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1.
Clin Cancer Res ; 29(8): 1381-1383, 2023 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-36757332

RESUMO

Precision oncology is predicated on optimal molecular profiling that is "fit for purpose" to identify therapeutic vulnerabilities. Liquid biopsies may compensate for inadequate genotyping, but remain less sensitive and specific compared with tissue biopsies. The liquid biopsy toolbox is poised to expand through novel assays and insights from longitudinal profiling. See related article by Sugimoto et al., p. 1506.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Estudos Prospectivos , Genótipo , Biomarcadores Tumorais/genética , Medicina de Precisão , Biópsia Líquida
3.
J Diabetes Complications ; 36(9): 108258, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35905511

RESUMO

AIMS: To examine the longitudinal association between skeletal muscle mass (SMM) loss and cognitive decline over time in type 2 diabetes mellitus (T2DM). METHODS: We conducted a prospective cohort study of 453 patients from SMART2D cohort with follow-up intervals of 1.6 to 6.4 years. Baseline and follow-up measurements included bio-impedance analysis (BIA) measure of skeletal muscle mass index (SMI) and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) measure of cognitive function. We examined the association between annual rate of SMI and RBANS scores using linear regression, adjusting for demographics, education, depression, clinical co-variables and presence of apolipoprotein E4 (APOE) Ɛ4 allele. RESULTS: The mean age of participants was 60.3 ± 7.4 years. Compared to patients with Tertile 1 SMI change, the group with greater SMI decline (Tertile 3 SMI change) experienced 0.30 decline in RBANS total score (95%CI -0.57 to -0.03; p = 0.030) in the adjusted analysis. RBANS scores for subdomains in immediate memory and visuo-spatial/construction were lower in Tertile 3 SMI change group with corresponding coefficients -0.54 (95%CI -1.01 to -0.06; p = 0.026), and -0.71 (95%CI -1.30 to -0.12; p = 0.019) respectively. CONCLUSION: In patients with T2DM, BIA measure of muscle mass loss over time was independently associated with cognitive decline globally and in the domains of memory and visuo-spatial/construction.


Assuntos
Disfunção Cognitiva , Diabetes Mellitus Tipo 2 , Sarcopenia , Idoso , Apolipoproteína E4 , Disfunção Cognitiva/complicações , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Humanos , Pessoa de Meia-Idade , Músculo Esquelético , Estudos Prospectivos , Sarcopenia/complicações
4.
J Diabetes Complications ; 36(7): 108209, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35660335

RESUMO

AIMS: Type 2 diabetes mellitus (T2DM) has been shown to be associated with cognitive decline and dementia. As earlier onset of diabetes implies a longer disease duration and an increased risk to complications, we sought to investigate the effect of T2DM onset on cognitive function of our patients. METHODS: We administered the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to T2DM patients aged 45-85 from our SMART2D cohort. We assessed the association of the T2DM onset age (both continuous and stratified into 3 groups: early-onset ≤40 (n = 326), middle-aged onset 41-64 (n = 703) and late-onset ≥65 years old (n = 38)) and RBANS cognitive indices in 1067 patients. Potential mediation of this association by vascular compliance using mediation analysis was investigated. RESULTS: T2DM onset associates significantly with RBANS total score. Patients with early T2DM onset have lower RBANS total score as compared to patients with middle-aged onset (ß = -2.01, p = 0.0102) and those with late-onset (ß = -5.80, p = 0.005). This association was partially mediated by pulse pressure index (25.8%), with indirect effect of 0.028 (Bootstrapped-CI: 0.008-0.047). CONCLUSIONS: Association of early-onset T2DM with cognitive impairment is partly mediated by diminished vascular compliance. Appropriate screening and assessment of cognitive function is important for early intervention and management of cognitive impairment.


Assuntos
Disfunção Cognitiva , Diabetes Mellitus Tipo 2 , Idoso , Pressão Sanguínea , Cognição , Disfunção Cognitiva/complicações , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/psicologia , Humanos , Pessoa de Meia-Idade , Testes Neuropsicológicos
5.
J Alzheimers Dis ; 88(1): 241-249, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35570489

RESUMO

BACKGROUND: Type 2 diabetes mellitus (T2DM) has been shown to increase the risks of cognitive decline and dementia. Paired box gene 4 (PAX4), a transcription factor for beta cell development and function, has recently been implicated in pathways intersecting Alzheimer's disease and T2DM. OBJECTIVE: In this report, we evaluated the association of the ethnic-specific PAX4 R192H variant, a T2DM risk factor for East Asians which contributes to earlier diabetes onset, and cognitive function of Chinese T2DM patients. METHODS: 590 Chinese patients aged 45-86 from the SMART2D study were genotyped for PAX4 R192H variation using Illumina OmniExpress-24 Array. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) which had been validated in the Singapore population was administered to assess five cognitive domains: immediate memory, visuospatial/constructional, language, attention, and delayed memory. Multiple linear regression was used to assess the association of the R192H risk allele and cognitive domains. RESULTS: Patients with two PAX4 R192H risk alleles showed significantly lower attention index score (ß= -8.46, 95% CI [-13.71, -3.21], p = 0.002) than patients with wild-type alleles after adjusting for age, gender, diabetes onset age, HbA1c, body-mass index, renal function, lipid profiles, systolic blood pressure, metformin usage, smoking history, education level, Geriatric Depression Scale score, and presence of APOEɛ4 allele. CONCLUSION: Ethnic-specific R192H variation in PAX4 is associated with attention-specific cognitive impairment in Chinese with T2DM. Pending further validation studies, determining PAX4 R192H genotype may be helpful for early risk assessment of early-onset T2DM and cognitive impairment to improve diabetes care.


Assuntos
Disfunção Cognitiva , Diabetes Mellitus Tipo 2 , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/genética , Atenção , China , Diabetes Mellitus Tipo 2/complicações , Proteínas de Homeodomínio/genética , Humanos , Idioma , Pessoa de Meia-Idade , Fatores de Transcrição Box Pareados/genética , Fatores de Transcrição Box Pareados/metabolismo , Fatores de Risco
6.
J Alzheimers Dis ; 87(2): 635-642, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35342091

RESUMO

BACKGROUND: The association between sodium-glucose cotransporter-2 inhibitors (SGLT2i) use and cognitive function in type 2 diabetes remains unclear. OBJECTIVE: Explore the association between SGLT2i and longitudinal changes in cognitive function in adults with type 2 diabetes (T2DM) and assessed the cognitive domains which were impacted by SGLT2i. METHODS: We conducted a prospective cohort study of 476 patients aged 60.6±7.4 years with follow-up period up to 6.4 years. Data on SGLT2i use was derived from questionnaire and verified with clinical database. We used Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to assess cognition. The association between SGLT2i use and rate of RBANS score change was examined using multiple linear regression. RESULTS: There were 138 patients (29.0%) on SGLT2i, including 84 (17.7%) for < 3 years and 54 (11.3%) for ≥3 years. SGLT2i use was positively associated with RBANS total score increase in language (coefficient 0.60; 95% CI 0.10-1.11; p = 0.019) in unadjusted analysis. This positive association persisted in fully adjusted model (coefficient 0.74; 95% CI 0.12 to 1.36; p = 0.019). SGLT2i use for ≥3 years was positively associated with RBANS score increase globally and in language domain in fully adjusted analysis with coefficients 0.54 (95% CI 0.13 to 0.95; p = 0.010) and 1.12 (95% CI 0.27 to 1.97; p = 0.010) respectively. CONCLUSION: Our findings revealed a previously unobserved association between ≥3 years SGLT2i use and improved cognitive scores globally and in language domain and executive function. Future studies should investigate the role of SGLT2i in ameliorating cognitive decline.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores do Transportador 2 de Sódio-Glicose , Cognição , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose , Humanos , Estudos Longitudinais , Estudos Prospectivos , Sódio , Transportador 2 de Glucose-Sódio , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
7.
Front Endocrinol (Lausanne) ; 13: 844040, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35350098

RESUMO

The management of diabetes mellitus in an insulin-dependent patient is challenging in the setting of concomitant antibody-mediated-insulin hypersensitivity. We report a case of a 62-year-old woman with pre-existing type 2 diabetes mellitus of 10 years duration who developed type 3 hypersensitivity reaction to insulin analogue detemir, and subsequently, severe diabetic ketoacidosis (DKA). She was C-peptide negative and was diagnosed with insulin-dependent diabetes. Despite increasing dose adjustments, insulin-meal matching, and compliance with insulin, she experienced episodes of unexpected hyperglycaemia and hypoglycaemia. The development of rash after detemir initiation and rapid progression to DKA suggests an aberrant immune response leading to the insulin allergy and antibody-induced interference with insulin analogues. Glycaemic control in the patient initially improved after being started on subcutaneous insulin infusion pump with reduced insulin requirements. However, after a year on pump therapy, localised insulin hypersensitivity reactions started, and glycaemic control gradually deteriorated.


Assuntos
Diabetes Mellitus Tipo 2 , Cetoacidose Diabética , Hipersensibilidade , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cetoacidose Diabética/induzido quimicamente , Cetoacidose Diabética/tratamento farmacológico , Feminino , Humanos , Hipersensibilidade/tratamento farmacológico , Insulina/efeitos adversos , Sistemas de Infusão de Insulina , Pessoa de Meia-Idade
8.
Diabetes Res Clin Pract ; 186: 109803, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35218850

RESUMO

AIMS: Little is known about pathophysiology of sarcopenia in diabetes. We aimed to study amino acid profile associated with skeletal muscle mass loss longitudinally in Type 2 Diabetes Mellitus (T2DM). METHODS: This is a prospective study of 1140 patients aged 56.6 ± 10.6 years from the SMART2D cohort. Skeletal muscle mass was measured using bio-impedance analysis at baseline and follow-up. Amino acids were measured by mass spectrometry. RESULTS: Over a period of up to 7.9 years, 43.9% experienced skeletal muscle mass loss. Lower baseline valine, leucine and isoleucine levels were associated with decreased skeletal muscle mass index (SMI) with corresponding coefficient 0.251(95 %CI 0.009 to 0.493), 0.298(95 %CI 0.051 to 0.544)) and 0.366(95 %CI 0.131 to 0.600). Higher baseline valine, leucine, isoleucine, alanine and tryptophan levels were associated with reduced odds of muscle mass loss with corresponding odds ratio (OR)0.797 (95 %CI 0.690 to 0.921), 0.825 (95 %CI 0.713 to 0.955), 0.826 (95 %CI 0.718-0.950), 0.847 (95 %CI 0.739-0.969) and 0.835 (95 %CI 0.720-0.979). CONCLUSION: The branched-chain amino acids valine, leucine and isoleucine were positively associated with change in SMI and reduced odds of muscle mass loss longitudinally. Further studies should be conducted to elucidate the pathophysiological mechanisms underlying the relationship between these amino acids and muscle mass loss in T2DM.


Assuntos
Diabetes Mellitus Tipo 2 , Aminoácidos , Aminoácidos de Cadeia Ramificada/metabolismo , Povo Asiático , Diabetes Mellitus Tipo 2/complicações , Humanos , Isoleucina , Leucina , Estudos Longitudinais , Músculo Esquelético , Estudos Prospectivos , Valina
9.
J Investig Med High Impact Case Rep ; 10: 23247096211065626, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35038894

RESUMO

From our monogenic diabetes registry set-up at a secondary-care diabetes center, we identified a nontrivial subpopulation (~15%) of maturity-onset diabetes of the young (MODY) among people with young-onset diabetes. In this report, we describe the diagnostic caveats, clinical features and long-term renal-trajectory of people with HNF1B mutations (HNF1B-MODY). Between 2013 and 2020, we received 267 referrals to evaluate MODY from endocrinologists in both public and private practice. Every participant was subjected to a previously reported structured evaluation process, high-throughput nucleotide sequencing and gene-dosage analysis. Out of 40 individuals with confirmed MODY, 4 (10%) had HNF1B-MODY (harboring either a HNF1B whole-gene deletion or duplication). Postsequencing follow-up biochemical and radiological evaluations revealed the known HNF1B-MODY associated systemic-features, such as transaminitis and structural renal-lesions. These anomalies could have been missed without prior knowledge of the nucleotide-sequencing results. Interestingly, preliminary longitudinal observation (up to 15 years) suggested possibly 2 distinct patterns of renal-deterioration (albuminuric vs. nonalbuminuric chronic kidney disease). Monogenic diabetes like HNF1B-MODY may be missed among young-onset diabetes in a resource-limited routine-care clinic. Collaboration with a MODY-evaluation center may fill the care-gap. The long-term renal-trajectories of HNF1B-MODY will require further studies by dedicated registries and international consortium.


Assuntos
Diabetes Mellitus Tipo 2 , Doenças Renais Císticas , Diabetes Mellitus Tipo 2/genética , Fator 1-beta Nuclear de Hepatócito/genética , Humanos , Encaminhamento e Consulta , Singapura
10.
Artigo em Inglês | MEDLINE | ID: mdl-34184638

RESUMO

SUMMARY: Activating mutation of glucokinase gene (GCK) causes resetting of insulin inhibition at a lower glucose threshold causing hyperinsulinaemic hypoglycaemia (GCK-HH). This is the first reported case who tolerated years of regular fasting during Ramadhan, presenting only with seizure and syncope now. We describe a case with GCK gene variant p.T65I diagnosed in a 51-year-old woman with hypoglycaemia unawareness even at glucose level of 1.6 mmol/L. Insulin and C-peptide levels during hypoglycaemia were suggestive of hyperinsulinism, but at a day after intravenous glucagon, hypoglycaemia occurred with low insulin and C-peptide levels, pointing against insulinoma as the underlying aetiology. Imaging studies of the pancreas and calcium arterial stimulation venous sampling were unremarkable. A review of old medical records revealed asymptomatic hypoglycaemia years ago. Genetic testing confirmed activating mutation of GCK. Hypoglycaemia was successfully controlled with a somatostatin analogue. This case highlights the importance of consideration of genetic causes of hypoglycaemia in adulthood, especially when imaging is uninformative. LEARNING POINTS: Consider genetic causes of endogenous hyperinsulinism hypoglycaemia in adulthood, especially when imaging is uninformative. Late presentation of activating mutation of GCK can occur because of hypoglycaemia unawareness. Long-acting somatostatin analogue may be useful for the treatment of activating mutation of GCK causing hypoglycaemia. Depending on the glucose level when the blood was taken, and the threshold of glucose-stimulated insulin release (GSIR), the serum insulin and C-peptide levels may be raised (hyperinsulinaemic) or low (hypoinsulinaemic) in patients with activating mutation of GCK. Glucagon may be useful to hasten the process of unmasking the low insulin level during hypoglycaemia below the GSIR level of which insulin released is suppressed.

11.
Nat Commun ; 12(1): 3133, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34035238

RESUMO

Heterozygous HNF1A gene mutations can cause maturity onset diabetes of the young 3 (MODY3), characterized by insulin secretion defects. However, specific mechanisms of MODY3 in humans remain unclear due to lack of access to diseased human pancreatic cells. Here, we utilize MODY3 patient-derived human induced pluripotent stem cells (hiPSCs) to study the effect(s) of a causal HNF1A+/H126D mutation on pancreatic function. Molecular dynamics simulations predict that the H126D mutation could compromise DNA binding and gene target transcription. Genome-wide RNA-Seq and ChIP-Seq analyses on MODY3 hiPSC-derived endocrine progenitors reveal numerous HNF1A gene targets affected by the mutation. We find decreased glucose transporter GLUT2 expression, which is associated with reduced glucose uptake and ATP production in the MODY3 hiPSC-derived ß-like cells. Overall, our findings reveal the importance of HNF1A in regulating GLUT2 and several genes involved in insulin secretion that can account for the insulin secretory defect clinically observed in MODY3 patients.


Assuntos
Diabetes Mellitus Tipo 2/genética , Transportador de Glucose Tipo 2/genética , Glucose/metabolismo , Fator 1-alfa Nuclear de Hepatócito/genética , Secreção de Insulina/genética , Células Secretoras de Insulina/metabolismo , Mutação , Células Cultivadas , Sequenciamento de Cromatina por Imunoprecipitação/métodos , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Transportador de Glucose Tipo 2/metabolismo , Fator 1-alfa Nuclear de Hepatócito/química , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Células Secretoras de Insulina/citologia , Masculino , Simulação de Dinâmica Molecular , Linhagem , Domínios Proteicos
12.
Diabetes Res Clin Pract ; 174: 108777, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33745995

RESUMO

AIMS: We examined the longitudinal relationship between baseline skeletal muscle mass and its change over time with eGFR decline and albuminuria progression among Asians with type 2 diabetes(T2D). METHODS: This was a prospective cohort study of 1272 T2D patients. Skeletal muscle mass was estimated using tetra-polar multi-frequency bio-impedance analysis and Skeletal Muscle Mass Index(SMI) was defined as skeletal muscle mass/weight * 100. RESULTS: After up to 8 years of follow-up, 33.3% of participants had CKD progression and 28.3% albuminuria progression. Every 1-SD above baseline SMI was associated with 18% lower risk of CKD progression[Hazards Ratio(HR)0.82; 95%CI 0.70-0.97; p = 0.018] and 17% lower risk of albuminuria progression [HR 0.83 (95%CI 0.71-0.97; p = 0.017)]. The largest decrease in SMI over time was associated with 67% higher risk of CKD progression, compared to those with the smallest change from baseline SMI tertile 2[HR 1.67 (95%CI 1.10-2.55); p = 0.016]. Pigment epithelium-derived factor(PEDF) and plasma leucine-rich α-2-glycoprotein (LRG1) accounted for 40.1% of the association between SMI and CKD progression. CONCLUSIONS: Low baseline skeletal muscle mass and its reduction over time is associated with increased risk of progression of CKD among Asians with T2D. PEDF and LRG1 mediated the inverse relationship between SMI and CKD progression.


Assuntos
Albuminúria/patologia , Povo Asiático/estatística & dados numéricos , Diabetes Mellitus Tipo 2/complicações , Músculo Esquelético/patologia , Insuficiência Renal Crônica/patologia , Sarcopenia/patologia , Adulto , Albuminúria/etiologia , Albuminúria/metabolismo , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismo , Sarcopenia/etiologia , Sarcopenia/metabolismo
13.
J Nephrol ; 34(5): 1429-1444, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33492590

RESUMO

BACKGROUND AND AIMS: Arterial stiffness is a risk factor for chronic kidney disease progression (CKD). Pulse pressure is a surrogate marker of arterial stiffness. It is unclear if pulse pressure predicts CKD progression in type 2 diabetes mellitus. METHODS: This was prospective study involving 1494 patients with estimated glomerular filtration rate (eGFR) ≥ 15 ml/min/1.73 m2. Carotid-femoral pulse wave velocity was measured using applanation tonometry. Pulse pressure was calculated as difference between systolic and diastolic blood pressures. CKD progression was defined as worsening of eGFR categories (stage 1, ≥ 90 ml/min/1.73 m2; stage 2, 60-89 ml/min/1.73 m2; stage 3a, 45-59 ml/min/1.73 m2; stage 3b, 30-44 ml/min/1.73 m2; stage 4; 15-29 ml/min/1.73 m2; and stage 5, < 15 ml/min/1.73 m2) with ≥ 25% decrease in eGFR from baseline. RESULTS: After follow-up of up to 6 years, CKD progression occurred in 33.5% of subjects. Subjects in 2nd, 3rd and 4th quartiles of peripheral pulse pressure experienced higher risk of CKD progression with unadjusted hazard ratios (HRs) 1.55 [95% confidence interval (CI) 1.13-2.11; p = 0.006], 2.58 (1.93-3.45; p < 0.001) and 3.41 (2.58-4.52; p < 0.001). In the fully adjusted model, the association for 2nd, 3rd and 4th quartiles remained with HRs 1.40 (1.02-1.93; p = 0.038), 1.87 (1.37-2.56; p < 0.001) and 1.75 (1.25-2.44; p = 0.001) respectively. Similarly, 2nd, 3rd and 4th quartiles of aortic pulse pressure were associated with higher hazards of CKD progression with HRs 1.73 (1.25-2.40; p = 0.001), 1.65 (1.18-2.29; p = 0.003) and 1.81 (1.26-2.60; p = 0.001). Increasing urinary albumin-to-creatinine ratio accounted for 44.0% of the association between peripheral pulse pressure and CKD progression. CONCLUSIONS: Individuals with high pulse pressure were more susceptible to deterioration of renal function. Pulse pressure could potentially be incorporated in clinical practice as an inexpensive and readily available biomarker of renal decline in type 2 diabetes mellitus. Graphic abstract.


Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Renal Crônica , Rigidez Vascular , Pressão Sanguínea , Diabetes Mellitus Tipo 2/diagnóstico , Progressão da Doença , Taxa de Filtração Glomerular , Humanos , Estudos Prospectivos , Análise de Onda de Pulso , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia
14.
J Psychiatry Neurosci ; 46(1): E176-E183, 2021 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-33464781

RESUMO

Background: Studies investigating the association between depression and aortic stiffness in older patients with type 2 diabetes are lacking. We postulated an association between depressive symptoms and aortic stiffness, and this relationship may be mediated by increased adiposity. Methods: We analyzed participants with type 2 diabetes aged 55 years or older (n = 958). We measured aortic stiffness using carotid-femoral pulse wave velocity (cut-off ≥ 12 m/s) using the tonometry method. We defined depressive symptoms as a score of greater than 5 on the Geriatric Depression Scale-15 (GDS-15). Adiposity indices we assessed were body mass index, waist circumference, waistto-height ratio, visceral fat area and fat mass. Results: Among the participants, 27.2% had aortic stiffness, of whom 6.5% had depressive symptoms. Score on the GDS-15 was correlated with pulse wave velocity, and both variables were correlated with the adiposity markers we analyzed (all p < 0.05). Depressive symptoms were associated with pulse wave velocity (B = 1.79, 95% confidence interval [CI] 0.83-2.75) or aortic stiffness (risk ratio 1.60, 95% CI 1.10-2.33) in the unadjusted model. The association persisted after controlling for demographics, duration of diabetes, glycated hemoglobin, comorbidities and medications. Further adjustment for visceral fat area and fat mass in separate models reduced the association between depressive symptoms and pulse wave velocity or aortic stiffness. Mediation models revealed that the mediation proportions of fat mass and visceral fat area on the association between depressive symptoms and pulse wave velocity were 11.8% and 9.7%, respectively. A preliminary analysis of longitudinal data (n = 184) showed similar findings. Limitations: Causality cannot be inferred from the associations we observed. Conclusion: Depressive symptoms are associated with elevated pulse wave velocity in older people with type 2 diabetes, and this relationship may be partially mediated by increased adiposity.


Assuntos
Adiposidade/fisiologia , Envelhecimento/fisiologia , Doenças Cardiovasculares/fisiopatologia , Depressão/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Rigidez Vascular/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Onda de Pulso , Adulto Jovem
15.
J Diabetes ; 13(3): 222-231, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32786001

RESUMO

BACKGROUND: Fluid imbalance is associated with various clinical conditions, but the association between elevated extracellular-water to total-body-water (ECW/TBW) ratio, an indicator of fluid balance, and cognitive impairment is unknown. We aimed to investigate relationship between ECW/TBW ratio and cognitive function in type 2 diabetes mellitus. METHODS: This study was a cross-sectional design, comparing 1233 patients aged 61.4 ± 8.0 years from the Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes (SMART2D) cohort. ECW/TBW was measured using bioelectrical impedance method. Cognitive function was assessed with Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Multiple linear regression was used to examine association between ECW/TBW and RBANS scores, adjusting for demographics, education, clinical covariates, and apolipoprotein E allele. RESULTS: In unadjusted analyses, there was an inverse dose-dependent association between ECW/TBW and RBANS total score. The associations persisted in fully adjusted model with ß = -1.18 (95% confidence interval [CI] -2.19 to -0.17; P = 0.022) for slight edema and -2.33 (-3.99 to -0.67; P = 0.006) for edema. Slight edema and edema were significantly associated with reduced cognitive function in delayed memory and attention. There was significant association between edema but not slight edema, with reduced cognitive function in language. Pulse pressure accounted for 16.8% of association between ECW/TBW and RBANS total score. CONCLUSIONS: Our novel finding of an independent association between higher ECW/TBW and poorer cognitive function highlights the potential importance of maintaining body fluid balance in the management of cognitive impairment.


Assuntos
Água Corporal/metabolismo , Cognição/fisiologia , Diabetes Mellitus Tipo 2/metabolismo , Espaço Extracelular/metabolismo , Água/metabolismo , Idoso , Pressão Sanguínea , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/psicologia , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos
16.
J Investig Med High Impact Case Rep ; 8: 2324709620974871, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33218273

RESUMO

A 43-year-old man, with severe obesity (43 kg/m2) and diabetes (presumed as type 2 diabetes [T2D]), underwent vertical sleeve gastrectomy in 2009 and Roux-en-Y gastric bypass in 2013. Recently, whole exome sequencing (conducted to search for monogenic obesity) serendipitously revealed that the individual harbored a heterozygous glucokinase (GCK) variant p.(Arg422Leu) that was bioinformatically strongly predicted to be likely pathogenic. Therefore, he is likely to have concomitant maturity-onset diabetes of the young (MODY) type 2 (GCK-MODY). A retrospective evaluation of the clinical data showed that the subject was diagnosed with T2D (given his severe obesity) in 2005 and was treated with oral antidiabetic monotherapy. His hyperglycemia was mostly mild (HbA1c [hemoglobin] < 8.1%), consistent with that of MODY2, despite severe obesity. After vertical sleeve gastrectomy, complete diabetes remission (HbA1c <6.0% and fasting plasma glucose <5.6 mmol/L without use of antidiabetic medication) was achieved. The percentage of maximum body weight loss attained after surgery was 23.6%. Euglycemia was maintained during the subsequent decade, up to the last follow-up in 2019, without any sign of hypoglycemia. In conclusion, we report a decade-long clinical experience of a man with severe obesity and diabetes likely due to the coexistence of GCK-MODY and T2D, serendipitously treated with metabolic surgery. Interestingly, metabolic surgery was effective and safe for him.


Assuntos
Diabetes Mellitus Tipo 2/cirurgia , Gastrectomia , Derivação Gástrica , Obesidade Mórbida/cirurgia , Adulto , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Quinases do Centro Germinativo/genética , Hemoglobinas Glicadas/análise , Heterozigoto , Humanos , Hiperglicemia/sangue , Masculino , Obesidade Mórbida/fisiopatologia , Resultado do Tratamento , Sequenciamento do Exoma
17.
J Diabetes Complications ; 34(12): 107724, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32900592

RESUMO

AIM: To examine correlation between vascular measures and cognitive performance in type 2 diabetes (T2D). METHODS: This was a cross-sectional study on patients (N = 1167) aged ≥45 years attending Diabetes Centre in a tertiary hospital and primary care polyclinic. The following vascular measures were measured: systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), pulse pressure (PP), pulse wave velocity (PWV) and augmentation index (AI). Cognition was assessed by Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Multiple linear regression was used to examine relationships between vascular measures and cognition, adjusting for demographics, education, depression, clinical covariates and presence of APOE Ɛ4 allele. RESULTS: In unadjusted analyses, all the vascular measures, except for MAP, were associated with RBANS total score. In fully adjusted analyses, the association with RBANS total score persisted for peripheral PP, aortic PP and aortic DBP with ßs -0.05 (95%CI -0.07 to -0.02; p = 0.001), -0.04 (95%CI -0.06 to -0.01; p = 0.002) and 0.05 (95%CI 0.00 to 0.09; p = 0.033). Association between peripheral and aortic PP and RBANS total score was unaffected by age-stratification (age <60 and ≥60 years). In contrast, significant association between aortic DBP and RBANS total score was only observed for those ≥60 years. Peripheral and aortic PP (which estimate pulsatility) are negatively associated with attention, visuospatial/constructional and language ability. CONCLUSIONS: Peripheral and aortic PP, and aortic DBP were independently correlated with cognitive performance globally and in multiple domains. Further research should be conducted to establish the clinical relevance and importance.


Assuntos
Pressão Sanguínea , Cognição , Diabetes Mellitus Tipo 2 , Análise de Onda de Pulso , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/psicologia , Humanos , Pessoa de Meia-Idade
18.
Mol Biol Cell ; 31(22): 2475-2493, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32816642

RESUMO

The epithelial cell-specific clathrin adaptor protein (AP)-1B has a well-established role in polarized sorting of cargos to the basolateral membrane. Here we show that ß1 integrin was dependent on AP-1B and its coadaptor, autosomal recessive hypercholesterolemia protein (ARH), for sorting to the basolateral membrane. We further demonstrate an unprecedented role for AP-1B at the basal plasma membrane during collective cell migration of epithelial sheets. During wound healing, expression of AP-1B (and ARH in AP-1B-positive cells) slowed epithelial-cell migration. We show that AP-1B colocalized with ß1 integrin in focal adhesions during cell migration using confocal microscopy and total internal reflection fluorescence microscopy on fixed specimens. Further, AP-1B labeling in cell protrusions was distinct from labeling for the endocytic adaptor complex AP-2. Using stochastic optical reconstruction microscopy we identified numerous AP-1B-coated structures at or close to the basal plasma membrane in cell protrusions. In addition, immunoelectron microscopy showed AP-1B in coated pits and vesicles at the plasma membrane during cell migration. Lastly, quantitative real-time reverse transcription PCR analysis of human epithelial-derived cell lines revealed a loss of AP-1B expression in highly migratory metastatic cancer cells suggesting that AP-1B's novel role at the basal plasma membrane during cell migration might be an anticancer mechanism.


Assuntos
Complexo 1 de Proteínas Adaptadoras/metabolismo , Subunidades beta do Complexo de Proteínas Adaptadoras/metabolismo , Movimento Celular/fisiologia , Complexo 1 de Proteínas Adaptadoras/genética , Complexo 2 de Proteínas Adaptadoras/metabolismo , Subunidades beta do Complexo de Proteínas Adaptadoras/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Polaridade Celular/fisiologia , Clatrina/metabolismo , Cães , Endossomos/metabolismo , Células Epiteliais/metabolismo , Humanos , Integrina beta1/metabolismo , Células Madin Darby de Rim Canino , Proteínas de Membrana/metabolismo , Transporte Proteico/fisiologia
19.
Diabetes Res Clin Pract ; 168: 108390, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32858097

RESUMO

AIMS: Monogenic diabetes (also known as maturity-onset diabetes of the young or MODY) affects a subset of individuals with young-onset diabetes. We report our diagnostic work-up experience for such individuals. METHODS: Serving as a regional secondary-care diabetes centre in a multi-ethnic population, we receive referrals to evaluate MODY from endocrinologists in both public and private practice. Key criteria for consideration of genetic-testing are onset age ≤ 35, negative GAD antibody, no history of diabetic ketoacidosis, strong family history of diabetes and BMI < 32.5 kg/m2. A monogenic diabetes registry was set up since 2017 to study their disease trajectories. RESULTS: We identified 30 out of 175 (17.1%) individuals with likely pathogenic/pathogenic variants. Importantly, 29 out of 30 (96.7%) occurred in clinically actionable genes. A continuous scale combining BMI, hs-CRP and HDL provided 80% (P < 0.001) diagnostic accuracy for MODY in our cohort, achieving a negative predictive value of 0.93 and sensitivity at 0.76. Subtyping MODY prior to genetic testing (if desired) will require specialist domain knowledge and additional biomarkers due to its genetic heterogeneity. CONCLUSIONS: Through systematic and structured evaluation, the prevalence of MODY is non-trivial (17.1%) in a referral centre. Diagnostic algorithm combining clinical criteria and readily available biomarkers can support clinical decision for MODY genetic testing.


Assuntos
Biomarcadores/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Adulto , Feminino , Humanos , Masculino , Encaminhamento e Consulta , Singapura
20.
Sci Rep ; 10(1): 2956, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32076075

RESUMO

Lower extremity skeletal muscle mass (LESM) in Type 2 Diabetes (T2D) has been linked to adverse clinical events, but it is not known whether it is associated with cognitive difficulties. We conducted a cross-sectional study on 1,235 people (mean age 61.4 ± 8.0 years) with T2D under primary and secondary care in Singapore. Bioelectrical impedance analyses (BIA) measures of upper extremity skeletal muscle mass (UESM), LESM and appendicular skeletal muscle index (SMI) were related to the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) measures of cognition, in multiple linear regression. In multivariable models, tertile 1 LESM (b = -2.62 (-3.92 to -1.32)) and tertile 2 LESM (b = -1.73 (-2.73 to -0.73)), referenced to tertile 3) were significantly associated with decreased RBANS total score. Significant associations of LESM with cognitive domain performances were observed for tertile 1 (b = -3.75 (-5.98 to -1.52)) and tertile 2 (b = -1.98 (-3.69 to -0.27)) with immediate memory, and for tertile 1 (b = -3.05 (-4.86 to -1.24)) and tertile 2 (b = -1.87 (-3.25 to -0.48)) with delayed memory, and for tertile 1 (b = -2.99 (-5.30 to -0.68)) with visuospatial/constructional ability. Tertile 1 SMI (b = -1.94 (-3.79 to -0.08) and tertile 2 SMI (b = -1.75 (-3.14 to -0.37)) were also associated with delayed memory. There were no associations between UESM with cognitive performance. Lower LESM may be a useful marker of possible co-occuring cognitive dysfunction.


Assuntos
Disfunção Cognitiva/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Extremidade Inferior/fisiologia , Músculo Esquelético/fisiopatologia , Sarcopenia/epidemiologia , Idoso , Composição Corporal/fisiologia , Cognição/fisiologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/fisiopatologia , Estudos Transversais , Diabetes Mellitus Tipo 2/fisiopatologia , Impedância Elétrica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos/estatística & dados numéricos , Sarcopenia/diagnóstico , Sarcopenia/etiologia , Sarcopenia/fisiopatologia , Singapura/epidemiologia
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