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1.
Diabetes Care ; 47(11): 1916-1921, 2024 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-39235839

RESUMO

OBJECTIVE: We explored the potential value of continuous glucose monitoring (CGM) in early pregnancy in predicting gestational diabetes mellitus (GDM) and pregnancy outcomes. RESEARCH DESIGN AND METHODS: The study recruited 103 multiethnic Asian pregnant women with overweight or obesity from a hospital-based, prospective cohort. All of them had worn blinded CGM devices in early pregnancy and underwent the universal GDM screening at 24-28 gestation weeks. Models were selected based on early pregnancy risk factors and CGM-derived parameters to compare their respective predictive values for GDM and pregnancy outcomes. RESULTS: Eighteen GDM cases were ascertained. CGM-derived novel parameters demonstrated greater performance (e.g., area under the curve: 0.953 vs. 0.722) for predicting incident GDM compared with the model using traditional risks. Such novel CGM-derived parameters significantly differentiated primary cesarean and large-for-gestational age babies. CONCLUSIONS: Our data suggest CGM's potential clinical utility in the first trimester for predicting GDM and adverse pregnancy outcomes, particularly in individuals with overweight or obesity.


Assuntos
Povo Asiático , Diabetes Gestacional , Resultado da Gravidez , Humanos , Gravidez , Feminino , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/sangue , Adulto , Glicemia/análise , Estudos Prospectivos , Automonitorização da Glicemia/métodos , Monitoramento Contínuo da Glicose
2.
Indian J Endocrinol Metab ; 28(2): 167-176, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38911114

RESUMO

Introduction: To describe the self-care challenges, diabetes technology awareness, current use, and satisfaction among adults with type 1 diabetes and parents of children with type 1 diabetes in Singapore. Methods: An anonymous online survey was administered between November 2020 and October 2021. Data are presented as mean (standard deviation) or count (percentages). Comparisons between groups were done using the independent samples T-test. Results: 251 people (176 adults, 75 parents) participated. The most challenging self-care burdens were carbohydrate counting (24.4%) among adults and insulin dose calculations (28%) among parents. Nocturnal awakenings for diabetes care of their child were a common event (25.3%). Despite high awareness about continuous glucose monitoring devices (77.8% adults, 78.7% parents) the use (24.9% adults, 55% children) remained low. Both adults and parents of children with type 1 diabetes found continuous glucose monitoring to be liberating and less restrictive. Despite overall low insulin pump use (23.9% adults, 29.3% children); satisfaction scores were higher among insulin pump users than insulin pen users (P = 0.02). Conclusion: Carbohydrate counting and insulin dose calculations were the most challenging self-care tasks among people with type 1 diabetes in Singapore. Diabetes technology use was relatively low in Singapore. Continuous glucose monitoring and Insulin pump users found them to be beneficial.

3.
Diabetes Res Clin Pract ; 211: 111678, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38642860

RESUMO

OBJECTIVE: We evaluated the impact of intermittently scanned continuous glucose monitoring(is-CGM)over self-monitoring of blood glucose(SMBG) in the context of diabetes self-management education (DSME) in sub-optimally controlled type 2 diabetes(T2D) in a multi-ethnicsetting. RESEARCH DESIGN AND METHOD: Randomized-controlled, open-label trial (NCT04564911), of T2D with HbA1c ≥ 7.5-≤10 %, on oral agents with/without basal insulin was carried out. Intervention arm received 6 weeks(w) continuous is-CGM, followed by one is-CGM/month till 24w. Control arm was advised to perform 4 SMBG/day. Educationwas delivered at weeks 0, 2, 8, 16. PRIMARY OUTCOME: Change in HbA1c from baseline at 24w. Modified intention-to-treat (mITT) analysis with linear mixed-effect model for repeated measurementswas performed. RESULTS: 176 subjects, age 55 ± 10.7 years(y), DM duration 11 ± 7.3y, BMI 27.8 ± 5.9 kg/m2, 58 % Male, 29.5 % basal insulin users were analysed. Within each arm,from baseline to 24w, mean HbA1c decreasedby -0.6 % (-6.6.mmol/mol, p-value < 0.01)and weight decreased(isCGM: -1.44 kg; SMBG: -1.25 kg, both p < 0.01). These changes were sustained to one year. However, there wasno significant difference in these parameters between arms (p-value > 0.05). CONCLUSION: In the context of DSME, use of either SMBG or is-CGM led to improved glycaemia and reduced weight over a period of 24 weeks, sustained to one year.


Assuntos
Automonitorização da Glicemia , Glicemia , Diabetes Mellitus Tipo 2 , Hemoglobinas Glicadas , Hipoglicemiantes , Humanos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/terapia , Pessoa de Meia-Idade , Automonitorização da Glicemia/métodos , Masculino , Feminino , Glicemia/análise , Hemoglobinas Glicadas/análise , Hemoglobinas Glicadas/metabolismo , Hipoglicemiantes/uso terapêutico , Idoso , Insulina/uso terapêutico , Insulina/administração & dosagem , Autogestão/métodos , Singapura , Educação de Pacientes como Assunto/métodos , Adulto , Controle Glicêmico/métodos , Monitoramento Contínuo da Glicose
4.
J Diabetes Investig ; 15(6): 786-789, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38444298

RESUMO

Fulminant type 1 diabetes (FT1D) is a unique subtype of type 1 diabetes, characterized by acute absolute insulin deficiency, severe ketosis, and increased risk of hypoglycemia, glycemic variability and microvascular complications. Seven people with FT1D were identified from two tertiary centers in Singapore. Six were Chinese, the mean age was 35 years and all were lean (mean body mass index 20.3 kg/m2). All presented with diabetes ketosis or ketoacidosis and low C-peptide. All but one had low glutamic acid decarboxylase antibodies. Nearly half had a missed/delayed diagnosis of FT1D. Three had frequent hypoglycemia, which improved after transition to continuous subcutaneous insulin infusion therapy. Individuals with FT1D experience unique diagnostic and management challenges associated with rapid absolute insulin deficiency. Greater awareness about this clinical entity is required.


Assuntos
Diabetes Mellitus Tipo 1 , Cetoacidose Diabética , Humanos , Diabetes Mellitus Tipo 1/diagnóstico , Masculino , Singapura , Adulto , Feminino , Cetoacidose Diabética/diagnóstico , Cetoacidose Diabética/etiologia , Pessoa de Meia-Idade , Insulina/administração & dosagem , Hipoglicemia/diagnóstico , Hipoglicemia/etiologia , Adulto Jovem
5.
Diabetes Technol Ther ; 26(5): 324-334, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38215206

RESUMO

Background: Despite advances in technology, glycemic outcomes in people with type 1 diabetes (T1D) remain suboptimal. The MiniMed 780G (MM780G) advanced hybrid closed-loop (AHCL) system is the latest technology for T1D management with established safety and efficacy. This study explores the cost-effectiveness of MM780G AHCL compared against multiple daily injections (MDI) plus intermittently scanned continuous glucose monitor (isCGM). Methods: A cost-utility analysis was conducted, simulating lifetime outcomes for 1000 T1D individuals, with baseline hemoglobin A1c of 8.4%, using the IQVIA Core Diabetes Model (CDM) v9.5. A Singapore health care payer perspective was taken with 2023 costs applied. Treatment effects were taken from the ADAPT study and treatment-related events from a combination of sources. T1D complication costs were derived from local literature, and health state utilities and disutilities from published literature. Scenario analyses and probabilistic sensitivity analyses (PSAs) explored uncertainty. Cost-effectiveness was assessed based on willingness-to-pay (WTP) thresholds set to Singapore Dollars (SGD) 45,000 (United States Dollars [USD] 33,087) per quality-adjusted life year (QALY) and Singapore's gross domestic product (GDP) per capita of SGD 114,165 (USD 83,941) per QALY. Results: A switch from MDI plus isCGM to MM780G resulted in expected gains in life-years (+0.78) and QALYs (+1.45). Cost savings through reduction in T1D complications (SGD 25,465; USD 18,723) partially offset the higher treatment costs in the AHCL arm (+SGD 74,538; +USD 54,805), resulting in an estimated incremental cost-effectiveness ratio of SGD 33,797 (USD 24,850) per QALY gained. Findings were robust, with PSA outputs indicating 81% and 99% probabilities of cost-effectiveness at the stated WTP thresholds. Conclusion: MM780G is a cost-effective option for people with T1D managed in a Singapore setting.


Assuntos
Automonitorização da Glicemia , Análise Custo-Benefício , Diabetes Mellitus Tipo 1 , Hipoglicemiantes , Sistemas de Infusão de Insulina , Anos de Vida Ajustados por Qualidade de Vida , Humanos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/economia , Diabetes Mellitus Tipo 1/sangue , Singapura , Hipoglicemiantes/economia , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Sistemas de Infusão de Insulina/economia , Masculino , Feminino , Automonitorização da Glicemia/economia , Insulina/administração & dosagem , Insulina/economia , Insulina/uso terapêutico , Adulto , Glicemia/análise , Hemoglobinas Glicadas/análise , Pessoa de Meia-Idade
6.
Sci Rep ; 13(1): 20887, 2023 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-38017001

RESUMO

This pilot study explores the relationship between nocturnal hypoglycemia (NH) and subjective sleep quality in people with type 1 diabetes (T1D). Twenty-seven adults with T1D wore a Freestyle Libre Pro CGM and recorded subjective sleep quality daily, as assessed by a single Likert scale question. Frequency, duration, area under the curve (AUC) of NH (00:00-06:00) defined as sensor glucose below threshold (< 3.9 mmol/L; < 3 mmol/L) for ≥ 15 min, nocturnal mean glucose, Time in Range (3.9-10 mmol/L), and coefficient of variation were calculated. Twenty-seven adults, 18 (66.7%) women, with median (IQR) age of 27 (26, 32) years and HbA1c of 7.6 (7.1, 8.1) participated. Nights with NH < 3.9 mmol/L resulted in a lower (worse) sleep score than nights without NH [Mean (SD): 3.3 (1.2) vs 3.5 (1.0), p = 0.03). A higher frequency and longer duration but not AUC [adjusted OR (95% CI) 0.52 (0.38, 0.72), 0.961 (0.932, 0.991), 0.999 (0.998, 1.001) respectively)], of NH < 3.9 mmol/L, were associated with a lower sleep score. NH < 3.0 mmol/L metrics were not associated with sleep quality. Recurrent NH < 3.9 mmol/L, rather than prolonged NH < 3.0 mmol/L, seems associated with subjective sleep quality, implying that those with the highest burden of NH are likely unaware of it.


Assuntos
Diabetes Mellitus Tipo 1 , Hipoglicemia , Adulto , Humanos , Feminino , Masculino , Diabetes Mellitus Tipo 1/complicações , Glicemia , Qualidade do Sono , Projetos Piloto , Automonitorização da Glicemia/métodos , Hipoglicemia/complicações , Glucose , Hipoglicemiantes , Insulina
7.
Trials ; 24(1): 728, 2023 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-37964330

RESUMO

BACKGROUND: Type 2 diabetes (T2D), a major risk factor for cardiovascular disease and other adverse health conditions, is on the rise in Singapore. TRIPOD is a randomized controlled trial aimed to determine whether complementing usual care with an evidence-based diabetes management package (DMP) -comprising access to an evidence-based app, health coaching, pedometer, glucometer and weighing scale, with or without a financial rewards scheme (M-POWER rewards), can improve mean HbA1c levels at months 6 and 12. METHODS: The protocol was published in Trials, accessible via https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-019-3749-x 1. This manuscript updates the protocol with changes to the study design due to challenges with recruitment and presents baseline characteristics. Key updates include changing the arm allocation ratio from 1:1:1 (Arm 1-Usual Care: Arm 2-DMP: Arm 3-DMP+M-POWER rewards) to 10:1:10, the sample size from 339 to 269, the intervention period from two to one year, and the primary hypothesis to focus solely on differences between Usual Care and DMP+M-POWER rewards. Recruitment for the study began on 19 October 2019 and ended on 4 June 2022. RESULTS: The average age of participants was 55.0 (SD9.7) years old and 64.2% were male. The majority of participants (76.8%) were Chinese, 4.9% Malay and 18.3% Indian and of other ethnicities. 67.0% had a monthly household income of SGD$4000 or more. The mean baseline HbA1c was 8.10% (SD 0.95) and the mean body mass index was 26.8 kg/m2 (SD 5.3). DISCUSSION: The final participant completed month 12 follow-up data collection on 8 June 2023. All pre-planned analyses will be conducted and final results reported. TRIAL REGISTRATION: ClinicalTrials.gov NCT03800680 . Registered on 11 January 2019.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Humanos , Masculino , Criança , Feminino , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/terapia , Projetos de Pesquisa , Tamanho da Amostra , Fatores de Risco , Ensaios Clínicos Controlados Aleatórios como Assunto
8.
Nat Commun ; 14(1): 6119, 2023 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-37777536

RESUMO

The coding variant (p.Arg192His) in the transcription factor PAX4 is associated with an altered risk for type 2 diabetes (T2D) in East Asian populations. In mice, Pax4 is essential for beta cell formation but its role on human beta cell development and/or function is unknown. Participants carrying the PAX4 p.His192 allele exhibited decreased pancreatic beta cell function compared to homozygotes for the p.192Arg allele in a cross-sectional study in which we carried out an intravenous glucose tolerance test and an oral glucose tolerance test. In a pedigree of a patient with young onset diabetes, several members carry a newly identified p.Tyr186X allele. In the human beta cell model, EndoC-ßH1, PAX4 knockdown led to impaired insulin secretion, reduced total insulin content, and altered hormone gene expression. Deletion of PAX4 in human induced pluripotent stem cell (hiPSC)-derived islet-like cells resulted in derepression of alpha cell gene expression. In vitro differentiation of hiPSCs carrying PAX4 p.His192 and p.X186 risk alleles exhibited increased polyhormonal endocrine cell formation and reduced insulin content that can be reversed with gene correction. Together, we demonstrate the role of PAX4 in human endocrine cell development, beta cell function, and its contribution to T2D-risk.


Assuntos
Diabetes Mellitus Tipo 2 , Células Secretoras de Glucagon , Células-Tronco Pluripotentes Induzidas , Células Secretoras de Insulina , Humanos , Camundongos , Animais , Proteínas de Homeodomínio/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Estudos Transversais , Fatores de Transcrição Box Pareados/genética , Fatores de Transcrição Box Pareados/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Glucagon/metabolismo
9.
Diabetes Res Clin Pract ; 203: 110878, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37591346

RESUMO

AIMS: To assess three well-established type 2 diabetes (T2D) risk prediction models based on fasting plasma glucose (FPG) in Chinese, Malays, and Indians, and to develop simplified risk models based on either FPG or HbA1c. METHODS: We used a prospective multiethnic Singapore cohort to evaluate the established models and develop simplified models. 6,217 participants without T2D at baseline were included, with an average follow-up duration of 8.3 years. The simplified risk models were validated in two independent multiethnic Singapore cohorts (N = 12,720). RESULTS: The established risk models had moderate-to-good discrimination (area under the receiver operating characteristic curves, AUCs 0.762 - 0.828) but a lack of fit (P-values < 0.05). Simplified risk models that included fewer predictors (age, BMI, systolic blood pressure, triglycerides, and HbA1c or FPG) showed good discrimination in all cohorts (AUCs ≥ 0.810), and sufficiently captured differences between the ethnic groups. While recalibration improved fit the simplified models in validation cohorts, there remained evidence of miscalibration in Chinese (p ≤ 0.012). CONCLUSIONS: Simplified risk models including HbA1c or FPG had good discrimination in predicting incidence of T2D in three major Asian ethnic groups. Risk functions with HbA1c performed as well as those with FPG.

10.
J Diabetes Sci Technol ; : 19322968231186401, 2023 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-37439017

RESUMO

BACKGROUND: Nocturnal hypoglycemia (NH) remains a major burden for people with type 1 diabetes (T1D). Daytime physical activity (PA) increases the risk of NH. This pilot study tested whether cumulative daytime PA measured using a smartphone-based step tracker was associated with NH. METHODS: Adults with T1D for ≥ 5 years (y) on multiple daily insulin or continuous insulin infusion, not using continuous glucose monitoring and HbA1c 6 to 10% wore blinded Freestyle Libre Pro sensors and recorded total daily carbohydrate (TDC) and total daily dose (TDD) of insulin. During this time, daily step count (DSC) was tracked using the smartphone-based Fitbit MobileTrack application. Mixed effects logistic regression was used to estimate the effect of DSC on NH (sensor glucose <70, <54 mg/dl for ≥15 minutes), while adjusting for TDC and TDD of insulin, and treating participants as a random effect. RESULTS: Twenty-six adults, with 65.4% females, median age 27 years (interquartile range: 26-32) mean body mass index 23.9 kg/m2, median HbA1c 7.6% (7.1-8.1) and mean Gold Score 2.1 (standard deviation 1.0) formed the study population. The median DSC for the whole group was 2867 (1820-4807). There was a significant effect of DSC on NH episodes <70 mg/dl. (odds ratio 1.11 [95% CI: 1.01-1.23, P = .04]. There was no significant effect on NH <54 mg/dl. CONCLUSION: Daily PA measured by a smartphone-based step tracker was associated with the risk of NH in people with type 1 diabetes.

11.
J Diabetes Sci Technol ; 17(4): 909-915, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36825611

RESUMO

BACKGROUND: Delayed initiation and inadequate titration remain critical challenges to optimizing insulin therapy in type 2 diabetes (T2D). We aimed to study whether hemoglobin A1c (HbA1c) can be lowered in people with insulin-treated T2D using telemonitoring. METHODS: This single-center study recruited adults with greater than or equal to six months of diabetes, greater than or equal to three months of insulin therapy, HbA1c ≥8.5% and ≤12.5%, and body mass index (BMI) ≤40 kg/m2. All participants received a connected glucose meter and the accompanying smartphone application. Participants sent weekly blood glucose (BG) diary to their primary endocrinologist via email. Adjustments in insulin doses were communicated to the participants. HbA1c, proportion of BG readings in range (70-180 mg/dL, PIR), below range (<70 mg/dL, PBR) and above range (>180 mg/dL, PAR), and glycemic variability as the coefficient of variation (% CV) were measured at baseline, week 12, and week 24 and compared using repeated-measures analysis of variance (ANOVA) or Friedman's ANOVA. RESULTS: We recruited 40 people (55% women). Mean age was 57.9 years, BMI 27.8 kg/m2, and baseline HbA1c 9.8% (83.7 mmol/mol). Mean HbA1c improved by 1.7%, % CV reduced from 32.9% to 30.7%, PIR increased from 58.8% to 67.1% (all P <.01) by week 24, without any change in PBR. This was achieved with a 0.04 U/kg/d median increase in total daily dose of insulin and 0.9 kg weight gain over 24 weeks. CONCLUSION: Telemonitoring and titration of insulin using a connected glucose meter resulted in significant improvements in glycemia, characterized by a reduction in HbA1c, increase in PIR, and reduction in glycemic variability without any increase in hypoglycemia.


Assuntos
Diabetes Mellitus Tipo 2 , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Masculino , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina/uso terapêutico , Hipoglicemiantes/uso terapêutico , Hemoglobinas Glicadas , Glucose , Glicemia , Insulina Regular Humana/uso terapêutico
13.
Nutrients ; 14(2)2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-35057547

RESUMO

We examined how dietary and physical activity behaviors influence fluctuations in blood glucose levels over a seven-day period in people at high risk for diabetes. Twenty-eight participants underwent a mixed meal tolerance test to assess glucose homeostasis at baseline. Subsequently, they wore an accelerometer to assess movement behaviors, recorded their dietary intakes through a mobile phone application, and wore a flash glucose monitoring device that measured glucose levels every 15 min for seven days. Generalized estimating equation models were used to assess the associations of metabolic and lifestyle risk factors with glycemic variability. Higher BMI, amount of body fat, and selected markers of hyperglycemia and insulin resistance from the meal tolerance test were associated with higher mean glucose levels during the seven days. Moderate- to vigorous-intensity physical activity and polyunsaturated fat intake were independently associated with less variation in glucose levels (CV%). Higher protein and polyunsaturated fatty acid intakes were associated with more time-in-range. In contrast, higher carbohydrate intake was associated with less time-in-range. Our findings suggest that dietary composition (a higher intake of polyunsaturated fat and protein and lower intake of carbohydrates) and moderate-to-vigorous physical activity may reduce fluctuations in glucose levels in persons at high risk of diabetes.


Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 2/epidemiologia , Dieta/métodos , Exercício Físico , Acelerometria/métodos , Adulto , Automonitorização da Glicemia/métodos , Diabetes Mellitus Tipo 2/sangue , Carboidratos da Dieta/administração & dosagem , Proteínas Alimentares/administração & dosagem , Ingestão de Energia , Ácidos Graxos Insaturados/administração & dosagem , Comportamento Alimentar , Feminino , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Comportamento Sedentário , Adulto Jovem
14.
AACE Clin Case Rep ; 7(6): 346-349, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34765729

RESUMO

OBJECTIVE: Insulin allergy, although uncommon, poses a significant challenge in those with type 1 diabetes mellitus (T1D) as insulin replacement is a necessity. Our objective is to describe a patient in whom rapid desensitization to insulin aspart was achieved using an insulin pump. METHODS: A 40-year-old woman with newly diagnosed T1D developed pruritic wheals over the abdomen after being injected with insulin glargine U-300 (Toujeo) and insulin aspart. Type 1 insulin hypersensitivity was confirmed through intradermal testing and positive insulin-specific immunoglobulin E levels. RESULT: The patient underwent rapid desensitization with an insulin pump. Half the anticipated daily basal requirement was initially subcutaneously administered before initiating low-dose insulin via the pump (0.000025 units/h) and increasing the dose every 30 minutes to reach her basal requirements within 5 hours. Subsequent larger bolus insulin doses did not produce any local or anaphylactic reactions. No pretreatment with corticosteroids or antihistamines was provided. CONCLUSION: Previous protocols for insulin desensitization span over days and often involve routine premedication. The case we presented suggests that insulin desensitization can be achieved over several hours using an insulin pump. A subcutaneous basal insulin cover should be provided prior to desensitization to avoid hyperglycemia necessitating an insulin bolus. Routine premedication may not always be necessary depending on reaction severity.

16.
Diabetologia ; 64(11): 2534-2549, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34448879

RESUMO

AIMS/HYPOTHESIS: We studied the effects of heterozygous human INS gene mutations on insulin secretion, endoplasmic reticulum (ER) stress and other mechanisms in both MIN6 and human induced pluripotent stem cells (hiPSC)-derived beta-like cells, as well as the effects of prolonged overexpression of mutant human INS in MIN6 cells. METHODS: We modelled the structure of mutant C109Y and G32V proinsulin computationally to examine the in silico effects. We then overexpressed either wild-type (WT), mutant (C109Y or G32V), or both WT and mutant human preproinsulin in MIN6 cells, both transiently and stably over several weeks. We measured the levels of human and rodent insulin secreted, and examined the transcript and protein levels of several ER stress and apoptotic markers. We also reprogrammed human donor fibroblasts heterozygous for the C109Y mutation into hiPSCs and differentiated these into pancreatic beta-like cells, which were subjected to single-cell RNA-sequencing and transcript and protein analyses for ER stress and apoptotic markers. RESULTS: The computational modelling studies, and short-term and long-term expression studies in beta cells, revealed the presence of ER stress, organelle changes and insulin processing defects, resulting in a decreased amount of insulin secreted but not the ability to secrete insulin. By 9 weeks of expression of mutant human INS, dominant-negative effects of mutant INS were evident and beta cell insulin secretory capacity declined. INS+/C109Y patient-derived beta-like cells and single-cell RNA-sequencing analyses then revealed compensatory upregulation in genes involved in insulin secretion, processing and inflammatory response. CONCLUSIONS/INTERPRETATION: The results provide deeper insights into the mechanisms of beta cell failure during INS mutation-mediated diabetes disease progression. Decreasing spliced X-box binding protein 1 (sXBP1) or inflammatory response could be avenues to restore the function of the remaining WT INS allele.


Assuntos
Estresse do Retículo Endoplasmático/fisiologia , Células Secretoras de Insulina/metabolismo , Insulina/genética , Mutação , Pancreatopatias/metabolismo , Transporte Biológico , Células Cultivadas , Diabetes Mellitus/metabolismo , Técnica Indireta de Fluorescência para Anticorpo , Regulação da Expressão Gênica/fisiologia , Vetores Genéticos , Glucose/farmacologia , Humanos , Lactente , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/ultraestrutura , Cariotipagem , Microscopia Eletrônica de Transmissão , Pancreatopatias/patologia , Células-Tronco Pluripotentes/efeitos dos fármacos , Células-Tronco Pluripotentes/metabolismo , Proinsulina/genética , Reação em Cadeia da Polimerase em Tempo Real , Transfecção
17.
Artigo em Inglês | MEDLINE | ID: mdl-34013888

RESUMO

SUMMARY: Gestational hypertriglyceridemia-induced pancreatitis is associated with significant maternal and fetal morbidity and mortality. We report a case of gestational hypertriglyceridemia-induced pancreatitis in a primigravida at 31-weeks gestation, complicated by impending preterm labor and metabolic acidosis requiring hemodialysis. This was successfully managed with therapeutic plasma exchange (TPE), followed by i.v. insulin, low-fat diet, and omega-3. Triglyceride levels stabilized after TPE and the patient underwent an uncomplicated term delivery. In pregnancy, elevated estrogen and insulin resistance exacerbate hypertriglyceridemia. Management is challenging as risks and benefits of treatment options need to be weighed against fetal wellbeing. We discuss management options including a review of previous case reports detailing TPE use, dietary optimization, and delivery timing. This case emphasizes the importance of multidisciplinary care to optimize maternal and fetal outcomes. LEARNING POINTS: Gestational hypertriglyceridemia-induced pancreatitis has high morbidity. A multidisciplinary team approach is a key as maternal and fetal needs must be addressed. Rapid lowering of triglycerides is crucial and can be achieved successfully and safely with plasma exchange. A low-fat diet while ensuring adequate nutrition in pregnancy is important. Timing of delivery requires consideration of fetal maturity and risk of recurrent pancreatitis.

19.
Artigo em Inglês | MEDLINE | ID: mdl-33431706

RESUMO

SUMMARY: Thyroid storm is a rare but potentially life-threatening complication of excessive thyroid hormone action. It is associated with a hypercoagulable state and reported to increase the risk of thromboembolism. However, the role of anticoagulation in thyroid storm still remains controversial and inconclusive. A 22-year-old male with no significant past medical history presented with acute severe generalised abdominal pain. He was found to be profoundly thyrotoxic on arrival at our institution and subsequently diagnosed with thyroid storm secondary to newly diagnosed Graves' disease. Extensive thromboses of the splanchnic, iliac, femoral veins and pulmonary arteries were subsequently demonstrated on CT scan. He had prolonged bowel ileus as a sequela of mesenteric ischaemia requiring total parenteral nutrition and non-oral forms of anti-thyroid drugs for management of hyperthyroidism. He was in sinus rhythm throughout his inpatient stay, and there was no personal history of prothrombotic conditions. His thrombophilia screen was normal. He eventually required jejunectomy due to jejunal ischaemia from extensive involvement of portal and mesenteric veins. He underwent radioiodine ablation for definitive treatment. He is currently hypothyroid and receiving thyroxine replacement. Thyroid storms are hypercoagulable states and can be associated with extensive thromboembolism even in the absence of atrial fibrillation. To our knowledge, this is the first report of severe extensive thromboembolism complicated by severe mesenteric ischaemia and bowel ileus in the setting of a thyroid storm. Routine prophylactic anticoagulation should be considered in those presenting with thyroid storms. LEARNING POINTS: Prolonged use of rectal propylthiouracil (PTU) for managing hyperthyroidism was effective in a patient who cannot take oral anti-thyroid drugs. Hyperthyroidism is a hypercoagulable state due to an imbalance between coagulation and fibrinolytic factors. Thyroid storm can be associated with extensive thromboembolism even in the absence of atrial fibrillation; routine prophylactic anticoagulation should be considered in the setting of thyroid storms.

20.
Diabetes Metab J ; 45(1): 67-76, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32602276

RESUMO

BACKGROUND: There is little longitudinal information on psychological burden and metabolic outcomes in young adults with diabetes (YAD) in Asia. We aimed to evaluate the association between psychological status and glycemia at baseline and 2 years following transition in a cohort of YAD in Singapore. METHODS: Subjects with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), aged 17 to 25 years, were recruited from the YAD clinic in Singapore General Hospital. The Hospital Anxiety and Depression and Problem Areas for Diabetes scales were administered at transition (baseline) and at 18 to 24 months. Glycosylated hemoglobin (HbA1c) assessed during routine visits was tracked longitudinally. RESULTS: A total of 98 T1DM (74.8%) and 33 T2DM (25.2%) subjects were recruited between January 2011 and November 2017. At baseline, mean HbA1c was 8.6%±1.7%. Only 26.0% achieved HbA1c of ≤7.5% and 16.8% achieved HbA1c of <7%. At baseline, prevalence of anxiety was 29.8%. At 24 months, 14.1% had persistent anxiety. Those with persistent anxiety had the highest mean HbA1c, particularly at 6 months (persistently anxious vs. persistently non-anxious: 9.9%±1.2% vs. 8.2%±1.9%, P=0.009). At baseline, 9.2% of subjects had depression. This group also had poorer glycemia at baseline (HbA1c of depressed vs non-depressed: 9.6%±2.1% vs. 8.5%±1.6%, P=0.04), which persisted up to 24 months. CONCLUSION: The majority of YAD in Singapore have suboptimal glycemia. Psychological distress is a critical harbinger of poorer metabolic outcomes.


Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Transição para Assistência do Adulto , Ansiedade/epidemiologia , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 2/epidemiologia , Hemoglobinas Glicadas/análise , Humanos , Adulto Jovem
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