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1.
Int J Mol Sci ; 25(9)2024 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-38731945

RESUMEN

The main hallmark in the development of both type 1 and type 2 diabetes is a decline in functional ß-cell mass. This decline is predominantly attributed to ß-cell death, although recent findings suggest that the loss of ß-cell identity may also contribute to ß-cell dysfunction. This phenomenon is characterized by a reduced expression of key markers associated with ß-cell identity. This review delves into the insights gained from single-cell omics research specifically focused on ß-cell identity. It highlights how single-cell omics based studies have uncovered an unexpected level of heterogeneity among ß-cells and have facilitated the identification of distinct ß-cell subpopulations through the discovery of cell surface markers, transcriptional regulators, the upregulation of stress-related genes, and alterations in chromatin activity. Furthermore, specific subsets of ß-cells have been identified in diabetes, such as displaying an immature, dedifferentiated gene signature, expressing significantly lower insulin mRNA levels, and expressing increased ß-cell precursor markers. Additionally, single-cell omics has increased insight into the detrimental effects of diabetes-associated conditions, including endoplasmic reticulum stress, oxidative stress, and inflammation, on ß-cell identity. Lastly, this review outlines the factors that may influence the identification of ß-cell subpopulations when designing and performing a single-cell omics experiment.


Asunto(s)
Células Secretoras de Insulina , Análisis de la Célula Individual , Células Secretoras de Insulina/metabolismo , Humanos , Análisis de la Célula Individual/métodos , Animales , Genómica/métodos , Estrés del Retículo Endoplásmico/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patología
2.
Front Immunol ; 15: 1381319, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38742118

RESUMEN

Introduction: Inflammation of the pancreas contributes to the development of diabetes mellitus. Although it is well-accepted that local inflammation leads to a progressive loss of functional beta cell mass that eventually causes the onset of the disease, the development of islet inflammation remains unclear. Methods: Here, we used single-cell RNA sequencing to explore the cell type-specific molecular response of primary human pancreatic cells exposed to an inflammatory environment. Results: We identified a duct subpopulation presenting a unique proinflammatory signature among all pancreatic cell types. Discussion: Overall, the findings of this study point towards a role for duct cells in the propagation of islet inflammation, and in immune cell recruitment and activation, which are key steps in the pathophysiology of diabetes mellitus.


Asunto(s)
Inflamación , Conductos Pancreáticos , Análisis de la Célula Individual , Transcriptoma , Humanos , Conductos Pancreáticos/patología , Conductos Pancreáticos/metabolismo , Conductos Pancreáticos/inmunología , Inflamación/inmunología , Inflamación/genética , Perfilación de la Expresión Génica , Diabetes Mellitus/inmunología , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Células Cultivadas , Mediadores de Inflamación/metabolismo
3.
Patient Educ Couns ; 125: 108295, 2024 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-38749345

RESUMEN

OBJECTIVE: To confirm described dimensions of making care fit and explore how patients and clinicians collaborate to make care fit in clinical practice. METHODS: As part of an ongoing study, we audiotaped and transcribed patient-clinician consultations in diabetes care. We purposively selected consultations based on participants' demographical, biomedical and biographical characteristics. We analysed transcripts using reflexive thematic analysis. We combined a deductive and inductive approach, using the pre-described dimensions of making care fit and adding new (sub-)dimensions when pertinent. RESULTS: We analysed 24 clinical consultations. Our data confirmed eight previously described dimensions and provided new sub-dimensions of making care fit with examples from clinical practice (problematic situation, influence of devices, sense of options, shared agenda setting, clinician context, adapting to changing organization of care, and possibility to reconsider). CONCLUSION: Our study confirmed, specified and enriched the conceptualization of making care fit through practice examples. We observed patient-clinician collaboration in exploration of patients' context, and by responsively changing, adapting or maintaining care plans. PRACTICE IMPLICATIONS: Our findings support clinicians and researchers with insights in important aspects of patient-clinician collaboration. Ultimately, this would lead to optimal design of care plans that fit well in each patient life.

4.
Transpl Int ; 37: 12278, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38601276

RESUMEN

A public health emergency such as the COVID-19 pandemic has behavioral, mental and physical implications in patients with type 1 diabetes (T1D). To what extent the presence of a transplant further increases this burden is not known. Therefore, we compared T1D patients with an islet or pancreas transplant (ß-cell Tx; n = 51) to control T1D patients (n = 272). Fear of coronavirus infection was higher in those with ß-cell Tx than without (Visual Analogue Scale 5.0 (3.0-7.0) vs. 3.0 (2.0-5.0), p = 0.004) and social isolation behavior was more stringent (45.8% vs. 14.0% reported not leaving the house, p < 0.001). A previous ß-cell Tx was the most important predictor of at-home isolation. Glycemic control worsened in patients with ß-cell Tx, but improved in control patients (ΔHbA1c +1.67 ± 8.74 vs. -1.72 ± 6.15 mmol/mol, p = 0.006; ΔTime-In-Range during continuous glucose monitoring -4.5% (-6.0%-1.5%) vs. +3.0% (-2.0%-6.0%), p = 0.038). Fewer patients with ß-cell Tx reported easier glycemic control during lockdown (10.4% vs. 22.6%, p = 0.015). All T1D patients, regardless of transplantation status, experienced stress (33.4%), anxiety (27.9%), decreased physical activity (42.0%), weight gain (40.5%), and increased insulin requirements (29.7%). In conclusion, T1D patients with ß-cell Tx are increasingly affected by a viral pandemic lockdown with higher fear of infection, more stringent social isolation behavior and deterioration of glycemic control. This trial has been registered in the clinicaltrials.gov registry under identifying number NCT05977205 (URL: https://clinicaltrials.gov/study/NCT05977205).


Asunto(s)
Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , Trasplante de Islotes Pancreáticos , Femenino , Humanos , Masculino , Ansiedad , Glucemia , Automonitorización de la Glucosa Sanguínea , Estudios Transversales , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/cirugía , Control Glucémico , Pandemias , Salud Pública
6.
Am J Physiol Endocrinol Metab ; 326(5): E673-E680, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38446636

RESUMEN

Residual beta cells are present in most patients with longstanding type 1 diabetes but it is unknown whether these beta cells react normally to different stimuli. Moreover a defect in proinsulin conversion and abnormal alpha cell response are also part of the islet dysfunction. A three-phase [euglycemia, hyperglycemia, and hyperglycemia + glucagon-like peptide 1 (GLP-1)] clamp was performed in patients with longstanding type 1 diabetes. Intravenous arginine boluses were administered at the end of each phase. On another day, a mixed meal stimulation test with a subsequent intravenous arginine bolus was performed. C-peptide was detectable in a subgroup of subjects at baseline (2/15) or only after stimulation (3/15). When detectable, C-peptide increased 2.9-fold [95% CI: 1.2-7.1] during the hyperglycemia phase and 14.1-fold [95% CI: 3.1-65.2] during the hyperglycemia + GLP-1 phase, and 22.3-fold [95% CI: 5.6-89.1] during hyperglycemia + GLP-1 + arginine phase when compared with baseline. The same subset of patients with a C-peptide response were identified during the mixed meal stimulation test as during the clamp. There was an inhibition of glucagon secretion (0.72-fold, [95% CI: 0.63-0.84]) during the glucose clamp irrespective of the presence of detectable beta cell function. Proinsulin was only present in a subset of subjects with detectable C-peptide (3/15) and proinsulin mimicked the C-peptide response to the different stimuli when detectable. Residual beta cells in longstanding type 1 diabetes respond adequately to different stimuli and could be of clinical benefit.NEW & NOTEWORTHY If beta cell function is detectable, the beta cells react relatively normal to the different stimuli except for the first phase response to intravenous glucose. An oral mixed meal followed by an intravenous arginine bolus can identify residual beta cell function/mass as well as the more commonly used glucose potentiated arginine-induced insulin secretion during a hyperglycemic clamp.


Asunto(s)
Arginina , Glucemia , Péptido C , Diabetes Mellitus Tipo 1 , Péptido 1 Similar al Glucagón , Técnica de Clampeo de la Glucosa , Comidas , Humanos , Arginina/administración & dosificación , Arginina/farmacología , Diabetes Mellitus Tipo 1/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Masculino , Femenino , Adulto , Péptido C/sangre , Péptido C/metabolismo , Persona de Mediana Edad , Glucemia/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/fisiología , Glucosa/administración & dosificación , Glucosa/metabolismo , Insulina/metabolismo , Insulina/administración & dosificación , Hiperglucemia/metabolismo , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/efectos de los fármacos , Glucagón/metabolismo
7.
Diabetologia ; 67(1): 124-136, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37924378

RESUMEN

AIMS/HYPOTHESIS: Inflammation induces beta cell dysfunction and demise but underlying molecular mechanisms remain unclear. The apolipoprotein L (APOL) family of genes has been associated with innate immunity and apoptosis in non-pancreatic cell types, but also with metabolic syndrome and type 2 diabetes mellitus. Here, we hypothesised that APOL genes play a role in inflammation-induced beta cell damage. METHODS: We used single-cell transcriptomics datasets of primary human pancreatic islet cells to study the expression of APOL genes upon specific stress conditions. Validation of the findings was carried out in EndoC-ßH1 cells and primary human islets. Finally, we performed loss- and gain-of-function experiments to investigate the role of APOL genes in beta cells. RESULTS: APOL genes are expressed in primary human beta cells and APOL1, 2 and 6 are strongly upregulated upon inflammation via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. APOL1 overexpression increases endoplasmic reticulum stress while APOL1 knockdown prevents cytokine-induced beta cell death and interferon-associated response. Furthermore, we found that APOL genes are upregulated in beta cells from donors with type 2 diabetes compared with donors without diabetes mellitus. CONCLUSIONS/INTERPRETATION: APOLs are novel regulators of islet inflammation and may contribute to beta cell damage during the development of diabetes. DATA AVAILABILITY: scRNAseq data generated by our laboratory and used in this study are available in the Gene Expression Omnibus (GEO; www.ncbi.nlm.nih.gov/geo/ ), accession number GSE218316.


Asunto(s)
Apolipoproteína L1 , Inflamación , Células Secretoras de Insulina , Humanos , Apolipoproteína L1/genética , Apolipoproteína L1/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Inflamación/genética , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología
8.
Transpl Int ; 36: 11077, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37908676

RESUMEN

Islet delivery devices (IDDs) offer potential benefits for islet transplantation and stem cell-based replacement in type 1 diabetes. Little is known about patient preferences regarding islet delivery device characteristics and implantation strategies. Patient preferences for IDDs and implantation strategies remain understudied. We invited patients, parents and caregivers to fill in an online questionnaire regarding IDDs. An online survey gathered responses from 809 type 1 diabetes patients and 47 caregivers. We also assessed diabetes distress in a subgroup of 412 patients. A significant majority (97%) expressed willingness to receive an IDD. Preferred IDD attributes included a 3.5 cm diameter for 37.7% of respondents, while when provided with all options, 30.4% found dimensions unimportant. Respondents were open to approximately 4 implants, each with a 5 cm incision. Many favored a device functioning for 12 months (33.4%) or 24 months (24.8%). Younger participants (16-30) were more inclined to accept a 6 months functional duration (p < 0.001). Functional duration outweighed implant quantity and size (p < 0.001) in device importance. This emphasizes patients' willingness to accommodate burdens related to IDD features and implantation methods, crucial for designing future beta cell replacement strategies.


Asunto(s)
Diabetes Mellitus Tipo 1 , Trasplante de Islotes Pancreáticos , Humanos , Diabetes Mellitus Tipo 1/cirugía , Trasplante de Islotes Pancreáticos/métodos , Prioridad del Paciente
9.
Diabetologia ; 66(12): 2213-2225, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37775611

RESUMEN

AIMS/HYPOTHESIS: There is a lack of e-health systems that integrate the complex variety of aspects relevant for diabetes self-management. We developed and field-tested an e-health system (POWER2DM) that integrates medical, psychological and behavioural aspects and connected wearables to support patients and healthcare professionals in shared decision making and diabetes self-management. METHODS: Participants with type 1 or type 2 diabetes (aged >18 years) from hospital outpatient diabetes clinics in the Netherlands and Spain were randomised using randomisation software to POWER2DM or usual care for 37 weeks. This RCT assessed the change in HbA1c between the POWER2DM and usual care groups at the end of the study (37 weeks) as a primary outcome measure. Participants and clinicians were not blinded to the intervention. Changes in quality of life (QoL) (WHO-5 Well-Being Index [WHO-5]), diabetes self-management (Diabetes Self-Management Questionnaire - Revised [DSMQ-R]), glycaemic profiles from continuous glucose monitoring devices, awareness of hypoglycaemia (Clarke hypoglycaemia unawareness instrument), incidence of hypoglycaemic episodes and technology acceptance were secondary outcome measures. Additionally, sub-analyses were performed for participants with type 1 and type 2 diabetes separately. RESULTS: A total of 226 participants participated in the trial (108 with type 1 diabetes; 118 with type 2 diabetes). In the POWER2DM group (n=111), HbA1c decreased from 60.6±14.7 mmol/mol (7.7±1.3%) to 56.7±12.1 mmol/mol (7.3±1.1%) (means ± SD, p<0.001), compared with no change in the usual care group (n=115) (baseline: 61.7±13.7 mmol/mol, 7.8±1.3%; end of study: 61.0±12.4 mmol/mol, 7.7±1.1%; p=0.19) (between-group difference 0.24%, p=0.008). In the sub-analyses in the POWER2DM group, HbA1c in participants with type 2 diabetes decreased from 62.3±17.3 mmol/mol (7.9±1.6%) to 54.3±11.1 mmol/mol (7.1±1.0%) (p<0.001) compared with no change in HbA1c in participants with type 1 diabetes (baseline: 58.8±11.2 mmol/mol [7.5±1.0%]; end of study: 59.2±12.7 mmol/mol [7.6±1.2%]; p=0.84). There was an increase in the time during which interstitial glucose levels were between 3.0 and 3.9 mmol/l in the POWER2DM group, but no increase in clinically relevant hypoglycaemia (interstitial glucose level below 3.0 mmol/l). QoL improved in participants with type 1 diabetes in the POWER2DM group compared with the usual care group (baseline: 15.7±3.8; end of study: 16.3±3.5; p=0.047 for between-group difference). Diabetes self-management improved in both participants with type 1 diabetes (from 7.3±1.2 to 7.7±1.2; p=0.002) and those with type 2 diabetes (from 6.5±1.3 to 6.7±1.3; p=0.003) within the POWER2DM group. The POWER2DM integrated e-health support was well accepted in daily life and no important adverse (or unexpected) effects or side effects were observed. CONCLUSIONS/INTERPRETATION: POWER2DM improves HbA1c levels compared with usual care in those with type 2 diabetes, improves QoL in those with type 1 diabetes, improves diabetes self-management in those with type 1 and type 2 diabetes, and is well accepted in daily life. TRIAL REGISTRATION: ClinicalTrials.gov NCT03588104. FUNDING: This study was funded by the European Union's Horizon 2020 Research and Innovation Programme (grant agreement number 689444).


Asunto(s)
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Hipoglucemia , Automanejo , Telemedicina , Humanos , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Calidad de Vida , Automonitorización de la Glucosa Sanguínea , Glucemia , Toma de Decisiones Conjunta , Hipoglucemia/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico
10.
Transpl Int ; 36: 11505, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37692453

RESUMEN

The purpose of pancreas or islet transplantation is to restore glycemic control in order to mitigate diabetes-related complications and prevent severe hypoglycemia. Complications from chronic pancreas allograft rejection may lead to transplantectomy, even when the endocrine function remains preserved. We present first evidence of a successful HLA incompatible islet re-transplantation with islets isolated from a rejecting pancreas allograft after simultaneous kidney pancreas transplantation. The pancreas allograft was removed because of progressively painful pancreatic panniculitis from clinically uncontrolled chronic rejection. The endocrine function was preserved. Induction treatment for this "islet alloautotransplantation" consisted of plasmapheresis, IVIg and alemtuzumab. At 1 year, the patient retained islet graft function with good glycemic control and absence of severe hypoglycemia, despite persistent low-grade HLA donor-specific antibodies. His panniculitis had resolved completely. In our point of view, islet alloautotransplantation derived from a chronically rejecting pancreas allograft is a potential option to salvage (partial) islet function, despite preformed donor-specific antibodies, in order to maintain stable glycemic control. Thereby it protects against severe hypoglycemia, and it potentially mitigates kidney graft dysfunction and other diabetes-related complications in patients with continued need for immunosuppression and who are otherwise difficult to retransplant.


Asunto(s)
Hipoglucemia , Páncreas , Humanos , Trasplante Homólogo , Riñón , Anticuerpos , Aloinjertos
11.
Am J Transplant ; 23(9): 1425-1433, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37307954

RESUMEN

Islet transplantation stabilizes glycemic control in patients with complicated diabetes mellitus. Rapid functional decline could be due to islet allograft rejection. However, there is no reliable method to assess rejection, and treatment protocols are absent. We aimed to characterize diagnostic features of islet allograft rejection and assess effectiveness of high-dose methylprednisolone treatment. Over a median follow-up of 61.8 months, 22% (9 of 41) of islet transplant recipients experienced 10 suspected rejection episodes (SREs). All first SREs occurred within 18 months after transplantation. Important features were unexplained hyperglycemia (all cases), unexplained C-peptide decrease (ΔC-peptide, 77.1% [-59.1% to -91.6%]; ΔC-peptide:glucose, -76.3% [-49.2% to -90.4%]), predisposing event (5 of 10 cases), and increased immunologic risk (5 of 10 cases). At 6 months post-SRE, patients who received protocolized methylprednisolone (n = 4) had significantly better islet function than untreated patients (n = 4), according to C-peptide (1.39 ± 0.59 vs 0.14 ± 0.19 nmol/L; P = .007), Igls score (good [4 of 4 cases] vs failure [3 of 4 cases] or marginal [1 of 4 cases]; P = .018) and ß score (6.0 [6.0-6.0] vs 1.0 [0.0-3.5]; P = .013). SREs are prevalent among islet transplant recipients and are associated with loss of islet graft function. Timely treatment with high-dose methylprednisolone mitigates this loss. Unexplained hyperglycemia, unexpected C-peptide decrease, a predisposing event, and elevated immunologic risk are diagnostic indicators for SRE.


Asunto(s)
Hiperglucemia , Trasplante de Islotes Pancreáticos , Humanos , Trasplante de Islotes Pancreáticos/métodos , Péptido C , Péptidos , Hiperglucemia/diagnóstico , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/etiología , Aloinjertos
13.
Diabetes ; 72(7): 898-907, 2023 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-37068261

RESUMEN

Intrahepatic transplantation of islets of Langerhans (ITx) is a treatment option for individuals with complicated type 1 diabetes and profoundly unstable glycemic control, but its therapeutic success is hampered by deterioration of graft function over time. To improve ITx strategies, technologies to noninvasively monitor the fate and survival of transplanted islets over time are of great potential value. We used [68Ga]Ga-NODAGA-exendin-4 (68Ga-exendin) positron emission tomography (PET)/computed tomography (CT) imaging to demonstrate the feasibility of quantifying ß-cell mass in intrahepatic islet grafts in 13 individuals with type 1 diabetes, nine after ITx with functional islet grafts and four control patients not treated with ITx. ß-Cell function was measured by mixed-meal tolerance test. With dynamic 68Ga-exendin PET/CT images, we determined tracer accumulation in hepatic hotspots, and intrahepatic fat was assessed using MRI and spectroscopy. Quantification of hepatic hotspots showed a significantly higher uptake of 68Ga-exendin in the ITx group compared with the control group (median 0.55 [interquartile range 0.51-0.63] vs. 0.43 [0.42-0.45]). GLP-1 receptor expression was found in transplanted islets by immunohistochemistry. Intrahepatic fat was not detected in a majority of the individuals. Our study provides the first clinical evidence that radiolabeled exendin imaging can be used to monitor viable transplanted islets after intraportal ITx. ARTICLE HIGHLIGHTS: This clinical study researched the potential of radiolabeled exendin to follow the fate and survival of intrahepatic islet grafts. Is it feasible to quantitatively detect intrahepatic islet transplants with [68Ga]Ga-NODAGA-exendin-4 (68Ga-exendin) positron emission tomography (PET) imaging? Our study findings indicate that the imaging technique 68Ga-exendin PET can be used to monitor viable islet mass after intrahepatic islet transplantation in humans. Alongside functional measures, 68Ga-exendin PET imaging could significantly aid in the evaluation of strategies designed to improve islet engraftment, survival, and function.


Asunto(s)
Diabetes Mellitus Tipo 1 , Trasplante de Islotes Pancreáticos , Humanos , Trasplante de Islotes Pancreáticos/métodos , Diabetes Mellitus Tipo 1/diagnóstico por imagen , Diabetes Mellitus Tipo 1/cirugía , Exenatida , Tomografía Computarizada por Tomografía de Emisión de Positrones , Supervivencia Celular , Tomografía de Emisión de Positrones/métodos
14.
BMJ Evid Based Med ; 28(3): 157-163, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36868578

RESUMEN

OBJECTIVES: To describe the range of collaborative approaches to shared decision-making (SDM) observed in clinical encounters of patients with diabetes and their clinicians. DESIGN: A secondary analysis of videorecordings obtained in a randomised trial comparing usual diabetes primary care with or without using a within-encounter conversation SDM tool. SETTING: Using the purposeful SDM framework, we classified the forms of SDM observed in a random sample of 100 video-recorded clinical encounters of patients with type 2 diabetes in primary care. MAIN OUTCOME MEASURES: We assessed the correlation between the extent to which each form of SDM was used and patient involvement (OPTION12-scale). RESULTS: We observed at least one instance of SDM in 86 of 100 encounters. In 31 (36%) of these 86 encounters, we found only one form of SDM, in 25 (29%) two forms, and in 30 (35%), we found ≥3 forms of SDM. In these encounters, 196 instances of SDM were identified, with weighing alternatives (n=64 of 196, 33%), negotiating conflicting desires (n=59, 30%) and problemsolving (n=70, 36%) being similarly prevalent and developing existential insight accounting for only 1% (n=3) of instances. Only the form of SDM focused on weighing alternatives was correlated with a higher OPTION12-score. More forms of SDM were used when medications were changed (2.4 SDM forms (SD 1.48) vs 1.8 (SD 1.46); p=0.050). CONCLUSIONS: After considering forms of SDM beyond weighing alternatives, SDM was present in most encounters. Clinicians and patients often used different forms of SDM within the same encounter. Recognising a range of SDM forms that clinicians and patients use to respond to problematic situations, as demonstrated in this study, opens new lines of research, education and practice that may advance patient-centred, evidence-based care.


Asunto(s)
Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/terapia , Toma de Decisiones Conjunta , Comunicación , Participación del Paciente , Proyectos de Investigación
15.
Diabetologia ; 66(5): 884-896, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36884057

RESUMEN

AIMS/HYPOTHESIS: Transcriptome analyses revealed insulin-gene-derived transcripts in non-beta endocrine islet cells. We studied alternative splicing of human INS mRNA in pancreatic islets. METHODS: Alternative splicing of insulin pre-mRNA was determined by PCR analysis performed on human islet RNA and single-cell RNA-seq analysis. Antisera were generated to detect insulin variants in human pancreatic tissue using immunohistochemistry, electron microscopy and single-cell western blot to confirm the expression of insulin variants. Cytotoxic T lymphocyte (CTL) activation was determined by MIP-1ß release. RESULTS: We identified an alternatively spliced INS product. This variant encodes the complete insulin signal peptide and B chain and an alternative C-terminus that largely overlaps with a previously identified defective ribosomal product of INS. Immunohistochemical analysis revealed that the translation product of this INS-derived splice transcript was detectable in somatostatin-producing delta cells but not in beta cells; this was confirmed by light and electron microscopy. Expression of this alternatively spliced INS product activated preproinsulin-specific CTLs in vitro. The exclusive presence of this alternatively spliced INS product in delta cells may be explained by its clearance from beta cells by insulin-degrading enzyme capturing its insulin B chain fragment and a lack of insulin-degrading enzyme expression in delta cells. CONCLUSIONS/INTERPRETATION: Our data demonstrate that delta cells can express an INS product derived from alternative splicing, containing both the diabetogenic insulin signal peptide and B chain, in their secretory granules. We propose that this alternative INS product may play a role in islet autoimmunity and pathology, as well as endocrine or paracrine function or islet development and endocrine destiny, and transdifferentiation between endocrine cells. INS promoter activity is not confined to beta cells and should be used with care when assigning beta cell identity and selectivity. DATA AVAILABILITY: The full EM dataset is available via www.nanotomy.org (for review: http://www.nanotomy.org/OA/Tienhoven2021SUB/6126-368/ ). Single-cell RNA-seq data was made available by Segerstolpe et al [13] and can be found at https://sandberglab.se/pancreas . The RNA and protein sequence of INS-splice was uploaded to GenBank (BankIt2546444 INS-splice OM489474).


Asunto(s)
Insulisina , Islotes Pancreáticos , Humanos , Células Secretoras de Somatostatina/metabolismo , Insulisina/metabolismo , Insulina/genética , Insulina/metabolismo , Islotes Pancreáticos/metabolismo , ARN , Señales de Clasificación de Proteína
16.
Genome Biol ; 23(1): 196, 2022 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-36109769

RESUMEN

BACKGROUND: Non-coding genetic variants that influence gene transcription in pancreatic islets play a major role in the susceptibility to type 2 diabetes (T2D), and likely also contribute to type 1 diabetes (T1D) risk. For many loci, however, the mechanisms through which non-coding variants influence diabetes susceptibility are unknown. RESULTS: We examine splicing QTLs (sQTLs) in pancreatic islets from 399 human donors and observe that common genetic variation has a widespread influence on the splicing of genes with established roles in islet biology and diabetes. In parallel, we profile expression QTLs (eQTLs) and use transcriptome-wide association as well as genetic co-localization studies to assign islet sQTLs or eQTLs to T2D and T1D susceptibility signals, many of which lack candidate effector genes. This analysis reveals biologically plausible mechanisms, including the association of T2D with an sQTL that creates a nonsense isoform in ERO1B, a regulator of ER-stress and proinsulin biosynthesis. The expanded list of T2D risk effector genes reveals overrepresented pathways, including regulators of G-protein-mediated cAMP production. The analysis of sQTLs also reveals candidate effector genes for T1D susceptibility such as DCLRE1B, a senescence regulator, and lncRNA MEG3. CONCLUSIONS: These data expose widespread effects of common genetic variants on RNA splicing in pancreatic islets. The results support a role for splicing variation in diabetes susceptibility, and offer a new set of genetic targets with potential therapeutic benefit.


Asunto(s)
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Islotes Pancreáticos , ARN Largo no Codificante , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/genética , Exodesoxirribonucleasas/genética , Exodesoxirribonucleasas/metabolismo , Humanos , Islotes Pancreáticos/metabolismo , Proinsulina/genética , Proinsulina/metabolismo , Isoformas de Proteínas/genética , Empalme del ARN , ARN Largo no Codificante/metabolismo
17.
Transpl Int ; 35: 10507, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36033644

RESUMEN

A global online survey was administered to 69 islet transplantation programs, covering 84 centers and 5 networks. The survey addressed questions on program organization and activity in the 2000-2020 period, including impact on activity of national health care coverage policies. We obtained full data from 55 institutions or networks worldwide and basic activity data from 6 centers. Additional data were obtained from alternative sources. A total of 94 institutions and 5 networks was identified as having performed islet allotransplantation. 4,365 islet allotransplants (2,608 in Europe, 1,475 in North America, 135 in Asia, 119 in Oceania, 28 in South America) were reported in 2,170 patients in the survey period. From 15 centers active at the start of the study period, the number of simultaneously active islet centers peaked at 54, to progressively decrease to 26 having performed islet allotransplants in 2020. Notably, only 16 centers/networks have done >100 islet allotransplants in the survey period. Types of transplants performed differed notably between North America and the rest of the world, in particular with respect to the near-absence of simultaneous islet-kidney transplantation. Absence of heath care coverage has significantly hampered transplant activity in the past years and the COVID-19 pandemic in 2020.


Asunto(s)
COVID-19 , Diabetes Mellitus Tipo 1 , Trasplante de Islotes Pancreáticos , Trasplante de Páncreas , Humanos , Pandemias
18.
J Diabetes Investig ; 13(8): 1294-1299, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-35511075

RESUMEN

Young adults living with type 1 diabetes often struggle to achieve what clinicians consider to be optimal levels of metabolic control. Despite the impact that this can have on a young person's future risk of complications, there are relatively few studies reporting new ways of organizing or delivering care to this cohort. In this article, we explore some of the reasons why young adult diabetes care is challenging, and describe approaches to "re-imagining" how care might be improved. The work is informed by the 'Making Care Fit' collaborative and by a program of research, entitled D1 Now, involving co-design of a complex person-centered intervention with young adults.


Asunto(s)
Diabetes Mellitus Tipo 1 , Adolescente , Diabetes Mellitus Tipo 1/terapia , Humanos , Adulto Joven
19.
Transpl Int ; 35: 10167, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35462792

RESUMEN

Assessment of specific ß-cell death can be used to determine the quality and viability of pancreatic islets prior to transplantation and hence predict the suitability of the pancreas for isolation. Recently, several groups have demonstrated that unmethylated insulin (INS)-DNA is correlated to ß-cell death in type 1 diabetes patients and during clinical islet isolation and subsequent transplantation. Here, we present a step-by-step protocol of our novel developed method for quantification of the relative amount of unmethylated INS-DNA using methylation sensitive restriction enzyme digital polymerase chain reaction This method provides a novel and sensitive way to quantify the relative amount of ß-cell derived unmethylated INS-DNA in cellular lysate. We therefore suggest that this technique can be of value to reliably determine the purity of an islet preparation and may also serve as a measure of the quality of islets prior to transplantation measuring unmethylated INS-DNA as a reflection of the relative amount of lysed ß-cells.


Asunto(s)
Células Secretoras de Insulina , Islotes Pancreáticos , ADN/genética , ADN/metabolismo , Metilación de ADN , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/fisiología , Reacción en Cadena de la Polimerasa
20.
Patient Prefer Adherence ; 16: 809-819, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35370405

RESUMEN

Purpose: Understanding which factors are important for healthcare decisions of patients with diabetes in clinical practice is important to personalise diabetes care strategies and tailor care plans to the individual. The main drivers for these healthcare decisions remain unclear. This study assessed which key factors are relevant for healthcare decisions during clinical consultations for patients with type 1 diabetes (T1DM) and type 2 diabetes (T2DM), according to healthcare professionals. Materials and Methods: Annual diabetes reviews were performed as part of a trial assessing the impact of a consultation model facilitating person-centred diabetes care in six hospital outpatient clinics. After each consultation, we asked healthcare professionals to choose a maximum of three out of 20 factors that were most relevant for healthcare decisions about treatment goals and the professional support needed during the upcoming year. Factors were characterised as either person or disease-related. Percentages reflect the number of annual diabetes reviews in which the key factor was reported. Results: Seventeen physicians and eight diabetes specialist nurses reported the key factors relevant for healthcare decisions in 285 annual diabetes reviews (T1DM n = 119, T2DM n = 166). Healthcare professionals most often reported quality of life (31.9%), motivation (27.0%) and diabetes self-management (25.6%), and to a lesser extent glycaemic control (24.2%), to be important for decisions about treatment goals. For decisions about the professional support needed during the upcoming year patient's preferences (33.7%), diabetes self-management (33.3%), quality of life (27.0%) and motivation (25.6%) were most often considered relevant by healthcare professionals. Conclusion: According to healthcare professionals, person-related factors such as quality of life, diabetes self-management and motivation are predominantly relevant for healthcare decisions about treatment goals and the professional support needed during the upcoming year.

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