Early-onset Diabetes Research Articles

Bax Inhibitor-1 preserves pancreatic β-cell proteostasis by limiting proinsulin misfolding and programmed cell death

The prevalence of diabetes steadily increases worldwide mirroring the prevalence of obesity. Endoplasmic reticulum (ER) stress is activated in diabetes and contributes to β-cell dysfunction and apoptosis through the activation of a terminal unfolded protein response (UPR). Our results uncover a new role for Bax Inhibitor-One (BI-1), a negative regulator of inositol-requiring enzyme 1 (IRE1α) in preserving β-cell health against terminal UPR-induced apoptosis and pyroptosis in the context of supraphysiological loads of insulin production. BI-1-deficient mice experience a decline in endocrine pancreatic function in physiological and pathophysiological conditions, namely obesity induced by high-fat diet (HFD). We observed early-onset diabetes characterized by hyperglycemia, reduced serum insulin levels, β-cell loss, increased pancreatic lipases and pro-inflammatory cytokines, and the progression of metabolic dysfunction. Pancreatic section analysis revealed that BI-1 deletion overburdens unfolded proinsulin in the ER of β-cells, confirmed by ultrastructural signs of ER stress with overwhelmed IRE1α endoribonuclease (RNase) activity in freshly isolated islets. ER stress led to β-cell dysfunction and islet loss, due to an increase in immature proinsulin granules and defects in insulin crystallization with the presence of Rod-like granules. These results correlated with the induction of autophagy, ER phagy, and crinophagy quality control mechanisms, likely to alleviate the atypical accumulation of misfolded proinsulin in the ER. In fine, BI-1 in β-cells limited IRE1α RNase activity from triggering programmed β-cell death through apoptosis and pyroptosis (caspase-1, IL-1β) via NLRP3 inflammasome activation and metabolic dysfunction. Pharmaceutical IRE1α inhibition with STF-083010 reversed β-cell failure and normalized the metabolic phenotype. These results uncover a new protective role for BI-1 in pancreatic β-cell physiology as a stress integrator to modulate the UPR triggered by accumulating unfolded proinsulin in the ER, as well as autophagy and programmed cell death, with consequences on β-cell function and insulin secretion.In pancreatic β-cells, BI-1–/– deficiency perturbs proteostasis with proinsulin misfolding, ER stress, terminal UPR with overwhelmed IRE1α/XBP1s/CHOP activation, inflammation, β-cell programmed cell death, and diabetes.

Variants APOA5 p.G185C and p.S19W associated with early-onset severe hypertriglyceridemia-induced pancreatitis and diabetes complications in a Vietnamese girl

An imbalance of glucose and severely high triglyceride are the key characteristics driving hypertriglyceridemia and hyperlipidemic pancreatitis. Hereditary factors considerably promote the increase of triglyceride levels and secondary complications. This study explored the clinical characteristics and genetic causes of a young girl with recurrent severe hypertriglyceridemia-developed pancreatitis at 9-year-olds and diabetes mellitus appearance at 14-year-olds. At 20 years old, she was admitted to the hospital in critical condition and had pancreatitis pain with triglyceride level at 26.22 mmol/L, HbA1c 15%, and glucose at 21.3 mmol/L. Whole exome sequencing analysis showed that she had two heterozygous variants of the APOA5 gene, (p.G185C and p.S19W), one homozygous variant of the APOE gene (p.C156R), which were previously reported to cause critical hypertriglyceridemia condition of patients. The results and analysis propose these variations were the underlying causes of a heightened of patient's plasma triglycerides and lead metabolic complication onset at a young age. These findings shed light on the molecular mechanism of her elevated plasma triglyceride and the early onset of diabetes following hyperlipidemic pancreatitis.

Age at Diagnosis of Diabetes in Young Men is Associated with Albuminuria.

Early-onset diabetes appears to be an aggressive phenotype of type 2 diabetes (T2D). The impact of the age of onset of T2D on albuminuria, especially high urinary albumin excretion, remains to be investigated. To determine whether adults diagnosed with T2D between the ages of 18 and 45 more aggressively develop albuminuria. Conducted at Taizhou People's Hospital from November 2018 to August 2020, this cross-sectional study enrolled T2D patients. Anthropometric measures, metabolic profiles, and urinary albumin creatinine ratio were examined. Patients were categorized into early-onset (≤45 years) and late-onset (> 45 years) groups. Univariate and multivariate analyses were performed to identify albuminuria risk factors. Subgroups were formed based on age at diabetes diagnosis and gender. Multivariate ordinal logistic regression analysis was then conducted to identify distinct risk factors within each subgroup. Analyzing 1900 T2D patients, it was found significantly higher albuminuria prevalence in early-onset patients (35.08% vs 29.92%, P = 0.022). The risk of albuminuria in early-onset patients was 1.509 times higher than that in late-onset patients, especially among male patients, where the risk increased to 1.980. For late-onset patients, disease duration and glycated hemoglobin (HbA1c) were identified as risk factors, whereas for early-onset patients, body-mass index (BMI) and systolic blood pressure were associated with increased risk. Among male patients, age at diagnosis of diabetes, blood pressure, and BMI were identified as risk factors, while for female patients, disease duration and HbA1c played a significant role. Additionally, high-density lipoprotein cholesterol was found to be a protective factor against albuminuria. Individuals diagnosed with T2D before 45 face heightened albuminuria risk, especially males. Risk factors vary by gender and onset age, highlighting the need for tailored management strategies.

Heterozygous missense variant in GLI2 impairs human endocrine pancreas development

Missense variants are the most common type of coding genetic variants. Their functional assessment is fundamental for defining any implication in human diseases and may also uncover genes that are essential for human organ development. Here, we apply CRISPR-Cas9 gene editing on human iPSCs to study a heterozygous missense variant in GLI2 identified in two siblings with early-onset and insulin-dependent diabetes of unknown cause. GLI2 is a primary mediator of the Hedgehog pathway, which regulates pancreatic β-cell development in mice. However, neither mutations in GLI2 nor Hedgehog dysregulation have been reported as cause or predisposition to diabetes. We establish and study a set of isogenic iPSC lines harbouring the missense variant for their ability to differentiate into pancreatic β-like cells. Interestingly, iPSCs carrying the missense variant show altered GLI2 transcriptional activity and impaired differentiation of pancreatic progenitors into endocrine cells. RNASeq and network analyses unveil a crosstalk between Hedgehog and WNT pathways, with the dysregulation of non-canonical WNT signaling in pancreatic progenitors carrying the GLI2 missense variant. Collectively, our findings underscore an essential role for GLI2 in human endocrine development and identify a gene variant that may lead to diabetes.

Clinical and imaging features of women with polygenic partial lipodystrophy: a case series.

Familial partial lipodystrophy (FPLD) is an inherited disorder of white adipose tissue that causes premature cardiometabolic disease. There is no clear diagnostic criteria for FPLD, and this may explain the under-detection of this condition. This pilot study aimed to describe the clinical features of women with FPLD and to explore the value of adipose tissue measurements that could be useful in diagnosis. In 8 women with FPLD and 4 controls, skinfold measurements, DXA and whole-body MRI were undertaken. Whole genome sequencing was negative for monogenic metabolic causes, but polygenic scores for partial lipodystrophy were elevated in keeping with FPLD type 1. The mean age of diagnosis of DM was 31 years in the FPLD group. Compared with controls, the FPLD group had increased HOMA-IR (10.3 vs 2.9, p = 0.028) and lower mean thigh skinfold thickness (19.5 mm vs 48.2 mm, p = 0.008). The FPLD group had lower percentage of leg fat and an increased ratio of trunk to leg fat percentage on DXA. By MRI, the FPLD group had decreased subcutaneous adipose tissue (SAT) volume in the femoral and calf regions (p < 0.01); abdominal SAT, visceral adipose tissue, and femoral and calf muscle volumes were not different from controls. Women with FPLD1 in Singapore have significant loss of adipose but not muscle tissue in lower limbs and have early onset of diabetes. Reduced thigh skinfold, and increased ratio of trunk to leg fat percentage on DXA are potentially clinically useful markers to identify FPLD1.

Prevalence of Chronic Kidney Disease in Individuals With Type 2 Diabetes Within Primary Care: A Cross-Sectional Study.

To assess the prevalence and risk factors for chronic kidney disease (CKD) among adults with type 2 diabetes within primary care. This cross-sectional study evaluated 1319 individuals receiving standard care across 26 primary units from July 2017 to January 2023. The estimated glomerular filtration rate (eGFR) and albuminuria were used for the diagnosis of CKD. CKD was defined by eGFR values of <60 mL/min/1.73 m2 and/or albumin-to-creatine ratio ≥30 mg/g. Logistic regression was applied to identify factors associated with CKD and study variables. The median age of participants (60.6% females) was 55 years and the median diabetes duration was 10 years. The overall CKD prevalence in the study population was 39.2%. Within the CKD group, the prevalence rates of albuminuria, albuminuria coupled with low eGFR and isolated low eGFR were 72.1%, 19%, and 8.9%, respectively. The prevalence of CKD was 30.6% among participants under 40 years old and a higher value was observed in middle-aged adults with early-onset diabetes (at age <40 years) compared with the later-onset group. Multivariable analyses identified associations between CKD and factors such as age, the male sex, diabetes duration, hypertension, retinopathy, and metformin use. A relatively high prevalence of CKD, especially in non-elderly adults, was revealed in this primary care study. Early recognition strategies for CKD are crucial for timely prevention within primary care.

Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants.

The BiP co-chaperone DNAJC3 protects cells during ER stress. In mice, the deficiency of DNAJC3 leads to beta-cell apoptosis and the gradual onset of hyperglycemia. In humans, biallelic DNAJC3 variants cause a multisystem disease, including early-onset diabetes mellitus. Recently, hyperinsulinemic hypoglycemia (HH) has been recognized as part of this syndrome. This report presents a case study of an individual with HH caused by DNAJC3 variants and provides an overview of the metabolic phenotype of individuals with HH and DNAJC3 variants. The study demonstrates that HH may be a primary symptom of DNAJC3 deficiency and can persist until adolescence. Additionally, glycemia and insulin release were analyzed in young DNACJ3 knockout (K.O.) mice, which are equivalent to human infants. In the youngest experimentally accessible age group of 4-week-old mice, the in vivo glycemic phenotype was already dominated by a reduced total insulin secretion capacity. However, on a cellular level, the degree of insulin release of DNAJC3 K.O. islets was higher during periods of increased synthetic activity (high-glucose stimulation). We propose that calcium leakage from the ER into the cytosol, due to disrupted DNAJC3-controlled gating of the Sec61 channel, is the most likely mechanism for HH. This is the first genetic mechanism explaining HH solely by the disruption of intracellular calcium homeostasis. Clinicians should screen for HH in DNAJC3 deficiency and consider DNAJC3 variants in the differential diagnosis of congenital hyperinsulinism.

Long-term PM2.5 exposure and early-onset diabetes: Does BMI link this risk?

ObjectiveLimited studies investigated the association between high-level fine particulate matter (PM2.5) pollution and early-onset diabetes, leaving the possible metabolic mechanisms unclear. We assessed the association of cumulative PM2.5 exposure with diabetes, including early-onset, in high-pollution areas of China and explored whether metabolic factors mediated this association. Methods124,204 participants (≥18 years) from 121 counties in Hunan province, China, were enrolled between 2005 and 2020, with follow-up until 2021. The ground-level air pollution concentrations at each participant's residence were calculated using a high-quality dataset in China. The independent association of PM2.5 with incident diabetes and early-onset diabetes was assessed by Cox proportional hazards models. Restricted cubic splines were utilized to establish the exposure-response relationships. The role of metabolism-related mediators was estimated by mediation analysis. ResultsDuring a median follow-up of 8.47 (IQR, 6.65–9.82) years, there were 3650 patients with new-onset diabetes. Each 1 μg/m3 increase in the level of cumulative PM2.5 exposure was positively related to an increased incidence of diabetes (HR 1.177, 95 % CI 1.172–1.181) among individuals in the PM2.5 > 50 μg/m3 group after adjusting for multiple variables. The relationship of the PM2.5 dose-response curve for diabetes was non-linear. Significant associations between PM2.5 exposure and early-onset diabetes risk were observed, with this risk showing an increase with the earlier age of early diabetes onset. Males, young individuals (≤45 years), and those with a lower body mass index (BMI <24 kg/m2) appeared to be more susceptible to diabetes. Moreover, change in BMI significantly mediated 31.06 % of the PM2.5-diabetes relationship. ConclusionsLong-term cumulative PM2.5 exposure increased the risk of early-onset diabetes, which is partially mediated by BMI. Sustained air pollution control measures, priority protection of vulnerable individuals, and effective management of BMI should be taken to reduce the burden of diabetes.

Questionnaire-Based Survey of Diabetes Self-Care Activities and Barriers among Young Korean Adults with Early-Onset Diabetes.

Self-management of diabetes is a significant challenge. This study aimed to assess diabetes self-care activities and barriers among Korean young adults with diabetes mellitus. This study recruited 209 Korean adults with diabetes, with an onset age of 20-39 years, from four university hospitals. Demographic characteristics and the Summary of Diabetes Self-Care Activities (SDSCA) measure and Diabetes Self-Care Barriers Assessment Scale for Older Adults (DSCB-OA) scores were assessed using questionnaires. The average age of study participants was 32.9±6.1 years. Their self-care activities, including adherence to recommended diabetes medication (5.6±2.4) and number of diabetes pills (5.5±2.3) in the SDSCA measure, were the most well-performed activities among all domains. Responses to inspection of the inside of shoes in the foot care activity (0.8±1.5) and specific exercise sessions in the exercise activity (1.6±1.9) reflected poor levels of compliance. According to the DSCB-OA questionnaire, the mean diabetes self-care barrier of DSCB-OA was 20.6±5.0 of total score 45. The greater perceived barriers to self-care on the DSCB-OA were having difficulty exercising regularly (1.9±0.7) and eating three meals and snacks leading to weight gain (1.9±0.8). Young adults with early-onset diabetes showed a greater barrier to regular exercise and poor compliance with foot care and blood sugar testing. Healthcare providers must strengthen their relationship with young adults with diabetes to provide more education and guidelines for lifestyle modification focused on exercise and to promote higher compliance with diabetic self-care activities for improving clinical outcomes.

Novel WFS1 variants are associated with different diabetes phenotypes.

The WFS1 gene encodes the protein wolframin, which is crucial for maintaining endoplasmic reticulum homeostasis. Variants in this gene are predominantly associated with Wolfram syndrome and have been implicated in other disorders such as diabetes mellitus and psychiatric diseases, which increases the rate of clinical misdiagnosis. Patients were diagnosed with early-onset unclassified diabetes according to their clinical and laboratory data. We performed whole-exome sequencing (WES) in 165 patients, interpreting variants according to the American College of Medical Genetics/Association for Molecular Pathology (ACMG/AMP) 2015 guidelines. Variant verification was done by Sanger sequencing. In vitro experiments were conducted to evaluate the effects of WFS1 compound heterozygous variants. We identified WFS1 compound heterozygous variants (p.A214fs*74/p.F329I and p.I427S/p.I304T) in two patients with Wolfram Syndrome-Like disorders (WSLD). Both WFS1 compound heterozygous variants were associated with increased ER stress, reduced cell viability, and decreased SERCA2b mRNA levels. Additionally, pathogenic or likely pathogenic WFS1 heterozygous variants were identified in the other three patients. Our results underscore the importance of early genetic testing for diagnosing young-onset diabetes and highlight the clinical relevance of WFS1 variants in increasing ER stress and reducing cell viability. Incorporating these genetic insights into clinical practice can reduce misdiagnoses and improve treatment strategies for related disorders.

Severe Early-Onset Obesity and Diabetic Ketoacidosis due to a Novel Homozygous c.169C>T p.Arg57* Variant in CEP19 Gene

Introduction: Early-onset severe obesity is usually the result of an underlying genetic disorder, and several genes have recently been shown to cause syndromic and nonsyndromic forms of obesity. The “centrosomal protein 19 (CEP19)” gene encodes for a centrosomal and ciliary protein. Homozygous variants in the CEP19 gene are extremely rare causes of early-onset severe monogenic obesity. Herein, we present a Turkish family with early-onset severe obesity with variable features. Methods: Sanger sequencing and whole-exome sequencing were performed to identify the genetic etiology in the family. Results: The index case was a 12-year-old female who presented with severe obesity (BMI of 62.7 kg/m²), metabolic syndrome, and diabetic ketoacidosis. Her nonidentical twin female siblings also had early-onset severe obesity, metabolic syndrome, and diabetes. In addition, one of the affected siblings had situs inversus abdominalis, polysplenia, lumbar vertebral fusion, and abnormal lateralization. A novel homozygous nonsense (c.169C>T, p. Arg57*) pathogenic variant was detected in exon 3 of the CEP19 gene in all affected members of the family. One unaffected sister and unaffected parents were heterozygous for the variant. This variant is predicted to cause a stop codon at amino acid sequence 57, leading to a truncated CEP19 protein. Discussion/Conclusion: Our study expands the phenotypical manifestations and variation database of CEP19 variants. The findings in one of our patients reaffirm its role in the assembly and function of both motile and immotile cilia.

An alternative approach using hs-CRP levels and age of onset in diagnostics of HNF1A-MODY.

The aim is to identify people with HNF1A-MODY among individuals in diabetic cohort solely based on low hs-CRP serum level and early diabetes onset. In 3537 participants, we analyzed the hs-CRP levels. We analyzed the HNF1A gene in 50 participants (1.4% of the cohort) with type 1 or type 2 diabetes who had hs-CRP ≤0.25 mg/L and were diagnosed with diabetes mellitus (DM) at the age of 8-40 years. We functionally characterized two identified missense variants. Three participants had a rare variant in the HNF1A gene, two of which we classified as likely pathogenic: c.1369_1384dup (p.Val462Aspfs*92) and c.737T>G (p.Val246Gly), and one as likely benign: c.1573A>T (p.Thr525Ser). Our functional studies revealed that p.Val246Gly decreased HNF1α transactivation activity to ~59% and the DNA binding ability to ~16% of the wild-type, while p.Thr525Ser variant showed no effect on transactivation activity, DNA binding, nor nuclear localization. Based on the two identified HNF1A-MODY patients among 3537 people with diabetes, we estimate 0.057% as the minimal HNF1A-MODY prevalence in Slovakia. A positive predictive value of hs-CRP ≤0.25 mg/L for finding HNF1A-MODY individuals was 4.0% (95% CI 0.7%, 13.5%). Hs-CRP value and age of DM onset could be an alternative approach to current diagnostic criteria with a potential to increase the diagnostic rate of HNF1A-MODY.

Overview of Diabetes as a Risk Factor for Developing Dementia: A Systematic Review

Background: There is debate over the relationship between diabetes and the main forms of dementia. The cognitive alterations associated with type 2 diabetes (T2D) mostly impact mental flexibility, mental speed, and learning and memory.&#x0D; Objectives: To ascertain the degree of the link between diabetes and dementia, we thoroughly reviewed papers on the incidence of dementia in individuals with diabetes mellitus in this study.&#x0D; Methods: PubMed, SCOPUS, Web of Science, and Science Direct were systematically searched for relevant literature. Rayyan QRCI was employed throughout this comprehensive process.&#x0D; Results and Interpretation: We included ten studies with a total of 173797 participants, and 78828 (45.4%) were males. All of the included studies were prospective cohorts. For diabetic patients, early-onset diabetes, poor glycemic management, and diabetes status are risk factors for dementia development. There was also a higher chance of dementia development in those with mild to severe motor cognitive impairment and hereditary variables. Longitudinal studies that involve comprehensive evaluations of comorbid diseases and diabetes-related variables, as well as rigorous assessments of cognition—ideally in conjunction with neuroimaging—will be necessary for this process. This method will work best with large population-based cohort studies of older adults with diabetes and with longitudinal studies of at-risk groups that look at the development of diabetes, metabolic syndrome, vascular disease, and cognitive decline.

Impact of albuminuria on early-onset type 2 diabetes mellitus: a nationwide population-based study.

Early-onset diabetes mellitus has a significant lifetime burden and is associated with higher morbidity and mortality. Since insulin resistance is one of the mechanisms of podocyte injury, we aimed to evaluate the effect of albuminuria on newly developed early-onset type 2 diabetes mellitus (T2DM). We screened 6,891,399 subjects aged ≥20 and <40 years without a history of prediabetes or diabetes from the Korean National Health Insurance Service database between 2009 and 2012. A multivariate Cox proportional hazard model was used to identify the impact of albuminuria on early-onset T2DM. Among a total of 5,383,779 subjects, 62,148 subjects (1.2%) developed early-onset diabetes over 7.3 ± 1.2 years. Albuminuria was significantly associated with early-onset T2DM (adjusted hazard ratio [aHR], 1.62; 95% confidence interval [CI], 1.55-1.70) after adjustment for age, sex, anthropometric data, physical exercise status, serum glucose, and total cholesterol. The risk of early-onset T2DM increased more in subjects with more components of metabolic syndrome (MetS). Among each component of MetS, hypertriglyceridemia was prominently associated with early-onset T2DM (aHR, 2.02; 95% CI, 1.81-2.25) in subjects with albuminuria. Dipstick albuminuria was significantly associated with early-onset T2DM in young adult populations. Close monitoring of albuminuria is warranted for disease risk modification, especially in subjects with MetS.

Risk for fetal malformations and unfavorable neonatal outcomes in early-onset gestational diabetes mellitus.

Early-onset gestational diabetes mellitus (GDM) is diagnosed before the 24th gestational week. Since early GDM is associated with first trimester hyperglycemia, many clinicians treat these women as having pre-GDM. However, whether early GDM increases the risk for unfavorable pregnancy outcomes and particularly for fetal malformations to a greater extent than late-onset GDM were not studied sufficiently. We aimed to examine the effect of early-onset GDM on unfavorable pregnancy outcomes. A retrospective cohort study of women with GDM delivering singletons during 2005-2018 was conducted. Women were divided into GDM diagnosed at the first (Trimester1; up to 13.6weeks; N = 117), the second (Trimester2; up to 23.6weeks; N = 126), and the third trimester (Trimester3; N = 2334). The primary outcomes were neonatal malformations and a composite of large-for-age newborns, hypoglycemia and hyperbilirubinemia treated with phototherapy. Comparisons were made between early- (Trimester1 + Trimester2-groups) and late-onset GDM (Trimester3-group), and between the three trimesters. Fetal malformations were low and comparable between the trimester1, trimester2, trimester3 groups (2 (1.7%), 3 (2.4%), and 110 (4.7%), respectively).The composite neonatal complications was similar between the groups (68 (58%), 58 (46%), and 1087 (47%), respectively). In early-onset, the rates of neonatal hypoglycemia and shoulder dystocia were higher than in the late-onset GDM group (OR 95% CI 3.5 [2.0-6.1] and 10.3 [2.4-44.6], respectively). Macrosomia was higher in trimester1 compared with trimester2 and trimester3 cohorts (OR 95% CI 5.3 [1.7-16.9] and 2.8 [1.5-5.2], respectively). The risk for fetal malformations was low and comparable between the first, second and third trimester GDM. Since the risks for macrosomia, shoulder dystocia, and neonatal hypoglycemia are higher in early-onset GDM, these women should undergo strict glycemic control, intensive monitoring, and careful neonatal evaluation.

Wolfram Syndrome: A Rare Genetic disorder affecting Multiple Organ Systems

Wolfram syndrome is a rare neurological disorder characterised by four main symptoms: diabetes mellitus, optic atrophy, deafness, and diabetes insipidus. It is caused by alterations in the CISD2 and WFS1 genes, which encode important proteins involved in cellular processes. Wolfram syndrome type 1 (WS1) has an earlier onset of diabetes and more severe neurological and ocular involvement compared to WS2. The diagnosis of Wolfram syndrome is based on the presence of early-onset diabetes and progressive optic atrophy. Genetic analysis, such as sequencing of the WFS1 gene, is used to confirm the diagnosis. The prevalence of Wolfram syndrome varies across populations, with a carrier frequency of 1 in 354. Individuals with Wolfram syndrome may experience a range of complications, including neurological abnormalities, urinary tract problems, depression, and an increased risk of suicide. The pathophysiology of Wolfram syndrome involves endoplasmic reticulum stress and unfolded protein responses, leading to cellular dysfunction and apoptosis. A differential diagnosis includes other genetic and mitochondrial disorders with similar symptoms. Although there is no cure for Wolfram syndrome, careful clinical observation and supportive therapy can help manage the symptoms and improve the quality of life for affected individuals.

Diabetes mellitus as a risk factor and comorbidity in gout.

Metabolic disorders are a public health issue because of the complications they cause, but they are also a major risk factor for the onset of gout.

The identification of a novel mutation (p.I223fs) in WRN associated with Werner syndrome.

Werner syndrome (WS) is a rare autosomal recessive genetic disease caused by mutations in the WRN gene, and it is characterized by multiple manifestations corresponding to early-onset aging. This study reports the case of a WS patient with a novel WRN mutation. A 36-year-old male patient with WS was evaluated after approval from the local ethics committee. The clinical and biochemical findings of the patient were described. Peripheral blood sample was collected to extract genomic DNA for WRN gene exome sequencing. The three-dimensional (3D) protein structural prediction analysis was performed via the AlphaFold 2.2 program and PyMol software. We report the case of a clinically diagnosed WS patient with consanguineous parents who presented with complex manifestations including early-onset diabetes mellitus, binocular cataracts, cerebral infarction, cerebral atherosclerosis, hypertension, dyslipidemia, hypothyroidism, and suspected meningioma, accompanied by short stature, gray hair, rough skin with subcutaneous fat atrophy, a high-pitched voice, palmoplantar keratoderma, bilateral flat feet, and an indolent deep ulceration on the foot. Exome sequencing identified a novel homozygous frameshift mutation in the WRN gene, c.666-669 del TATT, p.I223fs. The 3D structure prediction showed that premature termination and significant structural changes could occur in the mutant WRN protein. We identified a novel homozygous frameshift mutation, p.I223fs, in WRN in a Chinese patient with WS, expanding the spectrum of mutations in WS.

Clinical characteristics of patients with early-onset diabetes mellitus: a single-center retrospective study

BackgroundThe prevalence of diabetes mellitus (DM) is dramatically increasing around the world, and patients are getting younger with changes in living standards and lifestyle. This study summarized and analyzed the clinical characteristics of different types of newly diagnosed diabetes mellitus patients with an onset age between 18 and 40 years to provide clinical evidence for the early diagnosis and treatment of diabetes, reduce short-term and long-term complications and offer scientific and personalized management strategies.MethodsA total of 655 patients newly diagnosed with early-onset diabetes mellitus in the Department of Endocrinology, the First Medical Center of PLA General Hospital from January 2012 to December 2022 were retrospectively enrolled in this study, with an onset age of 18–40 years. Their clinical data were collected and investigated. All patients were divided into two groups according to whether they presented with diabetic microangiopathy. Similarly, patients with early-onset type-2 diabetes were grouped in accordance with whether they had ketosis at the time of diagnosis. Binary logistic regression analysis was performed to analyze risk factors, and receiver-operating characteristic (ROC) analysis was used to explore the predictive value of significant risk factors.ResultsThe findings were as follows: (1) Of 655 enrolled patients, 477 (72.8%) were male and 178 (27.1%) were female, with a mean age of onset of was 29.73 years ± 0.24 SD. (2) The prevalence of early-onset diabetes was gradually increasing. Type-2 diabetes was the most common type of early-onset diabetes (491, 75.0%). The ages of onset of early-onset type-1 diabetes, type-2 diabetes and LADA were mainly 18–24 years, 25–40 years and 33–40 years, respectively. (3) Initial clinical manifestations of early-onset diabetes were classic diabetes symptoms (361, 55.1%), followed by elevated blood glucose detected through medical examination (207, 31.6%). (4) Binary logistic regression analysis suggested that high serum uric acid (UA), a high urinary albumin-to-creatinine ratio (UACR) and diabetic peripheral neuropathy (DPN) were risk factors for microangiopathy in early-onset diabetes patients (P < 0.05). The area under the curve (AUC) on ROC analysis of the combination of UA, UACR and DPN was 0.848, 95% CI was 0.818 ~ 0.875, sensitivity was 73.8% and specificity was 85.9%, which had higher predictive value than those of UA, UACR and DPN separately. (5) Weight loss, high glycosylated hemoglobin (HbA1c) and young onset age were risk factors for ketosis in patients with early-onset type-2 diabetes (P < 0.05).Conclusion(1) Men were more likely to have early-onset diabetes than women. (2) Early-onset diabetes patients with high serum uric acid levels, high UACRs and peripheral neuropathy were prone to microangiopathy. Comprehensive evaluation of these risk factors could have higher predictive value in the prediction, diagnosis and treatment of microvascular lesions. (3) Patients with weight loss at onset, high HbA1c and young onset age were more likely to develop ketosis. Attention should be given to the metabolic disorders of these patients.

Blood-based Migration Signature Biomarker Panel Discriminates Early Stage New Onset Diabetes related Pancreatic Ductal Adenocarcinoma from Type 2 Diabetes

Background and aimsWhile type 2 diabetes is a well-known risk factor for pancreatic ductal adenocarcinoma (PDAC), PDAC-induced new-onset diabetes (PDAC-NOD) is a manifestation of underlying PDAC. In this study, we sought to identify potential blood-based biomarkers for distinguishing PDAC-NOD from type 2 diabetes (T2DM) without PDAC. Materials and methodsBy ELISA analysis, a migration signature biomarker panel comprising tissue factor pathway inhibitor (TFPI), tenascin C (TNC-FNIII-C) and CA 19–9 was analyzed in plasma samples from 50 PDAC-NOD and 50 T2DM controls. ResultsBoth TFPI (area under the curve (AUC) 0.71) and TNC-FNIII-C (AUC 0.69) outperformed CA 19–9 (AUC 0.60) in distinguishing all stages of PDAC-NOD from T2DM controls. The combined panel showed an AUC of 0.82 (95% CI = 0.73–0.90) (p = 0.002). In the PDAC-NOD early stage II samples, the three biomarkers had an AUC of 0.84 (95% CI = 0.73–0.93) vs CA 19-9, AUC = 0.60, (95% CI = 0.45–0.73), which also improved significance (p = 0.0123). ConclusionThe migration signature panel adds significantly to CA 19–9 to discriminate PDAC-NOD from T2DM controls and warrants further validation for high-risk group stratification.