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  • 1
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    Online Resource
    Circulating MicroRNAs Associated with Incident End-Stage Renal Disease in Chinese with Type 2 Diabetes
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. Supplement_1 ( 2018-07-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. Supplement_1 ( 2018-07-01)
    Abstract: Objectives: We aimed to identify novel serum micro(mi)RNAs associated with incident end-stage renal disease (ESRD) in Chinese with type 2 diabetes. Methods: We conducted a nested case-control study in patients with type 2 diabetes enrolled in the Hong Kong Diabetes Registry between 1995 and 2007. Cases were patients who were free from ESRD at enrolment but developed renal endpoint as defined as eGFR & lt; 15 ml/min/1.73m2 or dialysis during follow-up until 2015. Controls were patients who had normal renal function at both baseline and during observation period. MicroRNAs were extracted from stored serum collected at baseline. Discovery cohort included 22 cases and 21 controls and miRNAs were screened by Agilent microRNA microarray. Validation cohort included 361 ESRD cases and 241 T2D controls and miRNAs were quantitated using qRT-PCR. Two spike-in miRNAs were used to control for efficiency in RNA extraction and reverse transcription. Batch difference was adjusted by a positive RNA control. Results: In the discovery analysis, miR-X and miR-Y were elevated with respective fold-change of 5.97 and 4.43 in patients with incident ESRD compared to those without renal events on follow-up. Pathway analysis revealed that the two miRNAs may involve in signaling transduction, adrenergic signaling, or relate to peroxisome. Increased levels of miR-X and miR-Y were also detected in the validation cohort. Using binary logistic regression adjusted for age, sex and disease duration, doubling of miR-X and miR-Y were associated with 14.2% and 26.3% higher odds of progressing to ESRD, respectively. The association remained significant for miR-Y when further adjusted for metabolic indices, baseline albuminuria and eGFR. Conclusions: Baseline serum levels of miR-X and miR-Y are independently associated with higher risk of incident ESRD. These results indicate the potential of circulating miRNAs to serve as prognostic indicators for disease progression. Disclosure B. Fan: None. H. Lee: None. C.K.P. Lim: None. R. Choy: None. J.C. Chan: Consultant; Self; Bayer AG. Other Relationship; Self; Bayer AG. Consultant; Self; Sanofi. Other Relationship; Self; Sanofi, Eli Lilly and Company, Amgen Inc.. Consultant; Self; AstraZeneca, Merck & Co., Inc., Pfizer Inc.. Other Relationship; Self; Pfizer Inc.. Board Member; Self; Asia Diabetes Foundation. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; Merck Sharp & Dohme Corp.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novartis AG, Eli Lilly and Company. A. Luk: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc.. Research Support; Self; Sanofi. R.C. Ma: Research Support; Self; AstraZeneca, Bayer AG, Merck Sharp & Dohme Corp., Pfizer Inc.. Advisory Panel; Self; Boehringer Ingelheim GmbH, Nippon Boehringer Ingelheim Co. Ltd..
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-519-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 2
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    1001-P: HOMA2 IR and HOMA2 Beta on Onset and Progression of Diabetes in Young to Middle-Aged Subjects
    American Diabetes Association ; 2021
    In:  Diabetes Vol. 70, No. Supplement_1 ( 2021-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 70, No. Supplement_1 ( 2021-06-01)
    Abstract: Background: The roles of insulin deficiency (ID) and resistance (IR) in young patients with type 2 diabetes (T2D) are uncertain. We explored the associations of HOMA2 IR and HOMA2 %B using fasting C peptide and plasma glucose (FPG) with incident T2D and insulin use in Chinese aged 18-50 years. Methods: Cohort 1 included subjects without T2D in 1998-2002 with glycemic status ascertained in 2012-2013. Cohort 2 included patients with T2D (1995-2014) with documentation of glycemic deterioration (continuous insulin use or failure of 2 oral drugs). Results: In cohort 1, 62 subjects developed (T2D-progressors) and 285 did not develop T2D (T2D-non-progressors) during 10-year follow-up. In cohort 2 (n=737), 293 (39.8%) required insulin after a median follow-up period of 8.6 years. At baseline, T2D-non-progressors had lower HOMA2 IR [median (IQR) 0.77 (0.60, 1.06)] vs. 1.06 (0.81, 1.38)] and similar HOMA2 %B [84.3 (72, 111.5) vs. 85.1 (75.6, 100.7)] compared with T2D-progressors. Non-insulin-requiring T2D patients had lower HOMA2 IR [1.47 (1.02, 2.11) vs. 1.76 (1.19, 2.42)] and higher HOMA2 %B [62.4 (39.4, 87.4) vs. 45.4 (25.8, 71.8)] than insulin-requiring patients. When stratified by median values and using low HOMA2 %B plus low HOMA2 IR as referent, subjects with high HOMA2 %B plus high HOMA2 IR had age and sex-adjusted odds ratio (95% CI) of 2.47 (1.28, 4.93) and those with low HOMA2% B plus high HOMA2 IR had 5.27 (2.27, 12.84) of incident T2D. In the T2D cohort, using high HOMA2 %B plus low HOMA2 IR as referent, the hazard ratio (95% CI) for insulin use increased with low HOMA2 %B [2.18 (1.47, 3.23)] , high HOMA2 IR [2.45 (1.64, 3.64)] and low HOMA2 %B plus high HOMA2 IR [4.25 (2.82, 6.41)] adjusted for age, sex and disease duration. These associations were attenuated after adjusting for obesity, FPG, HbA1c and TG/HDL-C. Conclusions: In young to middle-aged Chinese, progressive worsening in IR and ID contribute to onset of T2D and insulin requirement, which can be attenuated by early control of metabolic factors. Disclosure B. Fan: None. E. Chow: Research Support; Self; Medtronic, Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation, Sanofi-Aventis. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc. A. Luk: None. J. C. Chan: Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, MSD Corporation, Sanofi, Other Relationship; Self; Asia Diabetes Foundation, GemVCare, Research Support; Self; Applied Therapeutics, AstraZeneca, Hua Medicine, Lilly Diabetes, Merck KGaA. H. Wu: None. M. Shi: None. A. Yang: None. C. H. Tam: None. E. S. H. Lau: None. D. Mao: None. C. K. P. Lim: Stock/Shareholder; Self; GemVCare Ltd. A. P. Kong: Advisory Panel; Self; Lilly Diabetes, Speaker’s Bureau; Self; Abbott, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Sanofi, Stock/Shareholder; Self; Aptorum.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db21-1001-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
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  • 3
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    261-OR: Dorzagliatin, a Dual-Acting Glucokinase Activator. Improves Insulin Secretion and Glucose Sensitivity in Glucokinase-Maturity-Onset Diabetes of the Young (GCK-MODY)
    American Diabetes Association ; 2022
    In:  Diabetes Vol. 71, No. Supplement_1 ( 2022-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 71, No. Supplement_1 ( 2022-06-01)
    Abstract: Glucokinase maturity onset diabetes of the young (GCK-MODY) is caused by heterozygous inactivating mutations in GCK that is not responsive to conventional glucose lowering drugs. We investigated the effects of dorzagliatin, a novel allosteric activator of hepatic and beta-cell GCK on insulin secretion rates (ISR) and glucose sensitivity (GS) in GCK-MODY and recent onset type 2 diabetes (T2D) . In a double-blind, randomized cross-over study, 8 GCK-MODY (mean±SD age 36.1­±6.4years) and T2D subjects (mean age 50.2±6.9 years, median T2D duration 0.90 [0.60-1.42] years) underwent 2-hour 12 mmol/L hyperglycemic clamps following a single oral dose of dorzagliatin 75mg or matched placebo. Insulin and C-peptide were measured. GCK-MODY group showed significantly higher absolute (mean±SD 432±85 versus 272±91 pmol/min/m2, p=0.002) and incremental (342­±91 vs. 241±74 pmol/min/m2, p=0.004) second-phase ISR following dorzagliatin versus placebo. Dorzagliatin significantly improved GS in GCK-MODY (51±21 vs. 33­±13 pmol/min/m2 per mmol/L p=0.028) with an upward and leftward shift in ISR-glucose response. In T2D, basal ISR was significantly improved following dorzagliatin (102±57 vs. 60±42, p=0.018) with smaller increases in second phase ISR and GS. Dorzagliatin improves second phase ISR and GS, with larger effects in GCK-MODY than T2D. Disclosure E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. L.Chen: Employee; Hua Medicine. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. K.Wang: None. C.K.P.Lim: None. S.Tsoi: None. B.Fan: None. A.Luk: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. E.Ferrannini: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk, Oramed Pharmaceuticals, Consultant; Elgia Therapeutics, Research Support; Janssen Research & Development, LLC, Oramed Pharmaceuticals, Sanofi-Aventis U.S., Speaker's Bureau; Boehringer Ingelheim International GmbH. A.Mari: Consultant; Lilly, Research Support; Lilly. Funding Hua Medicine Investigator Initiated Clinical Research
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db22-261-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2022
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  • 4
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    1211-P: Associations of C-peptide, HOMA2, and GADA with Insulin Initiation and Risk of Hypoglycemia in Type 2 Diabetes
    American Diabetes Association ; 2022
    In:  Diabetes Vol. 71, No. Supplement_1 ( 2022-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 71, No. Supplement_1 ( 2022-06-01)
    Abstract: Background: In patients with type 2 diabetes (T2D) and non-ketotic presentation, low C-peptide (CP) and positivity for glutamic acid decarboxylase antibodies (GADA+) indicate early insulin requirement. In GADA- patients, the associations of CP with insulin use, glycemic response and severe hypoglycemia event (SHE) are unknown. Methods: We measured fasting CP and GADA in 4590 Chinese patients with T2D enrolled in the Hong Kong Diabetes Register in 1995-2012 followed up till 2019. The updated homeostasis model assessment (HOMA2) was derived from fasting CP and plasma glucose. We defined incident insulin use as the first insulin prescription of at least 28 days, glycemic response as HbA1c reduction at one year after insulin initiation, and SHE using ICD-9 codes. Linear and Cox regression models were applied for association analyses. Results: At enrolment, 32% had low CP ( & lt;250 pmol/L) and 5% were GADA+. In the low CP group, 7% were GADA+. In the GADA+ group, 50% had low CP. During a mean follow-up of 10.8 years, 58.6% were started on insulin after a median of 6.5 years. The GADA+ group was more likely to initiate insulin [adjusted HR (95% CI) 1.55 (1.26-1.91) ] and experienced SHE [HR 1.45 (1.08-1.95) ] than the GADA- group. In the GADA- group, low CP had lower hazards of insulin use [HR 0.86 (0.77-0.97) ] than high CP especially in patients with HOMA2-IR (insulin resistance) above median. The low CP group had higher HR of 1.34 (1.13-1.59) of SHE than the high CP group. In the GADA+ group, low CP was associated with increased risk of SHE [HR 1.81 (1.25, 2.62) ] but not in patients with high CP (P interaction= 0.01) . Both CP and GADA did not predict glycemia response after controlling for baseline HbA1c. Conclusions: In patients with T2D, CP interacted with GADA to influence disease progressions including early insulin therapy and SHE. C-peptide might be correlated with IR in patients with GADA-. These subphenotypes allowed more precise classification of beta cell function to guide personalized treatment. Disclosure B.Fan: None. A.Luk: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. E.S.H.Lau: None. H.Wu: None. M.Shi: None. A.Yang: None. C.K.P.Lim: None. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. Funding The HKG Health Medical and Research Fund and RGC Research Impact Fund
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db22-1211-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2022
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  • 5
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    1133-P: Monogenic Diabetes in Chinese with Young-Onset Diabetes
    American Diabetes Association ; 2021
    In:  Diabetes Vol. 70, No. Supplement_1 ( 2021-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 70, No. Supplement_1 ( 2021-06-01)
    Abstract: Background: The clinical course of monogenic diabetes in Chinese is not well established. We determined the prevalence of mutation and variants of uncertain significance (VUS) in a panel of monogenic diabetes genes in a prospective cohort of Chinese with young-onset diabetes, and examined clinical characteristics and outcome of the affected individuals. Methods: From patients enrolled in Hong Kong Diabetes Register between 1995-2012, DNA samples of 316 Chinese with non-type 1 diabetes diagnosed age & lt;40 years were sequenced. A targeted panel of 34 genes related to monogenic diabetes was designed with AmpliSeq (Illumina). Variants were interpreted based on American College of Medical Genetics and Genomics Standards and Guidelines. Incident complications including cardiovascular disease (CVD) and death were captured until 2019. Baseline characteristics and complications were compared between patients with and without pathogenic/ likely pathogenic variants or VUS. Results: 24 (7.6%) patients had pathogenic/likely pathogenic variants and 39 (12.3%) had VUS in one or more monogenic diabetes genes. At baseline, patients with pathogenic/likely pathogenic variants had lower HbA1c (6.9 ± 1.0 vs. 7.9 ± 2.1%, p=0.02) and urine ACR (0.74 [0.44 - 2.03] vs. 1.71 [0.68 - 9.90] mg/mmol, p=0.01), and lower frequency of hypertension (20.8 vs. 46.9%, p=0.02) than those without mutation. Patients with and without VUS were similar for all characteristics. Over a median follow-up of 15.3 years, 4.3% of patients with pathogenic/likely pathogenic variants vs. 14.7% without mutation developed CVD (p=0.22), and 2.3% vs. 9.2% died (p=0.49). For patients with and without VUS, the frequencies were 14.7% vs. 14.7% (p=1.00) for incident CVD and 5.1% vs. 9.9% (p=0.55) for death. Conclusion: One in five Chinese with young-onset diabetes had either mutation or VUS in monogenic diabetes genes. Patients with monogenic diabetes gene mutation had more favorable metabolic profile but did not differ in incident complication compared with those with no mutation. Disclosure S. Tsoi: None. C. K. P. Lim: Stock/Shareholder; Self; GemVCare Ltd. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc. E. S. H. Lau: None. B. Fan: None. E. Chow: Research Support; Self; Medtronic, Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation, Sanofi-Aventis. A. P. Kong: Advisory Panel; Self; Lilly Diabetes, Speaker’s Bureau; Self; Abbott, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Sanofi, Stock/Shareholder; Self; Aptorum. J. C. Chan: Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, MSD Corporation, Sanofi, Other Relationship; Self; Asia Diabetes Foundation, GemVCare, Research Support; Self; Applied Therapeutics, AstraZeneca, Hua Medicine, Lilly Diabetes, Merck KGaA. A. Luk: None. Funding Research Grants Council of Hong Kong (14114918); Research Impact Fund (R4012-18)
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db21-1133-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
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  • 6
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    1829-PUB: Precision Medicine to Redefine Insulin Secretion and Monogenic Diabetes Randomised Controlled Trial (PRISM-RCT) in Chinese Patients with Young-Onset Diabetes—Study Design and Baseline Profile
    American Diabetes Association ; 2023
    In:  Diabetes Vol. 72, No. Supplement_1 ( 2023-06-23)
    Details
    In: Diabetes, American Diabetes Association, Vol. 72, No. Supplement_1 ( 2023-06-23)
    Abstract: Background: Young-onset diabetes (YOD) is heterogenous in aetiologies and clinical phenotypes. The PRISM study is a 3-year randomised controlled trial to evaluate the effect of precision treatment algorithm guided by biogenetic information on clinical outcomes in Chinese with YOD. Methods: In 2020-2021, we randomized 884 Chinese (18-50 years) with non-type 1 diabetes diagnosed ≤40 years to PRISM (n=443) or usual care (n=441). The PRISM group underwent assessment including biogenetic markers (anti-glutamic acid decarboxylase antibody [GADA], C-peptide, monogenic diabetes gene mutations and genetic risk scores predicting YOD, insulin requirement and complications) for issue of a personalized report to guide multidisciplinary care comprising endocrinologist consultation, counselling, empowerment on self-care, and reminders by supporting staff for 1 year at the Diabetes Research Centre before return to usual care. All patients return for assessment at year 3 for ascertainment of all-diabetes related endpoints. Results: Amongst 884 patients (mean±SD: age 40.7±6.5 years, median [IQR] age at diagnosis 34 [29,38] years, disease duration 7 [3,12] years, HbA1c 7.5±1.7%, 96.2% on glucose-lowering drugs, 27.7% on insulin), 74.7% had family history (19.7% both parents affected), 66.7% hypertension, 76.4% dyslipidaemia, 83% overweight and 35.4% albuminuria. Median fasting C-peptide was 0.6 (0.4, 0.9) nmol/L, 9.5% had C-peptide & lt;0.2 nmol/L, 5.1% were GADA positive. In the PRISM group, 21.9% had low birthweight, 50.7%, childhood obesity, 5.7%, steroid exposure in childhood, 1.8-17.3%, co-existing endocrinopathies (thyroid disease, Cushing’s syndrome, polycystic ovarian syndrome), 7.5%, thalassaemia trait, 7.1%, chronic hepatitis B infection and 10.3%, mental illness. Conclusions: Lifecourse factors, endocrinopathies and mental illnesses are prevalent in YOD. Disclosure A.Luk: Research Support; Novo Nordisk, Boehringer-Ingelheim, Bayer Inc., Speaker's Bureau; Eli Lilly and Company. E.Chow: Research Support; Medtronic, Merck KGaA, Speaker's Bureau; Novartis, Bayer Inc., Sanofi. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Speaker's Bureau; Abbott, AstraZeneca, Lilly, Bayer Inc., Boehringer Ingelheim Inc. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer Inc., Celltrion, Boehringer Ingelheim and Eli Lilly Alliance, Sanofi, Research Support; AstraZeneca, Servier Laboratories, Viatris Inc., Hua Medicine, Merck KGaA, Applied Therapeutics Inc., Lee Powder, Pfizer Inc., Speaker's Bureau; Novartis, Stock/Shareholder; GemVCare Ltd. Y.Fan: None. B.Fan: None. C.K.P.Lim: Stock/Shareholder; GemVCare Ltd. E.S.H.Lau: None. E.W.M.Poon: None. S.T.F.Tsoi: None. R.Ozaki: None. R.C.Ma: Advisory Panel; AstraZeneca, Merck & Co., Inc., Other Relationship; Bayer Inc., Boehringer-Ingelheim, Research Support; Tricida, Inc., Roche Diagnostics, Novo Nordisk. Funding Health and Medical Research Fund (CFS-CUHK2)
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db23-1829-PUB
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
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