Bioengineering and omics approaches for Type 1 diabetes practical research: advancements and constraints DOI Creative Commons
Xi Peng, Ling Li, Yani Peng

и другие.

Annals of Medicine, Год журнала: 2024, Номер 57(1)

Опубликована: Дек. 20, 2024

Insulin dependency arises from autoimmunity that targets the β cells of pancreas, resulting in Type 1 diabetes (T1D). Despite fact T1D patients require insulin for survival, does not provide a cure this disease or prevent its complications. extensive genetic, molecular, and cellular research on over years, translation understanding into effective clinical therapies continues to pose significant obstacle. It is therefore difficult develop treatment strategies without thorough pathophysiology. Pancreatic tissue bioengineering models human offer valuable approach examining controlling islet function while tackling various facets condition. And recent due advances high-throughput omics analysis, genotypic molecular profiles have become finer tuned. The present article will examine progress these areas, along with their utilization constraints realm T1D.

Язык: Английский

HumanIslets.com: Improving accessibility, integration, and usability of human research islet data DOI
Jessica Ewald, Yao Lü, Cara E. Ellis

и другие.

Cell Metabolism, Год журнала: 2024, Номер unknown

Опубликована: Окт. 1, 2024

Язык: Английский

Процитировано

14
Dysfunctional β-cell autophagy induces β-cell stress and enhances islet immunogenicity DOI Creative Commons
Matthew C. Austin,

Charanya Muralidharan,

Saptarshi Roy

и другие.

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Янв. 29, 2025

Background Type 1 Diabetes (T1D) is caused by a combination of genetic and environmental factors that trigger autoimmune-mediated destruction pancreatic β-cells. Defects in β-cell stress response pathways such as autophagy may play an important role activating and/or exacerbating the immune disease development. Previously, we discovered impaired prior to onset T1D, implicating this pathway T1D pathogenesis. Aims To assess health survival, whether defects render islets more immunogenic. Methods We knocked out critical enzyme, ATG7, β-cells mice (ATG7 Δβ-cell ) then monitored blood glucose, performed glucose tolerance tests, evaluated bulk islet mRNA protein. also assessed MHC-I expression presence CD45+ cells ATG7 how affects EndoC-βH1 HLA-I under basal IFNα stimulated conditions. Lastly, co-cultured with diabetogenic BDC2.5 helper T cell activation. Results found all developed diabetes between 11-15 weeks age. Gene ontology analysis revealed significant upregulation involved inflammatory processes, ER stress, ER-associated degradation pathway. Interestingly, observed proteins presentation, suggesting defective alter immunopeptidome, or antigen repertoire, enhance visibility. In support hypothesis, increased islets. demonstrate upregulated EndoC when autophagic inhibited. This effect was both Conversely, stimulator lysosome acidification/function, C381, decreased expression. showed autophagy, there enhanced Conclusions Our findings survival/function. Defective induces alters production, enhances MHC-I/HLA-I presentation surveilling cells. Overall, our results suggest make susceptible attack destruction.

Язык: Английский

Процитировано

2
Type 2 diabetes: a sacrifice program handling energy surplus DOI Creative Commons
Jianping Ye, Jun Yin

Life Metabolism, Год журнала: 2024, Номер 3(6)

Опубликована: Авг. 7, 2024

Abstract Type 2 diabetes mellitus (T2DM) is closely associated with obesity, while interactions between the two diseases remain to be fully elucidated. To this point, we offer perspective introduce a set of new insights into interpretation T2DM spanning etiology, pathogenesis, and treatment approaches. These include definition as an energy surplus-induced characterized by gradual decline β cell insulin secretion function, which ultimately aims prevent onset severe obesity through mechanisms weight loss. The body employs three adaptive strategies in response surplus: first one adipose tissue expansion store for gain under normal conditions; second resistance slow down overweight third following failure reverse obese conditions. primary signaling molecules driving compensatory responses are adenosine derivatives, such triphosphate (ATP), acetyl coenzyme A (acetyl-CoA), reduced nicotinamide adenine dinucleotide (NADH). exert their effects allosteric, post-translational, transcriptional regulation metabolic pathways. suggest that protective defense against excessive adiposity avert obesity. provides unified framework explaining opens avenues study T2DM.

Язык: Английский

Процитировано

5
HumanIslets: An integrated platform for human islet data access and analysis DOI Creative Commons
Jessica Ewald, Yao Lu, Cara E. Ellis

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 22, 2024

Comprehensive molecular and cellular phenotyping of human islets can enable deep mechanistic insights for diabetes research. We established the Human Islet Data Analysis Sharing (HI-DAS) consortium to advance goals in accessibility, usability, integration data from isolated donors with without at Alberta Diabetes Institute (ADI) IsletCore. Here we introduce HumanIslets.com, an open resource research community. This platform, which presently includes on 547 islet donors, allows users access linked datasets describing profiles, function donor phenotypes, perform various statistical functional analyses donor, single-cell levels. As example analytic capacity this show a dissociation between cell culture effects transcript protein expression, approach correct exocrine contamination found hand-picked islets. Finally, provide workflow visualization that highlights links type 2 status, SERCA3b Ca

Язык: Английский

Процитировано

4
Single cell multiome profiling of pancreatic islets reveals physiological changes in cell type-specific regulation associated with diabetes risk DOI Creative Commons
Hannah M Mummey, Weston S. Elison,

Katha Korgaonkar

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 6, 2024

Abstract Physiological variability in pancreatic cell type gene regulation and the impact on diabetes risk is poorly understood. In this study we mapped types using single multiomic (joint RNA-seq ATAC-seq) profiling 28 non-diabetic donors combination with data from 35 Human Pancreas Analysis Program. We identified widespread associations age, sex, BMI, HbA1c, where regulatory responses were highly type- phenotype-specific. beta cells, donor age associated hypoxia, apoptosis, unfolded protein response, external signal-dependent transcriptional regulators, while HbA1c inflammatory gender chromatin organization. 10.8K loci genetic variants QTLs for cis element (cRE) accessibility, including 20% lineage- or type-specific effects which disrupted distinct transcription factor motifs. Type 2 glycemic trait enriched both phenotype- QTL-associated cREs, whereas 1 showed limited enrichment. Variants at 226 other types, 40 that statistically colocalized, annotating target genes of colocalized revealed putatively novel roles disease. Our findings reveal diverse to phenotype genotype physiology, identify pathways, networks, through physiology impacts risk.

Язык: Английский

Процитировано

4
Signal transduction pathways controlling Ins2 gene activity and beta cell state transitions DOI Creative Commons
Chieh Min Jamie Chu,

Bhavya Sabbineni,

Haoning Howard Cen

и другие.

iScience, Год журнала: 2025, Номер 28(3), С. 112015 - 112015

Опубликована: Фев. 17, 2025

Pancreatic β cells exist in low and high insulin gene activity states that are dynamic on a scale of hours to days. Here, we used live 3D imaging, mass spectrometry proteomics, targeted perturbations cell signaling comprehensively investigate Ins2(GFP)HIGH Ins2(GFP)LOW states. We identified the two Ins2 intact isolated islets showed same state were more likely be nearer each other. report proteomes pure depth 5555 proteins show with had reduced immaturity factors, as well increased translation. activators cAMP (GLP1, IBMX) powerful drivers transitions. Okadaic acid cyclosporine A opposite effects. This study provides new insight into proteomic profiles regulation

Язык: Английский

Процитировано

0
Lysine Potentiates Insulin Secretion via AASS-Dependent Catabolism and Regulation of GABA Content and Signaling DOI

Felipe Muñoz,

Qian Gao, Matthias Mattanovich

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 3, 2025

Abstract Background and aim Lysine is an essential amino acid with insulinotropic effects in humans. In vitro , lysine also potentiates glucose-stimulated insulin secretion (GSIS) β cell lines rodent pancreatic islets. For decades it has been assumed that action of mediated by plasma membrane depolarization similar to arginine. Aminoadipate-Semialdehyde Synthase (AASS) a mitochondrial-located bifunctional enzyme engaged the first two steps catabolism. Whether AASS-dependent catabolism occurs cells whether required for its not investigated. Methods mRNA expression pathway genes was assessed human islets from non-diabetic (ND) type 2 diabetes (T2D) subjects. AASS silenced INS1 832/13 cells. metabolism function were investigated ELISA, extracellular flux analysis, live calcium imaging, transcriptomics metabolomics analyses. Results Expression involved catabolism, including AASS, ALDH7A1, DHTKD1 HADH reduced T2D donors. Silencing resulted lysine- Surprisingly, analysis Aass -KD suppressed identified γ-aminobutyric (GABA)/glutamate ratio as well altered implicated GABA metabolism. This accompanied mitochondrial TCA cycle oxidative phosphorylation (OXPHOS) activity, reflected elevated lactate/pyruvate whole-cell ATP/ADP content ATP-linked respiration. Glucose-and GABA-stimulated cytosolic Aass-KD Strikingly, addition recovered impaired Conclusion maintain adequate shunt signaling. addition, supports energy production, uptake secretion. Reduced may contribute depletion dysfunction patients.

Язык: Английский

Процитировано

0
Lysine Potentiates Insulin Secretion via AASS-Dependent Catabolism and Regulation of GABA Content and Signaling DOI Creative Commons
Luis Rodrigo Cataldo, Qian Gao, Matthias Mattanovich

и другие.

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Март 17, 2025

Abstract Background and aim: Lysine is an essential amino acid with insulinotropic effects in humans. In vitro, lysine also potentiates glucose-stimulated insulin secretion (GSIS) β cell lines rodent pancreatic islets. For decades it has been assumed that action of mediated by plasma membrane depolarization similar to arginine. Aminoadipate-Semialdehyde Synthase (AASS) a mitochondrial-located bifunctional enzyme engaged the first two steps catabolism. Whether AASS-dependent catabolism occurs cells whether required for its not investigated. Methods mRNA expression pathway genes was assessed human islets from non-diabetic (ND) type 2 diabetes (T2D) subjects. AASS silenced INS1 832/13 cells. metabolism function were investigated ELISA, extracellular flux analysis, live calcium imaging, transcriptomics metabolomics analyses. Results Expression involved catabolism, including AASS, ALDH7A1, DHTKD1 HADH, reduced T2D donors. Silencing AASS resulted lysine- Surprisingly, analysis Aass-KD suppressed identified γ-aminobutyric (GABA)/glutamate ratio as well altered implicated GABA metabolism. This accompanied mitochondrial TCA cycle oxidative phosphorylation (OXPHOS) activity, reflected elevated lactate/pyruvate whole-cell ATP/ADP content ATP-linked respiration. Glucose-and GABA-stimulated cytosolic Aass-KD Strikingly, addition recovered impaired Conclusion maintain adequate shunt signaling. In addition, supports energy production, uptake secretion. Reduced may contribute depletion dysfunction patients.

Язык: Английский

Процитировано

0
TMEM55A-mediated PI5P signalling regulates alpha cell actin depolymerisation and glucagon secretion DOI Creative Commons
Xiong Liu, Theodore dos Santos, Aliya F Spigelman

и другие.

Diabetologia, Год журнала: 2025, Номер unknown

Опубликована: Март 26, 2025

Язык: Английский

Процитировано

0
Persistent organic pollutant concentrations in human pancreas and peripancreatic adipose tissues correlate with markers of beta cell dysfunction DOI
Myriam P. Hoyeck, Ma. Enrica Angela Ching, Jana Palaniyandi

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Апрель 28, 2025

Abstract Epidemiological studies consistently report associations between circulating concentrations of persistent organic pollutants (POPs) and increased type 2 diabetes risk. Measures POP in pancreas are limited; given the role endocrine pathogenesis, this is an important gap literature. Additionally, no have correlated with direct measures beta cell function humans. We hypothesized that lipophilic POPs accumulate human correlate markers To test hypothesis, we measured concentration from 3 chemical classes – dioxins/furans, polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs) peripancreatic adipose tissue biopsies obtained 31 organ donors via Alberta Diabetes Institute IsletCore. Indeed, were detected pancreas, for some pollutants, at higher than adipose. next assessed correlations systemic indicators risk (BMI, age, %HbA1c) function. end, insulin secretion response to numerous secretagogues (i.e. glucose, fatty acids, amino exendin-4, or KCl) isolated islets same donors. Pancreas PCBs OCPs positively BMI, age basal but negatively stimulation index (ratio under high glucose / low conditions). In contrast, dioxins/furans acid- acid-stimulated secretion. These data confirm

Язык: Английский

Процитировано

0