medRxiv - Endocrinology最新文献

{"title":"Fat burning capacity in a mixed macronutrient meal protocol does not reflect metabolic flexibility in women who are overweight or obese","authors":"Mary M. Ahern, Virginia M. Artegoitia, Rémy Bosviel, John W. Newman, Nancy L. Keim, Sridevi Krishnan","doi":"10.1101/2024.08.29.24312791","DOIUrl":"https://doi.org/10.1101/2024.08.29.24312791","url":null,"abstract":"<strong>Introduction</strong> Metabolic flexibility, the ability to switch from glucose to fat as a fuel source, is considered a marker of metabolic health. Higher fat oxidation is often associated with greater flexibility and insulin sensitivity, while lower fat oxidation is linked to metabolic inflexibility and insulin resistance. However, our study challenges the universal validity of this relationship, uncovering a more nuanced understanding of the complex interplay between fuel source switching and fat oxidation, especially in the presence of insulin resistance.","PeriodicalId":501419,"journal":{"name":"medRxiv - Endocrinology","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142183878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fasting C-peptide in Gestational Diabetes Mellitus","authors":"Md. Rakibul Hasan, Nusrat Sultana, Mashfiqul Hasan, Sharmin Jahan, Muhammad Abul Hasanat","doi":"10.1101/2024.08.27.24312520","DOIUrl":"https://doi.org/10.1101/2024.08.27.24312520","url":null,"abstract":"<strong>Introduction</strong> Insulin secretion and sensitivity are thought to vary in gestational diabetes mellitus (GDM) as well as in different trimesters within the same individual.","PeriodicalId":501419,"journal":{"name":"medRxiv - Endocrinology","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142223908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The genotype-phenotype correlation of NR5A1 variants in 46,XY individuals: a study protocol","authors":"Renata Thomazini Dallago, Rafael Loch Batista, Berenice Bilharinho de Mendonça, Vania dos Santos Nunes Nogueira","doi":"10.1101/2024.08.27.24312633","DOIUrl":"https://doi.org/10.1101/2024.08.27.24312633","url":null,"abstract":"<strong>Introduction</strong> Disorders of sex development (DSDs) were defined as congenital conditions in which the development of chromosomal, gonadal and anatomic sex is atypical. Nuclear receptor subfamily 5 group A member 1 (<em>NR5A1</em>), previously known as steroidogenic factor 1 (<em>SF1</em>) plays a crucial role in transcriptional regulation of genes involved in steroidogenesis, adrenal and gonadal development, and reproduction. <em>NR5A1</em> emerged to be causative of 10 to 20% of 46,XY DSD.","PeriodicalId":501419,"journal":{"name":"medRxiv - Endocrinology","volume":"58 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142227762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SLC30A8 rare variant modify contribution of common genetic and lifestyle factors toward type 2 diabetes","authors":"Hye-Mi Jang, Mi Yeong Hwang, Yi Seul Park, Bong-Jo Kim, Young Jin Kim","doi":"10.1101/2024.08.28.24312708","DOIUrl":"https://doi.org/10.1101/2024.08.28.24312708","url":null,"abstract":"This study aimed to investigate the modifying effects of rare genetic variants on the risk of type 2 diabetes in the context of common genetic and lifestyle factors. We conducted a comprehensive analysis of genetic and lifestyle factors associated with type 2 diabetes in a cohort of 146,284 Korean individuals. Among them, 4,603 individuals developed type 2 diabetes during the follow-up period of up to 18 years. We calculated a polygenic risk score (PRS) for type 2 diabetes and identified carriers of the rare allele I349F at SLC30A8. A Healthy Lifestyle Score (HLS) was also derived from physical activity, obesity, smoking, diet, and sodium intake levels. Using Cox proportional hazards models, we analyzed how PRS, HLS, and I349F influenced type 2 diabetes incidence. Results showed that high PRS and poor lifestyle were associated with increased risk. Remarkably, I349F carriers exhibited a lower type 2 diabetes prevalence (5.4% compared to 11.7% in non-carriers) and reduced the impact of high PRS from 23.18% to 12.70%. This trend was consistent across different HLS categories, with I349F carriers displaying a lower risk of type 2 diabetes. The integration of common and rare genetic variants with lifestyle factors enhanced type 2 diabetes predictability in the Korean population. Our findings highlight the critical role of rare genetic variants in risk assessments and suggest that standard PRS and HLS metrics alone may be inadequate for predicting type 2 diabetes risk among carriers of such variants.","PeriodicalId":501419,"journal":{"name":"medRxiv - Endocrinology","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142183879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fasting Plasma Glucose as a Primary Screening Test for the Diagnosis of Gestational Diabetes mellitus","authors":"Md Rakibul Hasan, Nusrat Sultana, Sandesh Panthi, Mashfiqul Hasan, Sharmin Jahan, Yasmin Aktar, Muhammad Abul Hasanat","doi":"10.1101/2024.08.23.24312519","DOIUrl":"https://doi.org/10.1101/2024.08.23.24312519","url":null,"abstract":"Aim: To see the diagnostic efficacy of fasting plasma glucose (FPG) in respect to OGTT during pregnancy.\u0000Materials and Method: In this cross-sectional study, we enrolled 542 pregnant women 18 years or older by consecutive sampling irrespective of gestational age. 75gm three samples OGTT was done and categorized them to either normal glucose tolerance (NGT) or abnormal glucose tolerance (AGT) according to World Health Organization (WHO) 2013 criteria. Results: The sensitivity of FPG with a threshold of 5.1mmol/L was 47.3% among the study subjects, which was very low but specificity was very high (99.7%). However, changing the cut off value to 4.7mmo/L and 4.5mmol/L significantly increased the sensitivity to 64.8% and 73.3% with modestly decreased specificity to 86.2% and 73.2% respectively. In pregnant women with gestational age 24 to 28 weeks, FPG with a threshold of 4.5mmol/L could identify 75% of GDM subjects with specificity 76.8%. Furthermore, it has the highest sensitivity in detecting AGT in all three trimesters (80%, 74.4% and 68%) compared to 4.7mmol/L (80%, 68.9% and 50%) and 5.1 (80%, 47.8% and 30%) in 1st, 2nd and 3rd trimester respectively. FPG had positive correlation with maternal age (r=0.138, p=0.001), BMI (r=0.164, p&lt;0.001) but negative correlation with weeks of gestation (r= -0.242, p&lt;0.001). Conclusion: FPG with cut off value of 4.5mmol/L may be used as an initial screening test for GDM to reduce the need for OGTT. Keyword: Gestational Diabetes mellitus, Fasting Plasma Glucose, Screening Test.","PeriodicalId":501419,"journal":{"name":"medRxiv - Endocrinology","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142183663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling Genetic Associations: Investigating CLDN16, GRID2, NRG3, and CACNG4 Gene Polymorphisms with Insulin Resistance Risk Among Normal BMI Individuals in the Indian Population","authors":"Sabitha Thummala, Sarah Fathima, Nithya Kruthi, Junaid Ahmed Khan Ghori, Katherine Saikia, Balamurali AR, Rahul Ranganathan","doi":"10.1101/2024.08.22.24312447","DOIUrl":"https://doi.org/10.1101/2024.08.22.24312447","url":null,"abstract":"Studies estimate that India has about 65+ million diabetic patients with a substantial impending increase, making it the international diabetes capital. Diabetes Mellitus is a metabolic disorder which is signified by elevated blood sugar levels due to defects in insulin action, secretion or both. Insulin resistance (IR) or insulin resistance-linked obesity is also known to be a causing factor of Metabolic syndrome which is a combination of cardiovascular risk factors that include raised fasting plasma glucose, central obesity, hypertension, raised triglycerides, and reduced High-Density Lipoprotein (HDL) cholesterol. This study investigated the association between four single nucleotide polymorphisms (SNPs) in the selected genes - rs6801387 (CLDN16), rs72872727 (GRID2), rs1414756 (NRG3), and rs8065294 (CACNG4) and (IR) among a normal BMI Indian population. Through Chi-Square tests, we detected significant associations between SNP genotypes and (IR). Allele frequency analysis revealed higher frequencies of allele G (rs6801387) and T (rs72872727) among individuals with HOMA2-IR &gt;2, while allele T (rs8065294) indicated decreased risk, emphasizing the relevance of genetic factors in metabolic disorders. The differences in clinical parameters such as fat mass, serum triglycerides and HbA1c between the cases and controls highlights the multifactorial nature of the condition. Inheritance model suggested the dominant inheritance for rs6801387 and rs72872727 and codominant inheritance for rs1414756 and rs806529, offering insights into genetic associations with IR. Despite the study's moderate sample size, these genetic biomarkers exhibit strong susceptibility to the studied condition, showing the importance of exploring their functional significance and underlying biological mechanisms in future research endeavours.","PeriodicalId":501419,"journal":{"name":"medRxiv - Endocrinology","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142183664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insulin Resistance Risk in Normal BMI Individuals: Investigating the Role of Genetic Polymorphisms in RNF138, ABCA1, and ESRRG-GPATCH2 Genes - A Case-Control Study in the Indian Population","authors":"Sabitha Thummala, Sarah Fathima, Nithya Kruthi, Junaid Ahmed Khan Ghori, Katherine Saikia, Balamurali AR, Rahul Ranganathan","doi":"10.1101/2024.08.22.24311857","DOIUrl":"https://doi.org/10.1101/2024.08.22.24311857","url":null,"abstract":"Abstract Background: India, characterised as the \"diabetes capital\" of the world, faces a rapidly increasing diabetes crisis with over 65 million cases diagnosed. Despite the growing prevalence, the genetic underpinnings of insulin resistance (IR) among Indians with normal BMI remain understudied. This research aims to fill the knowledge gap by investigating the association of specific gene variants (RNF138, ABCA1, and ESRRG-GPATCH2) with IR risk in this demographic. Methods: A total of 191 participants (90 men, 101 women) were recruited for this cross-sectional study. Participants were categorized into cases (HOMA2-IR &gt; 2) and controls (HOMA2-IR &lt; 2) based on Homeostasis Model Assessment Insulin Resistance values. Genotyping for rs4799327 (RNF138), rs2275543 (ABCA1), and rs1497828 (ESRRG-GPATCH2) was performed using the Illumina Infinium Global Screening Array. Statistical analyses, including odds ratios (ORs), 95% confidence intervals (CIs), and inheritance model analysis, were conducted to assess the association between genotypes and IR. Results: Significant associations were found between IR and genetic variants rs4799327 in RNF138 and rs1497828 in ESRRG-GPATCH2 (dominant inheritance model) and rs2275543 in ABCA1 (additive model). The study highlights a notable susceptibility to IR linked to these genetic markers among normal BMI individuals in the Indian population. Conclusions:This study underscores the importance of genetic factors in the risk of developing insulin resistance among Indians with normal BMI, suggesting a complex interplay of genetics beyond traditional risk factors. These findings necessitate further research into the functional significance of these associations and their potential implications for targeted interventions and preventive strategies in high-risk populations.","PeriodicalId":501419,"journal":{"name":"medRxiv - Endocrinology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142183665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic Polymorphisms Associated with Insulin Resistance Risk in Normal BMI Indians","authors":"Sabitha Thummala, Junaid Ahmed Khan Ghori, Katherine Saikia, Balamurali AR, Sarah Fathima, Nithya Kruthi, Rahul Ranganathan","doi":"10.1101/2024.08.22.24311638","DOIUrl":"https://doi.org/10.1101/2024.08.22.24311638","url":null,"abstract":"Background: Type 2 diabetes mellitus and cardiovascular illnesses are two metabolic conditions that are greatly influenced by insulin resistance (IR). Identifying genetic markers associated with IR can offer insights into its mechanisms and potential therapeutic targets.\u0000Objective: This study investigated the association between four single nucleotide polymorphisms (SNPs) and insulin resistance among 191 individuals in the Indian population.\u0000Methods: A literature review identified four SNPs linked to IR. Participants were divided into groups based on insulin resistance and sensitivity, determined by the Homeostasis Model Assessment for Insulin Resistance (HOMA2-IR). DNA was extracted for genotyping using Illumina Infinium Global Screening Array (GSA) V3. Case-control analysis assessed SNP-genotype associations with insulin resistance and other clinical parameters.\u0000Results: Among 191 participants, 57 were insulin-resistant and 134 were insulin-sensitive. Significant associations (P &lt; 0.05) were found between selected SNPs and IR. SNP rs920590 showed the strongest association, with the T allele associated with increased IR risk (odds ratio = 4.01, 95% CI 1.55-10.34; p &lt; 0.0014). Additionally, serum LDL cholesterol, serum triglycerides, HbA1c, Insulin fasting and fat mass show significant differences in cases and controls.\u0000Conclusion: This study validates genetic markers linked to insulin resistance (IR) in the Indian population and elucidates their roles in IR pathogenesis. Understanding these markers can inform personalised therapeutic strategies for metabolic disorders.","PeriodicalId":501419,"journal":{"name":"medRxiv - Endocrinology","volume":"2019 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142183669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A prospective pilot study demonstrating non-invasive calibration-free glucose measurement","authors":"Martina Rothenbühler, Aritz Lizoain, Fabien Rebeaud, Adler Perotte, Marc Stoffel, J. Hans DeVries","doi":"10.1101/2024.08.17.24312052","DOIUrl":"https://doi.org/10.1101/2024.08.17.24312052","url":null,"abstract":"Glucose is an essential molecule in energy metabolism. Dysregulated glucose metabolism, the defining feature of diabetes, requires active monitoring to prevent significant morbidity and mortality. Current technologies for intermittent and continuous glucose measurement are invasive. Non-invasive glucose measurement would eliminate this barrier towards making glucose monitoring more accessible, extending the benefits from people living with diabetes to prediabetes and the healthy. We developed and investigated a spectroscopy-based system for measuring glucose non-invasively and without per-person calibration. Using data from a study including adults with insulin-treated diabetes, we constructed a computational model from a development cohort of 15 subjects and found a mean absolute relative difference of 14.5% in an independent validation cohort of five subjects. The correlation between the average model sensitivity by wavelength and the spectrum of glucose was 0.45 (p&lt;0.001). Our findings suggest that spectroscopy-based non-invasive measurement of glucose without invasive calibration is possible.","PeriodicalId":501419,"journal":{"name":"medRxiv - Endocrinology","volume":"55 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142183666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genotype-phenotype discrepancy among family members carrying a novel glucokinase mutation: insights into the interplay of GCK-MODY and insulin resistance","authors":"Shuhui Ji, Hua Shu, Hongqiang Zhao, Yuanyuan Ye, Xuan Liu, Shanshan Chen, Ying Yang, Wenli Feng, Jingting Qiao, Jinyang Zhen, Xiong Yang, Ziyue Zhang, Yu Fan, Yadi Huang, Qing He, Minxian Wang, Kunling Wang, Ming Liu","doi":"10.1101/2024.08.13.24311668","DOIUrl":"https://doi.org/10.1101/2024.08.13.24311668","url":null,"abstract":"Aims/Hypothesis: Heterozygous inactivating mutations in the glucokinase (GCK) gene are known to cause maturity-onset diabetes of the young (GCK-MODY). We identified a novel variant of uncertain significance (VUS) GCK mutation (c.77A&gt;T, p.Q26L) in two family members presenting markedly different severities of diabetic phenotypes. This study aimed to elucidate the potential diabetogenic effect of GCK-Q26L and to explore the mono- and poly-genetic background attributing to different diabetes phenotypes.\u0000Methods: Whole- exome sequencing (WES) and genetic analyses, including polygenic risk score (PRS) assessments, were performed in three members of a family with early-onset diabetes. To elucidate the impact of the GCK-Q26L mutation on glucose homeostasis, a global knock-in mouse model harboring this mutation in both heterozygous and homozygous states was generated. Insulin content and insulin secretion response to glucose and potassium were evaluated in isolated islets. Furthermore, the effects of dorzagliatin (a glucokinase activator, GKA) and liraglutide (a glucagon like peptide 1 receptor agonist, GLP-1RA) on glucose tolerance and insulin secretion were assessed in GCK-Q26L mutant mice.\u0000Results: The proband, who inherited the GCK-Q26L mutation from her father (presenting with non-progressive, mildly elevated blood glucose), exhibited severe diabetic phenotypes including polydipsia, polyuria, polyphagia, weight loss, and ketosis, accompanied by significant dyslipidemia. Genetic analyses revealed that the proband's severe phenotypes and metabolic profiles were associated with a high polygenic risk score (PRS) for insulin resistance that was inherited from her mother. Global heterozygous GCK-Q26L knock-in mice showed a mild increased fasting blood glucose, impaired glucose tolerance (IGT), and decreased serum insulin. Homozygous GCK-Q26L mice presented more severe phenotypes compared to their heterozygous counterparts, confirming the diabetogenic nature of the GCK-Q26Lmutation. Further analyses indicated that GCK-Q26L did not affect insulin sensitivity and islet insulin content. However, GCK-Q26L blunted islet responsiveness to different glucose concentrations and markedly impaired glucose-stimulated insulin secretion (GSIS) without affecting potassium chloride-stimulated insulin secretion (KSIS) and glucose inhibitory effects on glucagon secretion. Both GKA and GLP-1RA enhanced insulin secretion and improved glucose tolerance in mutant mice. Conclusions/Interpretation: This study demonstrates that GCK-Q26L is a GCK-MODY causing mutation. The interplay of GCK-Q26L with a high PRS for insulin resistance contributes to severe diabetic phenotypes. The findings not only expends the list of GCK-MODY causing mutations originally classified as VUS mutations, but also provides insights into interactions of GCK-MODY with polygenic risks of type 2 diabetes, highlighting the importance of considering polygenic backgrounds in the assessment and management of m","PeriodicalId":501419,"journal":{"name":"medRxiv - Endocrinology","volume":"43 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142223948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}