Early-onset Diabetes Research Articles

249-LB: PAX4 Loss of Function Alters Human Endocrine Cell Development and Influences Diabetes Risk

In an effort to identify disease-causing mechanisms, numerous genome-wide studies across different ancestries have discovered genetic variants influencing type 2 diabetes (T2D) risk. Amongst identified diabetes-associated loci, a PAX4 coding variant (p.Arg192His) is uniquely and reproducibly associated with altered T2D-risk in East Asian populations. PAX4 encodes a transcription factor, and in mice Pax4 is essential for beta cell development. Whether PAX4 plays a similar role in humans and how diabetes associated PAX4 variants impact beta cell development and/or function is unknown. We combined in vivo studies in human variant carriers with disease modelling in human stem cell models to address these questions. Carriers of the PAX4 p.Arg192His allele have reduced islet cell function compared to non-carriers (AIRg: p.Arg192 756.9 vs. p.His192 530.8 p<0.002) . Deletion of PAX4 by CRISPR-Cas9 genome-editing in isogenic human induced pluripotent stem cell (hiPSC) -derived beta-like cells caused de-repression of alpha cell gene expression, suggesting decreased function in carriers of PAX4 variants may be due to altered beta cell development. hiPSCs derived from carriers of either the PAX4 p.Arg192His or a novel p.Tyr186X allele identified in a proband with early onset diabetes, had increased polyhormonal endocrine cell formation and reduced insulin content following in vitro differentiation towards beta-like cells; correction of the diabetes-associated PAX4 alleles reversed these phenotypic changes. Our in vitro and in silico molecular studies of diabetes associated alleles support reduced PAX4 expression and/or function. PAX4 knockdown in the EndoC-βH1 human beta cell model altered hormone gene expression, reduced total insulin content, and impaired insulin secretion. In conclusion, we have demonstrated the importance of PAX4 for human endocrine cell development and provide a potential mechanism for diabetes-associated alleles through de-repression of alpha cell gene expression. Disclosure N. Krentz: None. S. Hoon: None. D. Gardner: None. S. Kao: None. E. Tai: Advisory Panel; Amgen Inc., Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk, Stock/Shareholder; Abbott, AbbVie Inc. A. L. Gloyn: Other Relationship; Genentech, Inc., Roche Pharmaceuticals. A. Teo: Stock/Shareholder; BetaLife Pte Ltd. H. Lau: None. F. Abaitua: Employee; Vertex Pharmaceuticals Incorporated. M. Perez-alcantara: None. J. Chan: None. J. N. Ajeian: None. B. Champon: None. H. Sun: None. A. Jha: None. Funding Wellcome (200837) ; National Institutes of Health (U01-DK105535, U01-DK085545, UM1DK126185, U01DK123743, U24DK098085, P30DK116074) ; Lee Foundation Grant (SHTX/LFG/002/2018) Paris-NUS 2021-06-R/UP-NUS (ANR-18-IDEX-0001)

369-OR: Defining the Role of RIPK3 in Beta Cells and the Mechanism of Its Activation by ER Stress

Receptor interacting protein kinase 3 (RIPK3) can activate and be activated by ER stress. Islet inflammation associated with underlying activation of RIPK3 is conserved from zebrafish to humans. However, the role of RIPK3 in mammalian beta cells and the mechanism by which ER stress activates RIPK3 are not well defined. To investigate the role of RIPK3 in beta cell function, we generated beta cell specific Ripk3 knockout mice (Ripk3ßKO) in C57BL/6J background with or without the Akita mutation (Ins2C96Y/+, which causes ER stress induced beta cell apoptosis and early onset diabetes) (Ripk3ßKOAkita) . We found that the glucose tolerance was worsened in Ripk3ßKO mice than wildtype controls after 16 weeks of high fat diet. Similarly, Ripk3ßKOAkita mice had higher random blood glucose, lower circulating insulin, and worse glucose tolerance than Akita C57BL/6J mice as early as 4 weeks of age. Unexpectedly, isolated islets from Ripk3ßKO and Ripk3ßKOAkita mice have comparable glucose stimulated insulin secretion (GSIS) and are more resilient to palmitate-induced lipotoxicity than their control counterparts. Similarly, pharmacological inhibition of RIPK3 protected human islets from palmitate-induced impairment of GSIS ex vivo. We are currently investigating the role of specific islet inflammation stages in the divergent GSIS phenotypes between in vivo and ex vivo. To investigate how ER stress activates RIPK3 in beta cells, we tested the effect of inhibiting classic UPR branches on RIPK3 activation in MIN6 cells, a mouse beta cell line. We found that IRE1a activation appears to play an essential role in RIPK3 activation. Interestingly, Ripk3 knockdown in MIN6 cells also decreased IRE1a levels. We next seek to define the mechanism underlying the crosstalk between RIPK3 and IRE1a signaling pathways. Disclosure L.Yang: None. B.Yang: None. X.Tong: None. C.Dai: None. Z.Tang: None. W.Chen: None. Funding National Institutes of Health (DK117147)

Early-Onset of Gestational Diabetes vs. Late-Onset: Can We Revamp Pregnancy Outcomes?

We assessed risk factors, antenatal and intrapartum complications associated with early-onset Gestational diabetes mellitus (GDM) in comparison with late-onset GDM. This retrospective study included 161 GDM women having singleton pregnancies, without previous medical disorder and delivered at a tertiary care Hospital in Ha'il City, KSA from Dec 2020 till Jun 2021. Women diagnosed at < 24 weeks of pregnancy were grouped as early-onset GDM (n=71) and those diagnosed at ≥ 24 weeks as late-onset GDM (n=90). Both groups were matched for background variables. Chi-square and binary logistic regression analysis were applied with P-value significance at 0.05. Past history of GDM, macrosomia and stillbirth were significant predictors for early-onset GDM (P value 0.000, 0.002 and 0.040 respectively). Regression analysis showed early-onset GDM significantly increases the risk for recurrent urinary tract infections (AOR 2.35), polyhydramnios (AOR 2.81), reduced fetal movements (AOR 2.13), intrauterine fetal demise (AOR 8.06), macrosomia (AOR 2.16), fetal birth trauma (2.58), low APGAR score at birth (AOR 8.06), and neonatal ICU admissions (AOR 2.65). Rate of preterm birth, hypertensive disorders, labor onset (natural vs. induced) and cesarean section and intrapartum maternal complications were same in both groups. Early-onset GDM significantly increases certain maternal (recurrent urinary tract infections, polyhydramnios and reduced fetal movements) and fetal complications (intrauterine fetal demise, macrosomia fetal birth trauma, low APGAR score at birth and neonatal ICU admissions). Most of these adverse pregnancy outcomes can be prevented through early registration and screening, close follow up, growth ultrasounds, and provision of efficient emergency and neonatal care services.

Diabetic Retinopathy and Diabetic Macular Edema in People With Early-Onset Diabetes.

This study examined the clinical profile, treatment profile, and vision outcomes of people ≤40 years of age with diabetes and diabetic macular edema (DME). Within this age-group, the prevalence of center-involving DME was 16%, with 74% of eyes showing cystoid edema, 37% showing spongiform edema, and 41% having neurosensory detachment. Longer diabetes duration (P = 0.001) and greater severity of diabetic retinopathy (P <0.001) were associated with DME prevalence. Thus, regular and more frequent follow-up, as well as early and aggressive treatment of diabetic eye disease, are required in people diagnosed early with diabetes.

Maturity-onset diabetes of the young (MODY)-related genetic variants in a Turkish patient cohort with early-onset diabetes: a cross-sectional study

Maturity-onset diabetes of the young (MODY)-related genetic variants in a Turkish patient cohort with early-onset diabetes: a cross-sectional study

The neonatal onset diabetes mellitus of Chinese neonate with congenital generalized lipodystrophy 2: a case report

BackgroundCongenital generalized lipodystrophy (CGL) is a clinically heterogeneous disorder characterized by near total absence of adipose tissue along with metabolic complications. Diabetes mellitus developed from CGL usually present between ages 15 and 20 years, and there are few reports in neonate.Case presentationIn this report, we described a rare clinical presentation of CGL in a 12-day-old Chinese female neonates with hyperglycemia, hyperlipidemia, and subsequently appeared diabetes, hepatomegaly and fatty liver. The two clinical-exome sequencing identified heterozygous null mutations (c.793C > T and c.565G > T) in BSCL2 gene which was inherited from father and mother respectively. To date, it was the firstly reported CGL patient with neonatal onset diabetes. The neonate was treated with antibiotic, insulin and deeply hydrolyzed formula milk to significantly decrease FBG and serum trigylcerides levels. ConclusionsOur case report analyzes the causes of early onset diabetes may relate with the locus of BSCL2 gene mutations and infection induction. It also suggests the importance of early identification, genetic analysis, and symptomatic treatment in the CGL, which are essential for improving the prognosis of children.

Identification of a novel hepatocyte nuclear factor-1 alpha (HNF1A) variant in maturity onset diabetes of the young type 3 (HNF1A-MODY).

SummaryWe identified an adolescent young woman with new-onset diabetes. Due to suspicious family history, she underwent genetic testing for common monogenic diabetes (MODY) genes. We discovered that she and her father carry a novel variant of uncertain significance in the HNF1A gene. She was successfully transitioned from insulin to a sulfonylurea with excellent glycemic control. Based on her family history and successful response to sulfonylurea, we propose that this is a novel pathogenic variant in HNF1A. This case highlights the utility of genetic testing for MODY, which has the potential to help affected patients control their diabetes without insulin.Learning pointsHNF1A mutations are a common cause of monogenic diabetes in patients presenting with early-onset diabetes and significant family history.Genetic testing in suspected patients allows for the identification of mutations causing monogenic diabetes.First-degree relatives of the affected individual should be considered for genetic testing.The use of sulfonylurea agents in patients with HNF1A-MODY can reduce dependence on insulin therapy and provide successful glycemic control.

Relationship between onset age of type 2 diabetes mellitus and vascular complications based on propensity score matching analysis.

Aims/IntroductionTo assess the relationship between type 2 diabetes mellitus onset age and vascular complications in China.Materials and MethodsA retrospective review of 3,568 patients with type 2 diabetes mellitus using a propensity score‐matched (PSM) cohort analysis was carried out in two different age of onset groups (age 40 and 60 years). These groups were then subdivided into two groups, early‐onset diabetes (EOD40 and EOD60; the onset age before 40 and 60 years, respectively) and late‐onset diabetes (LOD40 and LOD60: the onset age after 40 and 60 years, respectively). Macrovascular and microvascular complications were analyzed before and after PSM.ResultsPatients categorized in both the early‐onset disease (EOD) groups had a higher risk of developing macro‐ and microvascular complications before PSM. After PSM, no differences existed between the EOD and late‐onset disease groups in the risk of macrovascular complications. Compared with the late‐onset disease group, the odds ratio of having a microvascular complication of diabetic retinopathy, chronic kidney disease and diabetic peripheral neuropathy in the 40‐year‐old EOD group increased to 2.906, 1.967 and 1.672 (P < 0.05), respectively. The odds ratio of diabetic retinopathy and diabetic peripheral neuropathy in the 60‐year‐old EOD group was 1.763 and 1.675 (P < 0.05), respectively.ConclusionsThe earlier the onset of type 2 diabetes mellitus, the higher risk of microvascular, but not necessarily macrovascular, complications. It is not too late to prevent diabetes at any age. Pre‐emptive microvascular treatment or preventative measures in EOD patients who do not yet show symptoms, might be beneficial.

EP274: Frequency of Bardet-Biedl syndrome and Alström syndrome gene variants in a cohort with early-onset obesity

Bardet-Biedl syndrome (BBS) and Alström syndrome are rare, autosomal recessive ciliopathies that often lead to early-onset obesity and hyperphagia. Both BBS and Alström syndrome are diagnosed based on presentation of clinical features that may include early-onset obesity, early-onset diabetes, cardiomyopathy, hyperphagia, visual impairment, polydactyly, renal anomalies, and cognitive impairment. More than 20 genes are associated with BBS and Alström syndrome, but little is currently known about the frequency of variants in these genes in a population with severe, early-onset obesity, irrespective of clinical features. We sequenced 22 BBS genes and ALMS1 as part of the Uncovering Rare Obesity diagnostic genetic testing program in 8459 individuals with severe (Class III) obesity (<18 years old, >/=97th percentile body mass index (BMI) for age; >/=18 years old, BMI >/=40kg/m2). Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) criteria as pathogenic/likely pathogenic (P/LP) or as a variant of uncertain significance (VUS). Individuals were determined to be biallelic (2 or more alleles in 1 gene), heterozygous (1 allele in only 1 gene), or composite heterozygous (1 allele per gene in multiple BBS genes). In this cohort, 1.96% of individuals carried biallelic variants in BBS (1.36%) or ALMS1 (0.60%) genes, including 0.34% with >/=2 P/LP alleles (BBS 0.30%, ALMS1 0.04%); this frequency was 0.24% after excluding patients from a known BBS specialty clinic. In addition, 1.62% were biallelic with >/=1 VUS alleles, 26.8% carried a single heterozygous variant in only 1 gene, and 4.0% carried variants in more than one BBS gene. It is unknown whether patients were sequenced due to suspected BBS or Alström syndrome, and data is not available on related clinical characteristics, other than their severe early-onset obesity. In our cohort of 8459 individuals with early-onset obesity, 1.96% of individuals were biallelic for variants in genes associated with BBS or Alström syndrome. BBS and Alström syndrome are heterogenous diseases that present with a variety of symptoms that evolve over time, and more research is needed to determine whether identification of individuals with biallelic variants may help identify patients in need of follow-up support regarding BBS and Alström syndrome diagnosis. Today, these diseases are diagnosed based on clinical features, and genetic testing may help provide additional evidence to support a diagnosis.

Poor Glycaemic Control and its Associated Factors among Type 2 Diabetes Mellitus Patients in Southern Part of Peninsular Malaysia: A Registry-based Study

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a growing global health concern that is likely to reach a pandemic level by 2030 and is one of the leading causes of death globally. Recently, T2DM has been causing an increase in premature mortality including in developing countries.&#x0D; AIM: This study aimed to determine the prevalence and the factors associated with poor glycaemic control among Type 2 diabetes mellitus (T2DM) patients in Segamat, Malaysia. &#x0D; METHOD: The study population was selected from the National Diabetic Registry (NDR) database between June 2019 and September 2020 which included a total of 3,100 patients. General and clinical information were retrieved from the registry. Glycaemic control was categorised as good (HbA1c ≤6.5 %) or poor (HbA1c &gt;6.5%). Univariable and multivariable logistic regression were performed to assess the factors of poor glycaemic control&#x0D; RESULTS: More than half (59.2%) of the patients had poor glycaemic control. As high as 55.1% of older patients (≥60 years old) had poorer glycaemic control. Most patients with poor glycaemic control (62.0%) were obese. Multiple logistic regression analysis revealed that age (≥60 years old), ethnicity (Malay and Indian), more than 10 years of diabetes, obesity, early diabetes onset before 40 years, and dyslipidaemia were associated with poor glycaemic control.&#x0D; CONCLUSION: These findings can provide the necessary guidance for the stakeholders in identifying T2DM patients at risk of poor glycaemic control so that early preventive measures and organised care can be provided for the patients.

An intron mutation of HNF1A causes abnormal splicing and impairs its activity as a transcription factor

Mutations in HNF1A are associated with Maturity Onset Diabetes of the Young type 3 (MODY3) and most of them are in the coding region. Herein, we identified an intron mutation at the 6th nucleotide upstream of the end of intron 7 of HNF1A, named IVS7-6G > A, in a patient with early-onset diabetes. The “minigene” assay showed that IVS7-6G > A produced two aberrant mRNA variants translating into two truncated proteins: L502S fs* and G437A fs*, both affecting HNF1A transactivation domain (TAD). To determine functional consequences of IVS7-6G > A mutation, we made plasmids encoding truncated HNF1A containing different portions of HNF1A TAD and found that the TAD of HNF1A is important not only for its regulatory activities, but also for its nuclearization, and the residues 282–501 was more essential than 502–631. Our data suggested IVS7-6G > A impaired HNF1A splicing and may contribute to the pathogenesis of MODY3.

PTPN2 Regulates the Interferon Signaling and Endoplasmic Reticulum Stress Response in Pancreatic β-Cells in Autoimmune Diabetes.

Type 1 diabetes (T1D) results from autoimmune destruction of β-cells in the pancreas. Protein tyrosine phosphatases (PTPs) are candidate genes for T1D and play a key role in autoimmune disease development and β-cell dysfunction. Here, we assessed the global protein and individual PTP profiles in the pancreas from nonobese mice with early-onset diabetes (NOD) mice treated with an anti-CD3 monoclonal antibody and interleukin-1 receptor antagonist. The treatment reversed hyperglycemia, and we observed enhanced expression of PTPN2, a PTP family member and T1D candidate gene, and endoplasmic reticulum (ER) chaperones in the pancreatic islets. To address the functional role of PTPN2 in β-cells, we generated PTPN2-deficient human stem cell-derived β-like and EndoC-βH1 cells. Mechanistically, we demonstrated that PTPN2 inactivation in β-cells exacerbates type I and type II interferon signaling networks and the potential progression toward autoimmunity. Moreover, we established the capacity of PTPN2 to positively modulate the Ca2+-dependent unfolded protein response and ER stress outcome in β-cells. Adenovirus-induced overexpression of PTPN2 partially protected from ER stress-induced β-cell death. Our results postulate PTPN2 as a key protective factor in β-cells during inflammation and ER stress in autoimmune diabetes.

Loss-of-function mutation in Pcsk1 increases serum APOA1 level and LCAT activity in mice

BackgroundThe convertase subtilisin/kexin family 1 gene (PCSK1) has been associated in various human genetics studies with a wide spectrum of metabolic phenotypes, including early-onset obesity, hyperphagia, diabetes insipidus, and others. Despite the evident influence of PCSK1 on obesity and the known functions of other PCSKs in lipid metabolism, the role of PCSK1 specifically in lipid and cholesterol metabolism remains unclear. This study evaluated the effect of loss of PCSK1 function on high-density lipoprotein (HDL) metabolism in mice.ResultsHDL cholesterol, apolipoprotein A1 (APOA1) levels in serum and liver, and the activities of two enzymes (lecithin-cholesterol acyltransferase, LCAT and phospholipid transfer protein, PLTP) were evaluated in 8-week-old mice with a non-synonymous single nucleotide mutation leading to an amino acid substitution in PCSK1, which results in a loss of protein’s function. Mutant mice had similar serum HDL cholesterol concentration but increased levels of serum total and mature APOA1, and LCAT activity in comparison to controls.ConclusionsThis study presents the first evaluation of the role of PCSK1 in HDL metabolism using a loss-of-function mutant mouse model. Further investigations will be needed to determine the underlying molecular mechanism.

A Novel Nonsense INS Mutation Causes Inefficient Preproinsulin Translocation Into the Endoplasmic Reticulum.

Preproinsulin (PPI) translocation across the membrane of the endoplasmic reticulum (ER) is the first and critical step of insulin biosynthesis. Inefficient PPI translocation caused by signal peptide (SP) mutations can lead to β-cell failure and diabetes. However, the effect of proinsulin domain on the efficiency of PPI translocation remains unknown. With whole exome sequencing, we identified a novel INS nonsense mutation resulting in an early termination at the 46th residue of PPI (PPI-R46X) in two unrelated patients with early-onset diabetes. We examined biological behaviors of the mutant and compared them to that of an established neonatal diabetes causing mutant PPI-C96Y. Although both mutants were retained in the cells, unlike C96Y, R46X did not induce ER stress or form abnormal disulfide-linked proinsulin complexes. More importantly, R46X did not interact with co-expressed wild-type (WT) proinsulin in the ER, and did not impair proinsulin-WT folding, trafficking, and insulin production. Metabolic labeling experiments established that, despite with an intact SP, R46X failed to be efficiently translocated into the ER, suggesting that proinsulin domain downstream of SP plays an important unrecognized role in PPI translocation across the ER membrane. The study not only expends the list of INS mutations associated with diabetes, but also provides genetic and biological evidence underlying the regulation mechanism of PPI translocation.

Article Review: Present Perspectives of Hyperthyroidism During Pregnancy

Graves’ disease causes inflammatory hyperthyroidism in around 80% of hyperthyroidism cases inwomen of reproductive age. The hormonal changes in the maternal immune system after birth may belinked to the production and expression of diabetes other than gestational and early-onset diabetes. Asa result, in addition to hormonal influences, other anatomical modifications or abnormalities seen inthe body during pregnancy will affect the pregnancy test. Thyroid hormones are critical for a woman’shealth and the commencement of her pregnancy. These hormones are essential for early developmentand play a crucial role in the fetus’s continued growth after conception. Women with untreated orimproperly controlled hyperthyroidism are more likely to have complications during pregnancy. Futurediseases, particularly those that produce a large number of fetuses due to IUGRTH. The treatmentof hyperthyroid pregnant women is extremely difficult, and medical staff engagement is required toguarantee that it is properly monitored and treated. Anti-thyroid drugs are commonly administered topregnant women, and it is the medication of choice for the majority of them (ATDs). Despite the fact thatboth of these drugs are passed through the mother’s bloodstream to the fetus, they are highly effectivein the treatment of maternal hyperthyroidism. Nonetheless, they must exercise caution throughout thesecond half of pregnancy due to the risk of fetopathy. The most common side effect, except in thefirst trimesters from weeks 6 to 10, is fetal abnormalities; even with that proviso, the incidence ofbirth malformations is significant during the first trimester with the use of ATDs. The management ofhyperthyroidism during pregnancy is divided into four areas that obstetricians are currently concernedabout: Its aetiology, occurrence, correct identification, under treatment, complications, and actual ormissed diagnosis and intervention, and lastly, the technique of dealing with the problem are all factorsto consider.

A retrospective review of pregnancy outcomes in women with uncomplicated mild to moderate chronic hypertension

Objective To examine pregnancy complications in women with uncomplicated mild-moderate chronic hypertension (CHTN) treated with antihypertensives prior to 20 weeks compared to those not on antihypertensives. Study design This retrospective cohort study examined singleton pregnancies of women with mild-moderate CHTN who delivered from 01/2014-3/2019. Pregnancies complicated by hypertension at ≥ 20 weeks, end organ damage, preexisting diabetes mellitus, early-onset gestational diabetes, multifetal gestation, and fetal anomalies were excluded. Adjusted logistic regression analyses were performed for each of the outcomes. Adjusted odds ratios (aOR) were reported along with associated 95% confidence intervals (CI) and p-values. Main outcome measures Primary outcome was superimposed preeclampsia with severe features. Additional maternal outcomes were superimposed preeclampsia without severe features, severe hypertension, indicated preterm delivery, placental abruption, and mode of delivery. Neonatal outcomes included composite perinatal outcomes (fetal growth restriction, intrauterine fetal demise, and small for gestational age neonate), low birth weight, very low birth weight, admission to the neonatal intensive care unit, and Apgar score <7 at 5-minutes. Results 345 women were identified: 232 (67.2%) were not taking antihypertensives and 113 (32.8%) were taking ≥1 antihypertensive. There was no significant difference in the primary outcome (p = 0.65; aOR = 0.88; 95% CI 0.51−1.52) among the group taking antihypertensive therapy as compared to those not taking antihypertensives. No statistically significant differences were seen for any of the other secondary maternal or neonatal outcomes. Conclusions Our data supports that the use of antihypertensive therapy in women with mild-moderate CHTN does not reduce the risk of developing superimposed preeclampsia.

Functional Characterization of a Novel HeterozygousMutationin theGlucokinaseGene That Causes MODY2 in Chinese Pedigrees.

BackgroundGlucokinase (GCK) plays a central role in glucose regulation. The heterozygous mutations of GCK can cause a monogenic form of diabetes, maturity-onset diabetes of the young (MODY) directly. In our study, we aimed to explore the mechanism of the novel mutation GCK p.Ala259Thr leading to glucokinase deficiency and hyperglycemia.MethodsThirty early-onset diabetes pedigrees were referred to whole exome sequencing for novel mutations identification. Purified wild-type and mutant GCK proteins were obtained from E.coli systems and then subjected to the kinetic and thermal stability analysis to test the effects on GCK activity.ResultsOne novel missense mutation GCK p.Ala259Thr was identified and co-segregated with diabetes in a Chinese MODY2 pedigree. The kinetic analysis showed that this mutation result in a decreased affinity and catalytic capability for glucose. The thermal stability analysis also indicated that the mutant protein presented dramatically decreased activity at the same temperature.ConclusionOur study firstly identified a novel MODY2 mutation p.Ala259Thr in Chinese diabetes pedigrees. The kinetic and thermal stability analysis confirmed that this mutation caused hyperglycemia through severely damaging the enzyme activities and protein stability.

The opposing trends of body mass index and blood pressure during 1977\u20132020; nationwide registry of 2.8\xa0million male and female adolescents

BackgroundElevated blood pressure among adolescents has been shown to be associated with future adverse cardiovascular outcomes and early onset diabetes. Most data regarding systolic and diastolic blood pressure trends are based on surveys of selected populations within 10–20-year periods. The goal of this study was to characterize the secular trend of blood pressure given the rising prevalence of adolescent obesity.MethodsThis nationwide population-based study included 2,785,515 Israeli adolescents (41.6% females, mean age 17.4 years) who were medically evaluated and whose weight, height and blood pressure were measured, prior to mandatory military service between 1977 and 2020. The study period was divided into 5-year intervals. Linear regression models were used to describe the P for trend along the time intervals. Analysis of covariance was used to calculate means of blood pressure adjusted for body mass index.ResultsDuring the study period, the mean body mass index increased by 2.1 and 1.6 kg/m2 in males and females, respectively (P for trend < 0.001 in both sexes). The mean diastolic blood pressure decreased by 3.6 mmHg in males and by 2.9 mmHg in females (P < 0.001 in both sexes). The mean systolic blood pressure increased by 1.6 mmHg in males and decreased by 1.9 mmHg in females. These trends were also consistent when blood pressure values were adjusted to body mass index.ConclusionDespite the increase in body mass index over the last four decades, diastolic blood pressure decreased in both sexes while systolic blood pressure increased slightly in males and decreased in females.

P.157: NK and B Cell Subset Assessment in Type I Diabetes Patients on Waitlist for Pancreas Transplantation

Introduction: Type 1 Diabetes (T1D) is an immune mediated disease with near complete destruction of beta cells. About 40 % patients with T1D develop End Stage Renal disease (ESRD) during their lifetime and require kidney and/or kidney pancreas transplantation. Recent genetic studies have described differences in genomic regions associated with immune responses and types of cells infiltrating islets between patients with early onset of diabetes (< 7 yrs.) and later onset of diabetes (≥ 7 yrs.). Limited data are available regarding immune profiles of these subsets of patients especially when evaluated for transplantation. Therefore, we studied flow cytometric profiles of immune subsets in these patients with the long-term vision of developing personalized immunosuppression. Methods: After IRB approval, we prospectively performed quantitative B cell and Natural Killer (NK) cell subset immunophenotyping by flow cytometry, and measured Immunoglobulin (IgA, IgM and IgG) levels by Nephelometry on 18 T1D subjects with ESRD waitlisted for Simultaneous Pancreas and Kidney Transplantation (SPK) in two age and gender matched groups of patients: a) onset < 7 yrs. (Group 1, n=9), and b) onset > 7 yrs. (Group 2, n=9). Results: Detailed baseline demographics of the two groups are shown under Table 1, both groups were comparable. B cells, NK cells and their subsets are shown in Table 2. Group 1 showed a significantly lower number of CD 16 + 56- cells (p-value 0.027) as compared to group 2; other cells count, and percentages were not significantly different.Conclusion: While previous work has shown a link between altered NK cells and the early onset of type I diabetes, our data do not show a significant difference in the major NK cell subsets between the two groups of patients. Additional studies with a larger sample size could help resolve this disparity.

Early Intervention and Lifelong Treatment with GLP1 Receptor Agonist Liraglutide in a Wolfram Syndrome Rat Model with an Emphasis on Visual Neurodegeneration, Sensorineural Hearing Loss and Diabetic Phenotype.

Wolfram syndrome (WS), also known as a DIDMOAD (diabetes insipidus, early-onset diabetes mellitus, optic nerve atrophy and deafness) is a rare autosomal disorder caused by mutations in the Wolframin1 (WFS1) gene. Previous studies have revealed that glucagon-like peptide-1 receptor agonist (GLP1 RA) are effective in delaying and restoring blood glucose control in WS animal models and patients. The GLP1 RA liraglutide has also been shown to have neuroprotective properties in aged WS rats. WS is an early-onset, chronic condition. Therefore, early diagnosis and lifelong pharmacological treatment is the best solution to control disease progression. Hence, the aim of this study was to evaluate the efficacy of the long-term liraglutide treatment on the progression of WS symptoms. For this purpose, 2-month-old WS rats were treated with liraglutide up to the age of 18 months and changes in diabetes markers, visual acuity, and hearing sensitivity were monitored over the course of the treatment period. We found that treatment with liraglutide delayed the onset of diabetes and protected against vision loss in a rat model of WS. Therefore, early diagnosis and prophylactic treatment with the liraglutide may also prove to be a promising treatment option for WS patients by increasing the quality of life.