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BACKGROUND: We compared performance of high 1-hour PG level, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) in predicting type 2 diabetes in a longitudinal community-based cohort of Hong Kong Chinese. METHODS: Between 2001 and 2003, 472 adults aged 18-55 years without diabetes underwent 75-gram oral glucose tolerance test (OGTT). Between 2012 and 2014, progression to diabetes was ascertained by reviewing medical records or repeating OGTT and HbA1c. We defined high 1-hour PG as PG ≥ 8.6 mmol/L at 1-hour. RESULTS: In this cohort, 23.5% had normal glucose tolerance and high 1-hour PG, 10.0% had isolated IGT, 4.2% had isolated IFG. Over 12-year follow-up, 9.3% developed type 2 diabetes. In logistic regression, high 1-hour PG was associated with progression to type 2 diabetes with adjusted odds ratio (95% CI) of 4.20 (1.60, 12.40), independent of IFG, IGT and other clinical variables. Areas under ROC (95% CI) for type 2 diabetes were similar between 1-hour (0.84 [0.78, 0.89], 2-hour (0.79 [0.72, 0.86]) and fasting PG (0.79 [0.71, 0.86]). CONCLUSION: High 1-hour PG identified young Chinese with 5-fold increased risk of type 2 diabetes independent of other intermediate hyperglycaemia status and clinical factors. 1-hour PG is similar to fasting and 2-hour PG in predicting type 2 diabetes.
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Glicemia , Diabetes Mellitus Tipo 2 , Teste de Tolerância a Glucose , Humanos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/diagnóstico , Hong Kong/epidemiologia , Masculino , Adulto , Feminino , Pessoa de Meia-Idade , Glicemia/análise , Glicemia/metabolismo , Intolerância à Glucose/sangue , Intolerância à Glucose/epidemiologia , Intolerância à Glucose/diagnóstico , Adulto Jovem , Adolescente , Jejum/sangue , Povo Asiático/estatística & dados numéricos , Progressão da Doença , População do Leste AsiáticoRESUMO
AIMS: To examine the risk association of insomnia with incident chronic cognitive impairment in older adults with type 2 diabetes mellitus (T2D). METHODS: Between July 2010 and June 2015, patients with T2D aged ≥60 years enrolled in the Hong Kong Diabetes Register completed the Insomnia Severity Index (ISI) questionnaire. Patients were considered having insomnia if they had ISI score > 14. We prospectively followed up the cohort and censored outcome through reviewing diagnoses and clinical notes entered by attending physicians in electronic medical record to identify incident cases of mild cognitive impairment and dementia. RESULTS: After excluding shift workers and those with established chronic cognitive impairment at baseline, we included 986 patients with T2D in this study (58.3 % men, mean age ± standard deviation: 62.5 ± 2.6 years, disease duration of diabetes: 10.7 ± 8.2 years, HbA1c: 7.4 ± 1.3 %, insulin users: 28.7 %, insomnia: 9.1 %). After a median follow-up of 7.6 (interquartile range = 2.0) years, 41 (4.2 %) developed chronic cognitive impairment. Using Cox regression analysis, insomnia (hazard ratio, HR 2.909, p = 0.012) and HbA1c ≥ 7 % (HR 2.300, p = 0.038) were positively associated with incident chronic cognitive impairment while insulin use (HR 0.309, p = 0.028) showed negative association. CONCLUSIONS: Insomnia, suboptimal glycemic control and non-insulin use are independent risk factors for incident chronic cognitive impairment in older adults with T2D.
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Disfunção Cognitiva , Diabetes Mellitus Tipo 2 , Distúrbios do Início e da Manutenção do Sono , Masculino , Humanos , Idoso , Feminino , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Estudos Prospectivos , Hemoglobinas Glicadas , Hong Kong/epidemiologia , Distúrbios do Início e da Manutenção do Sono/complicações , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Fatores de Risco , Disfunção Cognitiva/complicações , Disfunção Cognitiva/epidemiologia , InsulinaRESUMO
AIMS: We aimed to examine the impact of non-alcoholic fatty liver disease (NAFLD) on the clinical outcomes in patients with type 2 diabetes (T2D). METHODS: Between 2013 and 2014, 1,734 patients with T2D underwent transient elastography (TE) to assess liver status indicated by controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). Liver steatosis was defined by CAP ≥ 248 dB/m and advanced liver fibrosis by LSM ≥ 10 kPa. In 2019, we assessed their clinical outcomes including hospitalizations and mortality. RESULTS: In this prospective cohort [56% men, mean (±standard deviation) age:60.8±11.5 years; glycated hemoglobin (HbA1c)7.8±1.6 %], 798 patients had liver steatosis, 296 patients had advanced liver fibrosis and 640 patients had normal liver at baseline. T2D with advanced liver fibrosis had higher body mass index, waist circumference, waist-hip ratio, fasting plasma glucose, HbA1c, blood pressure and lipid profiles than their counterparts with NAFLD or normal liver (all p < 0.05). After a median follow-up of 6.07 (interquartile range:5.84 to 6.30) years, there were 4,403 incident hospitalizations, 32,119 days of hospital stay, and 171 deaths. Using Cox regression analysis, advanced liver fibrosis was associated with increased risk of heart failure (hazard ratio [95% confidence interval] HR:3.07[1.08-8.68], p=0.035) and hospitalizations (HR:1.39[1.14-1.70], p=0.001) while liver steatosis was associated with reduced mortality (HR:0.60[0.41-0.87], p=0.007) compared to their counterparts with normal liver after adjustment for potential confounders. CONCLUSIONS: T2D comorbid with liver steatosis and advanced liver fibrosis are distinct clinical entities with differences in outcomes. Advanced liver fibrosis is an important predictor for worse outcomes including heart failure and hospitalizations in people with T2D.
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Diabetes Mellitus Tipo 2 , Técnicas de Imagem por Elasticidade , Insuficiência Cardíaca , Hepatopatia Gordurosa não Alcoólica , Masculino , Humanos , Pessoa de Meia-Idade , Idoso , Feminino , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Estudos Prospectivos , Hong Kong/epidemiologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/epidemiologia , Hospitalização , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/complicações , Fígado/diagnóstico por imagemRESUMO
Increased aortic stiffness is closely associated with central obesity whereas mesenteric fat is the key adipose tissue in central obesity. We investigated the associations of mesenteric fat thickness with aortic stiffness, with comparison to conventional obesity measures. We used ultrasound to measure mesenteric, pre-peritoneal and subcutaneous fat thickness, carotid intima-media thickness (CIMT) and carotid-femoral pulse wave velocity (c-f PWV), an index of central aortic stiffness. Anthropometric indexes, blood pressure, fasting plasma glucose and lipid profile were measured. One hundred forty-seven healthy volunteers (age [mean ± standard deviation]: 43.2 ± 13.3 y; 41.5% men) were assessed. On univariate analysis, mesenteric, preperitoneal and subcutaneous fat thickness, body mass index (BMI), waist circumference (WC), waist/hip ratio (WHR) and waist/height ratio (WHtR) were associated with c-f PWV with or without adjustment for age. The mesenteric fat thickness had the highest correlation coefficient (r = 0.48, p < 0.001) with c-f PWV among all the investigated obesity indexes. Using multiple linear regression analysis, only mesenteric fat thickness remained to be an independent determinant of c-f PWV after adjustments for other abdominal fat thickness, anthropometric and metabolic indexes and CIMT. In conclusion, mesenteric fat thickness is an independent risk factor for aortic stiffness and has a stronger association with aortic stiffness compared with conventional obesity indexes.
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Obesidade Abdominal , Rigidez Vascular , Masculino , Humanos , Feminino , Obesidade Abdominal/complicações , Espessura Intima-Media Carotídea , Análise de Onda de Pulso , Obesidade/diagnóstico por imagem , Obesidade/complicações , Tecido Adiposo/diagnóstico por imagem , Fatores de Risco , Circunferência da Cintura , Índice de Massa CorporalRESUMO
Aging and obesity are two global concerns in public health. Sarcopenic obesity (SO), defined as the combination of age-related sarcopenia and obesity, has become a pressing issue. This systematic review and meta-analysis summarize the current clinical evidence relevant to SO. PubMed, Embase, and Web of Science were searched, and 106 clinical studies with 167,151 elderlies were included. The estimated prevalence of SO was 9% in both men and women. Obesity was associated with 34% reduced risk of sarcopenia (odds ratio [OR] 0.66, 95% CI 0.48-0.91; p < 0.001). The pooled hazard ratio (HR) of all-cause mortality was 1.51 (95% CI 1.14-2.02; p < 0.001) for people with SO compared with healthy individuals. SO was associated with increased risk of cardiovascular disease and related mortality, metabolic disorders, cognitive impairment, arthritis, functional limitation, and lung diseases (all ORs > 1.0, p < 0.05). The attenuated risk of sarcopenia in elderlies with obesity ("obesity paradox") was dependent on higher muscle mass and strength. Apart from unifying the diagnosis of SO, more research is needed to subphenotype people with obesity and sarcopenia for individualized treatment. Meanwhile, the maintenance of proper body composition of muscle and fat may delay or attenuate the adverse outcomes of aging.
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Doenças Cardiovasculares , Sarcopenia , Masculino , Humanos , Feminino , Idoso , Sarcopenia/complicações , Sarcopenia/epidemiologia , Obesidade/complicações , Obesidade/epidemiologia , Envelhecimento/fisiologia , Composição Corporal , Doenças Cardiovasculares/complicaçõesRESUMO
BACKGROUND: Cancer is replacing cardiovascular-disease as a leading cause of death in type 2 diabetes (T2D). The association of RAS-inhibitors (RASi) and cancer, including differences between angiotensin-converting-enzyme-inhibitor (ACEi) and angiotensin-receptor-blocker (ARBs) as well as their associations independent of blood pressure lowering, remains inconclusive in T2D. METHODS: We conducted a cohort study with new-user design in 253,491 patients in the Hong-Kong-Diabetes-Surveillance-Database (HKDSD) in 2002-2019. We evaluated the associations of time-varying RASi use (ACEi and ARBs) with all-site cancer, diabetes-related cancers, and cancer-specific mortality including comparison with new-users of calcium-channel-blockers (CCBs) as an active-comparator group. FINDINGS: Of 253,491, 133,730 (52.8%) were new-RASi and 119,761 (47.2%) were non-RASi users with a median follow-up period of 6.3 (interquartile ragne: 3.4-9.2) years (1,678,719 patient-years). After propensity-score weighting and adjustment for time-varying covariables, RASi use was associated with lower risk of all-site cancer (HR=0.76, 95%CI: 0.74-0.79), diabetes-related cancer (HR=0.79, 95%CI: 0.75-0.84), cancer-specific mortality (HR=0.50, 95%CI: 0.47-0.53), and diabetes-related cancer mortality (HR=0.49, 95%CI: 0.45-0.54) versus non-RASi. Amongst RASi users, ARBs use was associated with lower risk of cancer-specific mortality versus ACEi (HR=0.77, 95%CI: 0.66-0.91). Use of RASi was associated with an estimated-prevention of 2.6 (95%CI: 2.3-3.0) all-site cancer per-1000-person-years and 2.2 (95%CI: 2.0-2.5) cancer-related mortality per-1000-person-years. Lower risk of cancer-specific mortality was similarly observed in new-RASi compared with new-CCBs users. INTERPRETATION: RASi use was independently associated with lower cancer risk in T2D with stronger associations in users of ARBs than ACEi. The benefits of RASi in patients with diabetes might go beyond cardiovascular-renal protection if confirmed by other real-world studies and trials. FUNDING: Dr. Aimin Yang was supported by a CUHK Impact-Research-Fellowship Scheme.
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Diabetes Mellitus Tipo 2 , Neoplasias , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Angiotensinas , Cálcio , Bloqueadores dos Canais de Cálcio , Estudos de Coortes , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Hong Kong/epidemiologia , Humanos , Neoplasias/epidemiologia , Neoplasias/etiologiaRESUMO
AIMS: We evaluated the effect of personalized risk counseling incorporating clinical and genetic risk factors on patient empowerment and risk factor control in diabetes. METHODS: Patients with type 2 diabetes (T2D) with suboptimal glycaemic control (HbA1c ≥ 7.5%) were randomized to a genetic counselling (GC) or control group. All patients underwent genetic testing for alleles at three loci associated with diabetic complications. The GC group received additional explanation of the joint associations of genetic and modifiable risk factors on risk of complications. All patients were reassessed at 12 months including validated questionnaires for patient reported outcomes. The primary outcome was proportion of patients reaching ≥ 3 of 5 predefined treatment targets (HbA1c < 7%, BP < 130/80 mmHg, LDL-C < 2.6 mmol/L, Triglyceride < 2.0 mmol/L, use of renin-angiotensin system inhibitors). Secondary outcomes included new-onset chronic kidney disease or microalbuminuria and patient reported outcome measures. RESULTS: A total of 435 patients were randomized and 420 patients were included in the modified intention-to-treat analysis. At 12 months, the proportion of patients who attained ≥ 3 targets increased from 41.6% to 52.3% in the GC group (p = 0.007) versus 49.5% to 62.6% in the control group (p = 0.003), without between-group difference. Both groups had similar reduction in HbA1c, LDL-C and increased use of medications. In per protocol analysis, the GC group had higher diabetes empowerment, with reduced diabetes distress. In the GC group, the greatest improvement in positive attitude and self-care activities was observed in the intermediate to high genetic risk score (GRS) groups. CONCLUSIONS: In patients with T2D receiving integrated care, additional counselling on genetic risk of complications did not further improve risk factor control, although the improvement in self-efficacy warrants long-term evaluation.
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Prestação Integrada de Cuidados de Saúde , Diabetes Mellitus Tipo 2 , LDL-Colesterol , Aconselhamento , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/terapia , Testes Genéticos , Hemoglobinas Glicadas/análise , Humanos , Participação do PacienteRESUMO
People with type 2 diabetes (T2D) have increased cancer risk. Liver cancer (LC) has a high prevalence in East Asia and is one of the leading causes of cancer death globally. Diagnosis of LC at early stage carries good prognosis. We used stored serum from patients of Hong Kong Diabetes Register before cancer diagnosis to extract RNA to screen for microRNA markers for early detection of LC in T2D. After screening with Affymetrix GeneChip microarray with serum RNA from 19 incident T2D LC (T2D-LC), 20 T2D cancer free (T2D-CF) and 20 non-T2D non-cancer patients, top signals were validated in a 3-group comparison including 1888 T2D-CF, 127 T2D-LC, and 487 T2D patients with non-liver cancer patients using qPCR. We detected 2.55-fold increase in miR-122-5p and 9.21-fold increase in miR-455-3p in the T2D-LC group. Using ROC analysis, miR-122-5p and miR-455-3p jointly predicted LC with an area under the curve of 0.770. After adjustment for confounders, each unit increase of miR-455-3p increased the odds ratio for liver cancer by 1.022. Increased serum levels of miR-122-5p and miR-455-3p were independently associated with increased risk of incident LC in T2D and may serve as potential biomarkers for early detection of LC in T2D.
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Biomarcadores Tumorais , MicroRNA Circulante , Diabetes Mellitus Tipo 2/complicações , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/diagnóstico , MicroRNAs/genética , Biologia Computacional/métodos , Detecção Precoce de Câncer , Feminino , Perfilação da Expressão Gênica , Humanos , Biópsia Líquida/métodos , Neoplasias Hepáticas/etiologia , Masculino , MicroRNAs/sangue , Prognóstico , Curva ROC , Reprodutibilidade dos Testes , TranscriptomaRESUMO
BACKGROUND: Type 2 diabetes (T2D) increases the risk of many types of cancer. Dysregulation of proteasome-related protein degradation leads to tumorigenesis, while Exendin-4, a glucagon-like peptide 1 receptor (GLP-1R) agonist, possesses anti-cancer effects. METHODS: We explored the co-expression of proteasome alpha 2 subunit (PSMA2) and GLP-1R in the Cancer Genome Atlas (TCGA) database and human cervical cancer specimens, supplemented by in vivo and in vitro studies using multiple cervical cancer cell lines. FINDINGS: PSMA2 expression was increased in 12 cancer types in TCGA database and cervical cancer specimens from patients with T2D (T2D vs non-T2D: 3.22 (95% confidence interval CI: 1.38, 5.05) vs 1.00 (0.66, 1.34) fold change, P = 0.01). psma2-shRNA decreased cell proliferation in vitro, and tumour volume and Ki67 expression in vivo. Exendin-4 decreased psma2 expression, tumour volume and Ki67 expression in vivo. There was no change in GLP-1R expression in 12 cancer types in TCGA database. However, GLP-1R expression (T2D vs non-T2D: 5.49 (3.0, 8.1) vs 1.00 (0.5, 1.5) fold change, P < 0.001) was increased and positively correlated with PSMA2 expression in T2D-related (r = 0.68) but not in non-T2D-related cervical cancer specimens. This correlation was corroborated by in vitro experiments where silencing glp-1r decreased psma2 expression. Exendin-4 attenuated phospho-p65 and -IκB expression in the NF-κB pathway. INTERPRETATION: PSMA2 and GLP-1R expression in T2D-related cervical cancer specimens was increased and positively correlated, suggesting hyperglycaemia might promote cancer growth by increasing PSMA2 expression which could be attenuated by Exendin-4. FUNDING: This project was supported by Postdoctoral Fellowship Scheme, Direct Grant, Diabetes Research and Education Fund from the Chinese University of Hong Kong (CUHK).
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Diabetes Mellitus Tipo 2/patologia , Exenatida/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Regulação para Cima/efeitos dos fármacos , Neoplasias do Colo do Útero/patologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Bases de Dados Genéticas , Diabetes Mellitus Tipo 2/complicações , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Humanos , Proteínas I-kappa B/metabolismo , Complexo de Endopeptidases do Proteassoma/química , Complexo de Endopeptidases do Proteassoma/genética , Subunidades Proteicas/antagonistas & inibidores , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Neoplasias do Colo do Útero/complicaçõesRESUMO
The augmented velocity index (Avi) is a new Doppler index associated with arterial stiffness. We examined associations of renal Avi with blood pressure (BP), aortic stiffness and carotid intima-media thickness (IMT), and compared its performance with that of resistive index (RI). One hundred forty-seven volunteers were recruited. Renal Avi had significant positive correlations with systolic BP (râ¯=â¯0.37, p < 0.001), diastolic BP (râ¯=â¯0.2, pâ¯=â¯0.016), mean arterial pressure (râ¯=â¯0.29, p < 0.001), pulse pressure (râ¯=â¯0.31, p < 0.001), carotid-femoral pulse wave velocity (râ¯=â¯0.49, p < 0.001) and carotid IMT (râ¯=â¯0.23, pâ¯=â¯0.005). RI correlated positively with pulse pressure (râ¯=â¯0.3, p < 0.001) only. After adjustments for co-variables, the associations remained similar. Patients with abnormal BP values (≥130/80 mm Hg), IMT and aortic stiffness (≥1 standard deviation of mean value) had higher Avi than those with normal values, but not RI. In conclusion, renal Avi had stronger associations with BP, arterial stiffness and carotid IMT than RI in apparently healthy volunteers, and was significantly increased in abnormal patients.
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Velocidade do Fluxo Sanguíneo , Pressão Sanguínea , Espessura Intima-Media Carotídea , Hipertensão/fisiopatologia , Artéria Renal/diagnóstico por imagem , Artéria Renal/fisiopatologia , Ultrassonografia Doppler em Cores , Resistência Vascular , Rigidez Vascular , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Patients with diabetes have increased risk of cancer and poor response to anti-cancer treatment. Increased protein synthesis is associated with endoplasmic reticulum (ER) stress which can trigger the unfolded protein response (UPR) to restore homeostasis, failure of which can lead to dysregulated cellular growth. We hypothesize that hyperglycemia may have legacy effect in promoting survival of cancer cells through dysregulation of UPR. Using HCT116 colorectal cancer cells as a model, we demonstrated the effects of high glucose (25 mM) on promoting cell growth which persisted despite return to normal glucose medium (5.6 mM). Using the Affymetrix gene expression microarray in HCT116 cells programmed by high glucose, we observed activation of genes related to cell proliferation and cell cycle progression and suppression of genes implicated in UPR including BiP and CHOP. These gene expression changes were validated in HCT116 cancer cells using quantitative real-time PCR and Western blot analysis. We further examined the effects of thapsigargin, an anti-cancer prodrug, which utilized ER stress pathway to induce apoptosis. High glucose attenuated thapsigargin-induced UPR and growth inhibition in HCT116 cells, which persisted despite return to normal glucose medium. Western blot analysis showed activation of caspase-3 in thapsigargin-treated cells in both normal and high glucose medium, albeit with lower levels of cleaved caspase-3 in cells exposed to high glucose, suggesting reduced apoptosis. Flow cytometry analysis confirmed fewer apoptotic cells under thapsigargin treatment in cells exposed to high glucose. Our results suggested that hyperglycemia altered gene expression involved in UPR with increased cell proliferation and facilitated survival of HCT116 cells under thapsigargin-induced ER stress by reducing the apoptotic response.
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BACKGROUND & AIMS: The paradox of hepatic insulin resistance describes the inability for liver to respond to bioenergetics hormones in suppressing gluconeogenesis whilst maintaining lipid synthesis. Here, we report the deficiency of miR-192-3p in the livers of mice with diabetes and its role in alleviating hepatic steatosis. METHODS: As conventional pre-microRNA (miRNA) stem-loop overexpression only boosts guiding strand (i.e. miR-192-5p) expression, we adopted an artificial AAV(DJ)-directed, RNA Pol III promoter-driven miRNA hairpin construct for star-strand-specific overexpression in the liver. Liver steatosis and insulin resistance markers were evaluated in primary hepatocytes, mice with diabetes, and mice with excessive carbohydrate consumption. RESULTS: Functional loss of miR-192-3p in liver exacerbated hepatic micro-vesicular steatosis and insulin resistance in either mice with diabetes or wild-type mice with excessive fructose consumption. Liver-specific overexpression of miR-192-3p effectively halted hepatic steatosis and ameliorated insulin resistance in these mice models. Likewise, hepatocytes overexpressing miR-192-3p exhibited improved lipid accumulation, accompanied with decreases in lipogenesis and lipid-accumulation-related transcripts. Mechanistically, glucocorticoid receptor (GCR, also known as nuclear receptor subfamily 3, group C, member 1 [NR3C1]) was demonstrated to be negatively regulated by miR-192-3p. The effect of miR-192-3p on mitigating micro-vesicular steatosis was ablated by the reactivation of NR3C1. CONCLUSIONS: The star strand miR-192-3p was an undermined glycerolipid regulator involved in controlling fat accumulation and insulin sensitivity in liver through blockade of hepatic GCR signalling; this miRNA may serve as a potential therapeutic option for the common co-mobility of diabetic mellitus and fatty liver disease. LAY SUMMARY: The potential regulatory activity of star strand microRNA (miRNA) species has been substantially underestimated. In this study, we investigate the role and mechanism of an overlooked star strand miRNA (miR-192-3p) in regulating hepatic steatosis and insulin signalling in the livers of mice with diabetes and mice under excessive carbohydrate consumption.
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BACKGROUND AND AIMS: Type 2 diabetes is an important risk factor for nonalcoholic fatty liver disease (NAFLD) and advanced fibrosis. Current international guidelines recommend the use of noninvasive tests as initial assessments for NAFLD, but the role of noninvasive tests as monitoring tools has not been established. We aimed to study the role of transient elastography as a monitoring tool in patients with type 2 diabetes. APPROACH AND RESULTS: We recruited patients with type 2 diabetes without viral hepatitis or excessive alcohol intake from a complication screening facility in Hong Kong in 2013-2014 and repeated the assessments in 2016-2018. The primary endpoint was an increase of liver stiffness measurement (LSM) to ≥10 kPa. The secondary endpoint was the change in the controlled attenuation parameter (CAP). A total of 611 patients with type 2 diabetes and a valid LSM (mean age, 57.7 ± 10.9 years; 342 men [56.0%]) were included in this study (568 also had a valid CAP). Overall, there was moderate correlation between the baseline and follow-up LSM (r = 0.689, P < 0.001). Among 487 patients with a baseline LSM <10 kPa, 21 (4.3%) had a follow-up LSM ≥10 kPa. Baseline body mass index, alanine aminotransferase (ALT), and ∆ALT were independent factors associated with LSM increase. Among 124 patients with a baseline LSM ≥10 kPa, 70 (56.5%) had a follow-up LSM <10 kPa. Among 198 patients with a CAP <248 dB/m at baseline, 103 (52.0%) had a CAP increased to ≥248 dB/m. CONCLUSIONS: The prevalence and incidence of NAFLD in patients with type 2 diabetes are high. Although advanced fibrosis is common in this population, few patients progress to advanced fibrosis in 3 years. Future studies should define the optimal surveillance interval in patients with diabetes.
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Diabetes Mellitus Tipo 2/complicações , Técnicas de Imagem por Elasticidade/métodos , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Idoso , Alanina Transaminase/sangue , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Feminino , Humanos , Cirrose Hepática/epidemiologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Estudos ProspectivosRESUMO
BACKGROUND: A missense variant (rs6967330) of the gene encoding cadherin-related family member 3 (CDHR3) was associated with recurrent severe exacerbations in pre-schoolers. However, there were limited data on its relationship with pre-school lung function and school-age asthma. This study replicated the association between polymorphic markers at the region of CDHR3 around rs6967330 and wheezing phenotypes in two independent cohorts of Chinese children. METHODS: Ten tagging SNPs located 10 kb around rs6967330 were selected by HaploView 5.0 based on 1000 Genomes database for Southern Han Chinese. Their associations with wheezing and lung function were examined in 1341 Chinese pre-school children, while those for asthma phenotypes were examined in an independent group of 2079 school-age children. Genotypic and haplotypic associations were analyzed by multivariate regression, and generalized multifactor dimensionality reduction was used to examine epistatic interactions for wheezing traits. RESULTS: The mean (SD) age of pre-school cohort was 4.7 (1.0) years. Rs6967330 was associated with current wheeze (odds ratio [OR] 1.63, 95% confidence interval [CI] 1.09-2.43) and its severity (OR 1.64, 95% CI 1.10-2.44) among pre-school children. This SNP was also associated with school-age asthma (OR 1.32, 95% CI 1.04-1.69). The minor allele of rs408223 was associated with lower FEV0.5 (ß = -2.411, P = .004) and FEV0.5 /FVC (ß = -1.292, P = .015). Lower spirometric indices were also associated with minor allele of rs140154310. GAC haplotype from rs4730125, rs6967330, and rs408223 was associated with pre-school current wheeze and school-age asthma. Epistatic interaction was found between unrelated CDHR3 SNPs for FEV0.5 among pre-schoolers. CONCLUSION: CDHR3 is a candidate gene for early-life wheezing, school-age asthma, and lung function in Chinese children.
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Asma/genética , Caderinas/genética , Genótipo , Proteínas de Membrana/genética , Sons Respiratórios/genética , Proteínas Relacionadas a Caderinas , Pré-Escolar , China , Estudos de Coortes , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Testes de Função RespiratóriaRESUMO
BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with increased metabolic risk, though data on long-term follow-up of cardiometabolic traits are limited. We postulated that Chinese women with PCOS would have higher risk of incident diabetes and cardiometabolic abnormalities than those without PCOS during long-term follow-up. METHODS AND FINDINGS: One hundred ninety-nine Chinese women with PCOS diagnosed by the Rotterdam criteria and with a mean age of 41.2 years (SD = 6.4) completed a follow-up evaluation after an average of 10.6 ± 1.3 years. Two hundred twenty-five women without PCOS (mean age: 54.1 ± 6.7 years) who underwent baseline and follow-up evaluation over the same period were used for comparison. Progression of glycaemic status of women both with and without PCOS was assessed by using 75-g oral glucose tolerance test (OGTT) screening with the adoption of 2009 American Diabetes Association diagnostic criteria. The frequency of impaired glucose regulation, hypertension, and hyperlipidaemia of women with PCOS at follow-up has increased from 31.7% (95% CI 25.2%-38.1%) to 47.2% (95% CI 40.3%-54.2%), 16.1% (95% CI 11.0%-21.2%) to 34.7% (95% CI 28.1%-41.3%), and 52.3% (95% CI 45.3%-59.2%) to 64.3% (95% CI 57.7%-71.0%), respectively. The cumulative incidence of diabetes mellitus (DM) in follow-up women with PCOS is 26.1% (95% CI 20.0%-32.2%), almost double that in the cohort of women without PCOS (p < 0.001). Age-standardised incidence of diabetes among women with PCOS was 22.12 per 1,000 person-years (95% CI 10.86-33.37) compared with the local female population incidence rate of 8.76 per 1,000 person-years (95% CI 8.72-8.80) and 10.09 per 1,000 person-years (95% CI 4.92-15.26, p < 0.001) for women without PCOS in our study. Incidence rate for women with PCOS aged 30-39 years was 20.56 per 1,000 person-years (95% CI 12.57-31.87), which is approximately 10-fold higher than that of the age-matched general female population in Hong Kong (1.88 per 1,000 person-years, [95% CI 1.85-1.92]). The incidence rate of type 2 DM (T2DM) of both normal-weight and overweight women with PCOS was around double that of corresponding control groups (normal weight: 8.96 [95% CI 3.92-17.72] versus 4.86 per 1,000 person-years [95% CI 2.13-9.62], p > 0.05; overweight/obese: 28.64 [95% CI 19.55-40.60] versus 14.1 per 1,000 person-years [95% CI 8.20-22.76], p < 0.05). Logistic regression analysis identified that baseline waist-to-hip ratio (odds ratio [OR] = 1.71 [95% CI 1.08-2.69], p < 0.05) and elevated triglyceride (OR = 6.63 [95% CI 1.23-35.69], p < 0.05) are associated with the progression to T2DM in PCOS. Limitations of this study include moderate sample size with limited number of incident diabetes during follow-up period and potential selection bias. CONCLUSIONS: High risk of diabetes and increased cardiovascular disease risk factors among Chinese women with PCOS are highlighted in this long-term follow-up study. Diabetes onset was, on average, 10 years earlier among women with PCOS than in women without PCOS.
Assuntos
Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Intolerância à Glucose , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/complicações , Adulto , Antropometria , Glicemia/análise , Doenças Cardiovasculares/complicações , Estudos de Casos e Controles , China/epidemiologia , Comorbidade , Complicações do Diabetes/terapia , Diabetes Mellitus Tipo 2/complicações , Progressão da Doença , Feminino , Seguimentos , Teste de Tolerância a Glucose , Humanos , Incidência , Pessoa de Meia-Idade , Obesidade/complicações , Sobrepeso/complicações , Síndrome do Ovário Policístico/terapia , Estado Pré-Diabético/diagnóstico , Estudos Prospectivos , Análise de Regressão , Fatores de Risco , Inquéritos e Questionários , Resultado do Tratamento , Triglicerídeos/sangue , Adulto JovemRESUMO
Augmented Velocity Index (Avi) is a new Doppler index developed to quantify velocity changes at the late systolic peak. We examined its reliability, association with arterial stiffness and cardiovascular risk factors. The Avi is calculated as (late systolic peak velocityâ¯-â¯early systolic peak velocity)/(highest peak systolic velocityâ¯-â¯end-diastolic velocity). Fifty volunteers (mean age ± standard deviation: 43.5 ± 14.2 y, men: 52%) without known medical illnesses or drug use were recruited. Carotid Doppler waveforms with measurements of Avi were recorded. Carotid pressure waveforms were obtained by applanation tonometry for measurement of the Augmentation Index (AI). Clinical measurements including body mass index (BMI) and blood pressure (BP) were assessed, and fasting blood was taken for measurement of glycemia and lipid profile. Another 15 volunteers (age range: 22-60 y, men: 33.3%) were recruited to study the reliability of Avi measurement. The results revealed that carotid Avi closely correlated with the index of arterial stiffness, AI (râ¯=â¯0.76, p < 0.001) on Pearson correlation. On multiple linear regression analysis, Avi remained a significant independent determinant of AI after adjustments for clinical variables. The Avi had significant associations with cardiovascular risk factors (age, BMI, total cholesterol, low-density lipoprotein cholesterol, systolic and diastolic BP). The intra-class correlation coefficients for inter-observer and intra-observer reliability of Avi measurements were 0.93 (95% confidence interval [CI]: 0.8-0.98) and 0.97 (95% CI: 0.92-0.99) respectively. In conclusion, the Avi is a reproducible new Doppler index, independently associated with arterial stiffness in terms of the AI, which initially correlated with cardiovascular risk factors.
Assuntos
Artérias Carótidas/fisiologia , Ultrassonografia Doppler/métodos , Rigidez Vascular/fisiologia , Adulto , Velocidade do Fluxo Sanguíneo/fisiologia , Artérias Carótidas/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos Testes , Adulto JovemRESUMO
STUDY OBJECTIVES: Insomnia is associated with insulin resistance and type 2 diabetes (T2D) in the general population. However, the associations between insomnia and glycemic control in T2D population are not consistently reported. In this study, we aimed to examine the associations between insomnia and glycemic control, and gender differences in these associations among Hong Kong Chinese patients with T2D. METHODS: This was a cross-sectional study involving T2D patients recruited from the Hong Kong Diabetes Registry between July 2010 and June 2015. Glycemic control was estimated by fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c). Participants with the Insomnia Severity Index score > 14 were considered as having insomnia. RESULTS: A total of 3753 patients were recruited. Compared with patients without insomnia, patients with insomnia had higher levels of FPG and HbA1c. After adjustment for potential confounding factors, insomnia was associated with higher FPG and HbA1c in the entire cohort. There were significant interactions between insomnia and gender for FPG (p = 0.001) and HbA1c (p = 0.025) in the full model. Subgroup analyses found that men with insomnia had higher FPG [8.23 (7.85-8.61) mmol/L versus 7.50 (7.39-7.61) mmol/L, p < 0.001] and HbA1c [7.79 (7.57-8.02)% versus 7.45 (7.39-7.52)%, p = 0.005] than men without insomnia after adjusted for confounding factors, whereas such difference was not observed in women. CONCLUSIONS: T2D patients with insomnia had worse glycemic control than the patients without insomnia. The associations were particularly pronounced in men.
Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 2/epidemiologia , Hemoglobinas Glicadas/análise , Resistência à Insulina/fisiologia , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Adulto , Estudos de Coortes , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Feminino , Hong Kong/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Distúrbios do Início e da Manutenção do Sono/sangueRESUMO
Diabetes is a major cause of end stage renal disease (ESRD), yet the natural history of diabetic kidney disease is not well understood. We aimed to identify patterns of estimated GFR (eGFR) trajectory and to determine the clinical and genetic factors and their associations of these different patterns with all-cause mortality in patients with type 2 diabetes. Among 6330 patients with baseline eGFR >60 ml/min per 1.73 m2 in the Hong Kong Diabetes Register, a total of 456 patients (7.2%) developed Stage 5 chronic kidney disease or ESRD over a median follow-up of 13 years (incidence rate 5.6 per 1000 person-years). Joint latent class modeling was used to identify different patterns of eGFR trajectory. Four distinct and non-linear trajectories of eGFR were identified: slow decline (84.3% of patients), curvilinear decline (6.5%), progressive decline (6.1%) and accelerated decline (3.1%). Microalbuminuria and retinopathy were associated with accelerated eGFR decline, which was itself associated with all-cause mortality (odds ratio [OR] 6.9; 95% confidence interval [CI]: 5.6-8.4 for comparison with slow eGFR decline). Of 68 candidate genetic loci evaluated, the inclusion of five loci (rs11803049, rs911119, rs1933182, rs11123170, and rs889472) improved the prediction of eGFR trajectories (net reclassification improvement 0.232; 95% CI: 0.057--0.406). Our study highlights substantial heterogeneity in the patterns of eGFR decline among patients with diabetic kidney disease, and identifies associated clinical and genetic factors that may help to identify those who are more likely to experience an accelerated decline in kidney function.
Assuntos
Albuminúria/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/epidemiologia , Retinopatia Diabética/epidemiologia , Falência Renal Crônica/epidemiologia , Idoso , Albuminúria/patologia , Albuminúria/fisiopatologia , Povo Asiático , Causas de Morte , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/mortalidade , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/fisiopatologia , Retinopatia Diabética/genética , Progressão da Doença , Feminino , Seguimentos , Loci Gênicos/genética , Taxa de Filtração Glomerular , Hong Kong/epidemiologia , Humanos , Incidência , Rim/fisiopatologia , Falência Renal Crônica/genética , Falência Renal Crônica/patologia , Falência Renal Crônica/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sistema de Registros/estatística & dados numéricosRESUMO
BACKGROUND: Acute myocardial infarction (AMI) is the leading cause of death among people with diabetes mellitus (DM) and has been found to occur more frequently with extreme temperatures. With the increasing prevalence of DM and the rising global mean temperature, the number of heat-related AMI cases among DM patients may increase. This study compares excess risk of AMI during periods of extreme temperatures between patients with DM and without DM. METHODS: Distributed lag nonlinear models (DLNMs) were used to estimate the short-term association between daily mean temperature and AMI admissions (International Classification of Diseases 9th revision [ICD-9] code: 410.00-410.99), stratified by DM status (ICD-9: 250.00-250.99), to all public hospitals in Hong Kong from 2002 to 2011, adjusting for other meteorological variables and air pollutants. Analyses were also stratified by season, age group, gender, and admission type (first admissions and readmissions). The admissions data and meteorological data were obtained from the Hong Kong Hospital Authority (HA) and the Hong Kong Observatory (HKO). FINDINGS: A total of 53,769 AMI admissions were included in the study. AMI admissions among DM patients were linearly and negatively associated with temperature in the cold season (cumulative relative risk [cumRR] [95% confidence interval] in lag 0-22 days (12 °C versus 24 °C) = 2.10 [1.62-2.72]), while those among patients without DM only started increasing when temperatures dropped below 22 °C with a weaker association (cumRR = 1.43 [1.21-1.69]). In the hot season, AMI hospitalizations among DM patients started increasing when the temperature dropped below or rose above 28.8 °C (cumRR in lag 0-4 days [30.4 versus 28.8 °C] = 1.14 [1.00-1.31]), while those among patients without DM showed no association with temperature. The differences in sensitivity to temperature between patients with DM and without DM were most apparent in the group <75 years old and among first-admission cases in the cold season. The main limitation of this study was the unavailability of data on individual exposure to ambient temperature. CONCLUSIONS: DM patients had a higher increased risk of AMI admissions than non-DM patients during extreme temperatures. AMI admissions risks among DM patients rise sharply in both high and low temperatures, with a stronger effect in low temperatures, while AMI risk among non-DM patients only increased mildly in low temperatures. Targeted health protection guidelines should be provided to warn DM patients and physicians about the dangers of extreme temperatures. Further studies to project the impacts of AMI risks on DM patients by climate change are warranted.
Assuntos
Temperatura Baixa/efeitos adversos , Diabetes Mellitus/epidemiologia , Exposição Ambiental/efeitos adversos , Temperatura Alta/efeitos adversos , Infarto do Miocárdio/epidemiologia , Admissão do Paciente , Estações do Ano , Idoso , Mudança Climática , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/mortalidade , Diabetes Mellitus/terapia , Feminino , Hong Kong/epidemiologia , Mortalidade Hospitalar , Hospitais Públicos , Humanos , Masculino , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/terapia , Readmissão do Paciente , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de TempoRESUMO
SIGNIFICANCE: The rising global prevalence of diabetes and its debilitating complications give rise to significant disability and premature mortality. Due to the silent nature of diabetes and its vascular complications, and limitations in current methods for detection, there is a need for novel biomarkers for early detection and prognosis. Recent Advances: Metabolic memory and epigenetic factors are important in the pathogenesis of diabetic complications and interact with genetic variants, metabolic factors, and clinical risk factors. Micro(mi)RNAs interact with epigenetic mechanisms and pleiotropically mediate the effects of hyperglycemia on the vasculature. Utilizing mature profiling techniques and platforms, an increasing number of miRNA signatures and interaction networks have been identified for diabetes and its related cardiorenal complications. As a result, these short, single-stranded molecules are emerging as potential diagnostic and predictive tools in human studies, and may function as disease biomarkers, as well as treatment targets. CRITICAL ISSUES: However, there is complex interaction between the genome and epigenome. The regulation of miRNAs may differ across species and tissues. Most profiling studies to date lack validation, often requiring large, well-characterized cohorts and reliable normalization strategies. Furthermore, the incremental benefits of miRNAs as biomarkers, beyond prediction provided by traditional risk factors, are critical issues to consider, yet often neglected in published studies. FUTURE DIRECTIONS: All in all, the future for miRNA-based diagnostics and therapeutics for diabetic complications appears promising. Improved understanding of the complex mechanisms underlying miRNA dysregulation, and more well-designed studies utilizing prospective samples would facilitate the translation to clinical use.