels were >or=140 mg/dl (PT140) and