The molecular mechanisms of early-onset multigenerational diabetes remain unknown. This study aimed to investigate the clinical and genetic characteristics of early-onset diabetes involving at least two consecutive generations. From 1296 inpatients with diabetes, we selected individuals who were ≤ 30 years of age and who were clinically suspected of having familial monogenic diabetes. Clinical data were collected from the probands and their family members. Whole-exome sequencing (WES) was used to identify possible causal variants for diabetes. Candidate pathogenic variants were verified by Sanger sequencing, assessed for cosegregation in family members, and evaluated on the basis of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines. Moreover, missense and synonymous variants were subjected to in silico pathogenicity prediction via MutationTaster and PolyPhen-2. RNAfold was used to predict RNA structural alterations for synonymous variants. Twenty-five early-onset diabetes patients with a history of familial diabetes were enrolled. Pathogenic/likely pathogenic variants (p.Gly292fs in HNF1A, p.Gly245Argfs*22 in PDX1, p.Asp329His in KCNJ11, p.Leu734Phe and p.Val606Gly in WFS1) were detected in four patients, who were diagnosed accurately and treated with reasonable hypoglycemic agents based on genetic testing results. The variants of uncertain significance (ABCC8 c.3039 G > A (p.Ser1013 = Ser), MAPK8IP1 p.Gln144_Gly145insSerGln, and TBC1D4 p.Arg1249Trp) were identified in three probands. Patients with early-onset diabetes involving at least two consecutive generations may harbor genetic variants. Genetic testing in this population enables precision diagnosis, informs individualized treatment, and facilitates genetic counseling.

To investigate the potential mediating effect of remnant cholesterol (RC) in the associations between angiopoietin-like 8 (ANGPTL8) and the risk of all-cause, cardiovascular disease (CVD), and cancer death. This prospective observational study included 3278 individuals from China. Binary logistic regression and mediation analyses were conducted to investigate the mediating effect of RC in the associations between ANGPTL8 and all-cause, CVD, and cancer death. During up to 5-year follow-up, a total of 265 deaths (8.08

Androgen insensitivity syndrome (AIS) is a rare disorder with X-linked recessive inheritance in 46 XY patients. The clinical manifestations vary between patients, especially regarding external genitalia development. Herein, the case of AIS in a 13-year-old male, who was born with hypospadias and presented to the hospital with gynaecomastia that had developed from 8 years of age, is reported. No micropenis, cryptorchidism or bifid scrotum were found. Testis volume was 12 ml on both sides. His testosterone and luteinizing hormone levels were normal compared with sex- and age-adjusted reference range. His bone age was approximately 13 years according to Greulich-Pyle assessment. Sequence analysis of the androgen receptor ( AR ) gene revealed a mutation (c.2041A>G) in exon 4, a novel mutation site in the AR gene. Prediction analysis suggested this to be a disease-causing variant. A milder clinical presentation and normal hormone levels in cases of partial AIS might differ from the usually reported signs and symptoms. A diagnosis of AIS should not be ignored in teenage patients who present with gynaecomastia and hypospadias, but normal hormone levels.

Previous studies have been limited by their inability to differentiate between the effects of insulin sensitivity and β-cell function on the risk of kidney function decline, cardiovascular disease (CVD), and all-cause mortality. To address this knowledge gap, we aimed to investigate whether the physiological subtypes based on homeostasis model assessment-2 (HOMA2) indices of β-cell function (HOMA2-B) and insulin sensitivity (HOMA2-S) could be used to identify individuals with subsequently high or low of clinical outcome risk. This retrospective cohort study included 7,317 participants with a follow-up of up to 5 years. Based on HOMA2 indices, participants were categorized into four physiologic subtypes: the normal phenotype (high insulin sensitivity and high β-cell function), the insulinopenic phenotype (high insulin sensitivity and low β-cell function), the hyperinsulinaemic phenotype (low insulin sensitivity and high β-cell function), and the classical phenotype (low insulin sensitivity and low β-cell function). The outcomes included kidney function decline, CVD events (fatal and nonfatal), and all-cause mortality. Cox regression models were used to calculate hazard ratios (HRs) for outcomes, and spline models were used to examine the dose-dependent associations of HOMA2-B and HOMA2-S with outcomes. A total of 1,488 (20.3

Background: Stickler syndrome (SS) is a group of hereditary collagenopathies caused by a variety of collagen and non-collagen genes. Affected patients have characteristic manifestations involving ophthalmic, articular, craniofacial and auditory disorders. SS is classified into several subtypes according to clinical and molecular features. Type 3 SS is an ultra-rare disease, known as non-ocular SS or otospondylomegaepiphyseal dysplasia (OSMED) with only a few pathogenic COL11A2 variants reported to date. Case presentation: A 29-year-old Chinese male was referred to our hospital for hearing loss and multiple joint pain. He presented a phenotype highly suggestive of OSMED, including progressive sensorineural deafness, spondyloepiphyseal dysplasia with large epiphyses, platyspondyly, degenerative osteoarthritis, and sunken nasal bridge. We detected compound heterozygous mutations in COL11A2, both of which were predicted to be splicing mutations. One is synonymous mutation c.3774C>T (p.Gly1258Gly) supposed to be a splice site mutation, the other is a novel intron mutation c.4750 + 5 G>A, which is a highly conservative site across several species. We also present a review of the current known pathogenic mutation spectrum of COL11A2 in patients with type 3 SS. Conclusion: Both synonymous extonic and intronic variants are easily overlooked by whole-exome sequencing. For patients with clinical manifestations suspected of SS syndrome, next-generation whole-genome sequencing is necessary for precision diagnosis and genetic counseling.

Objective:To summarize and analyze the clinical characteristics of hyperuricemia in adolescents, and improve the awareness of diagnosis and treatment among clinicians.Methods:Four adolescent cases of hyperuricemia with a clear family history were admitted to the Department of Endocrinology, Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology from November 2015 to August 2021. Their clinical manifestations, laboratory tests, gene sequencing, and therapeutic effects were analyzed.Results:Among the 4 patients, there were 2 cases with mutation in uromodulin(UMOD)gene(c.453C>T, 1 homozygous mutation in p. C151C; c. 453C>Y, 1 heterozygous mutation in p. C151C); 1 case with compound heterozygous mutation in adenosine triphosphate binding cassette transporter G2(ABCG2)gene(c.421C>A p. Q141K; c. 34G>A p. V12M); and 1 case with homozygous mutation in the ABCG2 gene(c.421C>A, p. Q141K). The blood uric acid levels of 4 patients decreased significantly after medical treatment and lifestyle interventions.Conclusions:In addition to primary etiology, the cause of hyperuricemia in the adolescent can be associated with certain acute and chronic diseases as well as genetic conditions. Genetic testing is recommended for patients with a family history. Medication safety should be stressed in the treatment of adolescents.

Aims: To investigate the associations between metabolic score for visceral fat (METS-VF) and clinical outcomes among populations with different glucose tolerance statuses.Methods: We analysed 6827 participants aged & GE; 40 years with different glucose tolerance statuses from a cohort study. The associations between METS-VF and cardiovascular disease (CVD) events and all-cause mortality were assessed using Cox regression, restricted cubic spline and receiver operating characteristic curves. Results: During a follow-up of 5.00 years, there were 338 CVD events and 307 subjects experienced all-cause death. The METS-VF quartile (Quartile 4 versus 1) was significantly related to CVD events [adjusted HRs and 95% CIs: 5.75 (2.67-12.42), 2.80 (1.76-4.48), and 3.31 (1.28-8.54) for subjects with normal glucose tolerance, prediabetes and diabetes, respectively] and all-cause mortality [adjusted HRs and 95% CIs: 2.80 (1.43-5.49), 4.15 (2.45-7.01), and 4.03 (1.72-9.42), respectively]. Restricted cubic spline suggested a dose-response asso-ciation of METS-VF with the risk of CVD events and all-cause mortality. The area under curve for CVD events and all-cause mortality was higher for METS-VF than for the other obesity and IR indexes in subjects with different glucose tolerance statuses. Conclusions: The METS-VF was associated with an increased risk of CVD events and all-cause mortality and could be used as a predictive index of the risk of CVD events and all-cause mortality among populations with different glucose tolerance statuses.

患者,42岁,社会性别男,已婚,未育,因"体检发现肾上腺肿物1周余"于2020年11月2日就诊于我院.患者2022年10月22日于当地医院体检,行腹部超声检查发现肾上腺肿块,CT检查提示双侧肾上腺结节灶,无明显不适症状,为求进一步诊治,来我院就诊,以"肾上腺肿物"收入院.患者30年前行尿道下裂手术,父母为近亲结婚,母亲孕期无特殊药物接触史.

患者,男,24岁,因"尿道下裂24年,双侧乳房发育9年"于2019年4月入院.患者24年前出生时即发现尿道下裂,伴右侧隐睾;22年前(2岁)行尿道下裂修复术;12年前(12岁)行右侧隐睾固定术,术后1 年出现右侧睾丸萎缩;9 年前( 15 岁)开始青春期发育,并发育迟缓,表现为阴茎短小,勃起长度约为5～6 cm,精液量少,伴胡须少、腋毛少、体毛少、喉结不突出.

Background Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) is a rare form of adrenal Cushing's syndrome. The slowly progressing expansion of bilateral adrenal tissues usually persists for dozens of years, leading to delayed onset with severe conditions due to chronic mild hypercortisolism. About 20-50% cases were found to be caused by inactivating mutation of armadillo repeat-containing protein 5 (ARMC5) gene. Case presentation A 51-year-old man was admitted for severe diabetes mellitus, resistant hypertension, centripedal obesity and edema. PBMAH was diagnosed after determination of adrenocorticotropic hormone and cortisol levels, dexamethasone suppression tests and abdominal contrast-enhanced CT scanning. The metabolic disorders of the patient remarkably improved after sequentially bilateral laparoscopic adrenalectomy combined with hormone replacement. Sanger sequencing showed germline nonsense mutation of ARMC5 c.967C>T (p.Gln323Ter). The second somatic missense mutation of ARMC5 was detected in one out of two resected nodules, reflecting the second-hit model of tumorigenesis. Routine genetic testing in his apparently healthy offspring showed one of two daughters and one son harbored the germline mutation. Conclusions In conclusion, our case report highlight the importance of genetic testing in the molecular diagnosis of PBMAH. Genetic screening in related family members will find out asymptomatic variant carriers to guide life-long follow-up.

Shi, Xiaoli; Ma, Delin; Li, Mengni; Xu, Weijie; Hu, Shuhong; Yu, Xuefeng; Yang, Yan Author Information

Acute myocardial infarction (AMI) is a scarce but fatal complication in Graves' disease (GD). Silent myocardial infarction (MI) associated with GD has never been reported. A 37-year-old male patient was admitted due to poorly controlled hyperthyroidism and persistent fever. But the patient did not complain of chest pain on admission. The electrocardiogram (ECG) showed Q waves and ST-segment elevations. Cardiac troponin I (cTnI) was sharply increased. He was qualified to an emergency coronary angiography which showed normal coronary arteries without any stenosis. The potential mechanisms for AMI with angiographically normal coronary arteries in the setting of hyperthyroidism may be attributed to the hyper-metabolic state due to thyrotoxicosis, severe vasospasm in coronary artery, coagulation abnormalities, and the inflammatory/autoimmune milieu. In conclusion, patients with GD-associated silent MI are unusual. Early recognition and diagnosis by clinicians provide a better prognosis. This case demonstrates the importance of ECG and cTnI screening among GD patients.

Background Insulinoma is the commonest functioning pancreatic neuroendocrine tumor causing hyperinsulinemic hypoglycemia. Aim This study is aimed to evaluate the clinical features, preoperative laboratory and imaging diagnosis and pathologic findings of insulinoma. Methods Data of the patients from 2001 to 2016 diagnosed as insulinoma in Tongji Hospital, China were retrospectively extracted and analyzed. Results A total of 40 patients were diagnosed as insulinoma with a male/female ratio of 0.68:1. The median onset age was 46.5 years. Nearly all the included patients presented neurological symptoms and 60% presented autonomic symptoms. More than 95% of the patients met the functional European Neuroendocrine Tumor Society criteria including glucose, insulin and C-peptide levels. The preoperative detection rates of ultrasonography, enhanced computed tomography, magnetic resonance imaging, and endoscopic ultrasonography were 60.50%, 84.95%, 80% and 83.3% respectively. The joint imaging examinations can markedly increase the detection rate. The mean tumor size was 1.89 ± 0.72 cm. Ki-67 index by histopathological diagnosis were all less than 20%. The positive rates of insulin, synaptophysin and chromogranin A were close to 100%. Conclusion Laboratory tests of glucose, insulin and C-peptide are reliable for preoperative diagnosis. Combination of the imaging examinations can improve the diagnosis.

Low-density lipoprotein (LDL) cholesterol (LDL-C) always underestimates the true cholesterol burden in diabetic patients. We aimed to explore the impact of the inclusion of apolipoprotein B (apoB) or non-high-density lipoprotein (HDL) cholesterol (non-HDL-C), which are alternative markers of LDL-related risk, results in a better classification of glycated hemoglobin (HbA1c)-defined diabetic patients into different dyslipidemic phenotypes.We used data from the nationwide China Health and Nutrition Survey 2009 in which standardized HbA1c was measured.The prevalence of abnormal LDL using non-HDL-cholesterol (74.1%) was similar to the prevalence rate using LDL-C (75.2%), whereas the prevalence was relatively lower when using apoB (69.6%). In normotriglyceridemic HbA1c-defined diabetic patients, apoB and non-HDL-C were not superior to LDL-C in detecting abnormal LDL. However, in hypertriglyceridemic patients, apoB and non-HDL-C were superior to LDL-C for the detection of abnormal lipid levels, but apoB was not superior to non-HDL-C in detecting abnormal LDL in hypertriglyceridemic participants.Both apoB and non-HDL-C identify high-risk dyslipidemic phenotypes that are not detected by LDL-C in hypertriglyceridemic HbA1c-defined diabetic patients, with the superiority of non-HDL- C over apoB.

Obesity could be classified into two phenotypes: metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUHO). This study investigated the ability of liver enzymes to identify obesity phenotype.

Congenital adrenal hyperplasia (CAH) is a rare autosomal recessive disorder caused by mutations in the cytochrome P450 family 17 subfamily A member 1 (CYP17A1) gene located on chromosome 10q24.3, which leads to a deficiency in 17 alpha-hydroxylase/17,20-lyase. The disorder is characterized by low blood levels of estrogens, androgens and cortisol, which leads to a compensatory increase in adrenocorticotropic hormone levels that stimulate the production of mineralocorticoid precursors. This subsequently leads to hypertension, hypokalemia, primary amenorrhea and sexual infantilism. Over 90 distinct genetic lesions have been identified in patients with this disorder. The prevalence of common mutation of CYP17A1 gene differs among ethnic groups. Treatment of this disorder involves replacement of glucocorticoids and sex steroids. Estrogen alone is prescribed for patients who are biologically male with 17 alpha-hydroxylase deficiencies that identify as female. However, genetically female patients may receive estrogen and progesterone supplementation. In the present study, a 17-year-old female with 17 alpha-hydroxylase/17,20-Iyase deficiency that presented with primary amenorrhea and sexual infantilism and no hypertension, was examined. The karyotype of the patient was 46, XX, and genetic analysis revealed the presence of a compound heterozygous mutation in exons 6 and 8, leading to the complete absence of 17 alpha-hydroxylase/17,20-Iyase activity. The patient was treated with prednisolone and ethinyl estradiol. In addition, a summary of the recent literature regarding CAH is presented.

Betatrophin is regarded as a liver-produced hormone induced by insulin resistance (IR). However, it remains largely unknown how IR regulates betatrophin expression. To study whether IR could regulate betatrophin expression and the corresponding molecular mechanisms, betatrophin levels were examined in 6 in vitro IR models which were established using human hepatocytes L02 with different agents, including tumor necrosis factor-α, interleukin-1β, dexamethasone, palmitate, high glucose and insulin and betatrophin levels were elevated only in the insulin group. These results suggest that it is insulin, not IR that promotes betatrophin expression. In the meantime, PI3K/Akt pathway was activated by insulin and suppressed by above agents that caused IR. Insulin-upregulated betatrophin expression was suppressed by PI3K/Akt inhibitors and IR, suggesting that insulin upregulates and IR decreases betatrophin production through PI3K/Akt pathway. Consistently, the treatment of insulin in mice dose-dependently upregulated betatrophin levels, and the administration of metformin in IR mice also stimulated betatrophin production since published study showed metformin improved PI3K/Akt pathway and IR. In humans, compared with those without insulin treatment, serum betatrophin levels were increased in type 2 diabetic patients with insulin treatment. In conclusion, insulin stimulates betatrophin secretion through PI3K/Akt pathway and IR may play an opposite role.

Objective To explore the clinical manifestations,diagnosis and treatments of the insulinoma.Methods The clinical data of 38 patients with insulinoma were retrospectively analyzed.Results Most insulinoma located in the body and tail of pancreas,presented with single and benign and characterized with fasting hypoglycemia as well as hyperinsulinism.In qualitative diagnosis,the false negative rates of insulin release index,amended insulin release index,C-peptide release index and amended C-peptide release index were 20.0%,36.0%,4.5% and 0% respectively.Meanwhile,the detection rate of ultrasound endoscopy was 86.7% which was the highest in the locative diagnosis.Conclusion Usually the patients of insulinoma are admitted with the psychological and nervous symptoms.The rates of missed diagnosis of the C-peptide release index and amended C-peptide release index are lower than those of insulin release index and amended insulin release index.Ultrasound endoscopy is superior to CT and MRI.

Aims/Introduction: Epidemiological evidence for the effect of omega-3 fatty acids on the risk of type 2 diabetes is controversial. A meta-analysis based on prospective cohorts was carried out to evaluate this issue.Materials and Methods: Pooled diabetic risk was calculated using a fixed or random effects model. The dose-response relationship was assessed by meta-regression analysis.Results: The study showed that consumption of single omega-3 was associated with an increased risk of type 2 diabetes (relative risk [RR] = 1.45, P < 0.001); whereas the RR for mixed omega-3 was statistically insignificant. The dose-response curve presented an inverted U-shape of diabetes risk corresponding to the dose of omega-3 consumption. Subanalysis showed that omega-3 was inversely associated with type 2 diabetes risk in Asians (RR = 0.82, P < 0.001); whereas the risk was increased in Westerners (RR = 1.30, P < 0.001). Studies with follow-up duration = 16 years and baseline age = 54 years showed a positive association between type 2 diabetes risk and omega-3 intake.Conclusions: The present findings suggest that dosage and composition of omega-3, ethnicity, trial duration, and age could influence the effect of omega-3 on type 2 diabetes progression.

Food intake has a great influence on blood glucose in patients with diabetes. This study was to determine the glycemic index (GI) and glycemic load (GL) of a particular pomelo named Majia pomelo and its effects on postprandial glucose (PPG) in patients with type 2 diabetes (T2D). Twenty healthy subjects and 20 T2D patients (controlled on lifestyle measures and/or metformin) were tested on 2 separate days with 50 g of glucose and 50 g equivalent of carbohydrates from Majia pomelo for GI measurement. To test effects of Majia pomelo on PPG, 19 hospitalized T2D patients (controlled on insulin therapy) were selected for a 9-day study. The dose of insulin for each patient was adjusted on the first 3 days. A total of 100 mg Majia pomelo was consumed per meal in the last 3 tested days. Blood glucose was measured to evaluate the glycemic excursions. The GIs for Majia pomelo in healthy individuals and T2D patients were 78.34±1.88 and 72.15±1.95 respectively. The value of GL was as low as 4.23 in diabetic patients with serving size of 100 g pomelo, indicting Majia pomelo as a high GI but low GL fruit. Consumption of Majia pomelo in hospitalized T2D patients did not cause significant glucose fluctuation. It was concluded that high GI pomelo can serve as a low GL fruit if it is consumed with a limited daily amount and thus can be supplied to diabetic patients. These results may mean more varieties of food choices for T2D patients.