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  • 1
    Online Resource
    Online Resource
    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
    detail.hit.zdb_id: 1501252-9
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  • 2
    Online Resource
    Online Resource
    Dorzagliatin, a Dual-Acting Glucokinase Activator, Increases Insulin Secretion and Glucose Sensitivity in Glucokinase Maturity-Onset Diabetes of the Young and Recent-Onset Type 2 Diabetes
    American Diabetes Association ; 2023
    In:  Diabetes Vol. 72, No. 2 ( 2023-02-01), p. 299-308
    Details
    In: Diabetes, American Diabetes Association, Vol. 72, No. 2 ( 2023-02-01), p. 299-308
    Abstract: Glucokinase (GK, gene symbol GCK) maturity-onset diabetes of the young (MODY) is caused by heterozygous inactivating mutations in GK and impaired glucose sensing. We investigated effects of dorzagliatin, a novel allosteric GK activator, on insulin secretion rates (ISRs) and β-cell glucose sensitivity (βCGS) in GCK-MODY and recent-onset type 2 diabetes. In a double-blind, randomized, crossover study, 8 participants with GCK-MODY and 10 participants with type 2 diabetes underwent 2-h 12 mmol/L hyperglycemic clamps following a single oral dose of dorzagliatin 75 mg or matched placebo. Effects of dorzagliatin on wild-type and mutant GK enzyme activity were investigated using an NADP+-coupled assay with glucose-6-phosphate dehydrogenase in vitro. In GCK-MODY, dorzagliatin significantly increased absolute and incremental second-phase ISRs versus placebo but not the acute insulin response. Dorzagliatin improved βCGS in GCK-MODY with an upward and leftward shift in ISR-glucose response. Dorzagliatin increased basal ISRs in type 2 diabetes, with smaller changes in second-phase ISRs versus GCK-MODY. In vitro, dorzagliatin directly reduced the glucose half saturation concentration of wild-type GK and selected GK mutants to varying degrees. Dorzagliatin directly restored enzyme activity of select GK mutants and enhanced wild-type GK activity, thereby correcting the primary defect of glucose sensing in GCK-MODY.
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db22-0708
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
    detail.hit.zdb_id: 1501252-9
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  • 3
    Online Resource
    Online Resource
    1477-P: Polygenic Risk Score (PRS) Derived from Common Variants of Monogenic Diabetes Genes (MDG) Predicts Young Onset Diabetes (YOD) and Cardiovascular(CV)-Kidney Complications
    American Diabetes Association ; 2024
    In:  Diabetes Vol. 73, No. Supplement_1 ( 2024-06-14)
    Details
    In: Diabetes, American Diabetes Association, Vol. 73, No. Supplement_1 ( 2024-06-14)
    Abstract: Introduction & Objectives: Monogenic diabetes are caused by rare mutations in genes usually implicated in β-cell reserve/function. Whether their common variants could jointly influence risk of YOD diagnosed before 40 years and CV-kidney events is underexplored. We hypothesized a positive association of a weighted PRS derived from common variants of MDG with these outcomes. Methods: We constructed three weighted PRS with common variants (minor allele frequency & gt;0.01) of 34 MDG based on three r2 thresholds (0.2, 0.4, 0.6) of linkage disequilibrium (LD), from a discovery cohort of adults with [n=453, median age (interquartile range) = 40.0 (35.0-47.0)] and without [n=405, age=56.7 (50.3-61.0)] YOD who had whole exome sequencing data followed by validation in an independent cohort with array-based genotyping. We further tested association of the best performer with incident CV-kidney events in a cohort of type 2 diabetes (T2D). Results: 135 single nucleotide polymorphisms were used to construct the PRS based on LD r2 threshold 0.2 which performed the best at validation in an independent cohort (920 YOD + 4909 non-YOD) where per standard deviation (SD) rise in PRS was associated with 8% increased risk of YOD after adjusting sex and BMI (OR 1.08, p=0.047). In an independent cohort of T2D free of CV-kidney events at baseline [n=2313, age = 53.4 (45.4-61.7), disease duration = 4.0 (1.0-9.0)], per SD rise in PRS was associated with 16%, 9% and 10% increased risk of incident CV (HR 1.16, p & lt;0.001), kidney (HR 1.09, p=0.011) and CV-kidney events (HR 1.10, p=0.003) respectively after adjusting sex, baseline age and metabolic control. Those at top 20% PRS and baseline diabetes duration (DD) 5 to & lt;10 years had higher hazards of incident CV-kidney events than those at bottom 20% PRS and DD ≥10 years (HR 1.66, p=0.019) by direct comparison. Conclusion: Common variants of MDG jointly affected the risk of YOD and CV-kidney complications. Disclosure C. O: Other Relationship; Novo Nordisk. B. Fan: None. S.T.F. Tsoi: None. C.H. Tam: None. R. Wan: None. E.S.H. Lau: None. M. Shi: None. C.K.P. Lim: None. E. Chow: Research Support; Merck KGaA. Speaker's Bureau; AstraZeneca. Advisory Panel; Boehringer-Ingelheim. Research Support; Medtronic. Speaker's Bureau; Zuellig Pharma Holdings Pte. Ltd., Abbott. A.P. Kong: Speaker's Bureau; Abbott. Advisory Panel; Merck Sharp & Dohme Corp. Speaker's Bureau; Boehringer-Ingelheim, Bayer Inc., AstraZeneca. Other Relationship; Dexcom, Inc. Speaker's Bureau; Eli Lilly and Company, Novo Nordisk, Sanofi. Advisory Panel; Kyowa Kirin Co., Ltd., Abbott. R.C. Ma: Advisory Panel; AstraZeneca. Other Relationship; Bayer Inc., Boehringer-Ingelheim. Advisory Panel; Merck & Co., Inc. Other Relationship; Roche Diagnostics, Novo Nordisk. Advisory Panel; Takeda Pharmaceutical Company Limited. Other Relationship; GemVCare Ltd. A. Luk: Research Support; Novo Nordisk, Amgen Inc., Merck Sharp & Dohme Corp., Roche Pharmaceuticals, Biogen, Boehringer-Ingelheim, Shanghai Junshi Biosciences CO.Ltd. J.C. Chan: Research Support; AstraZeneca, Hua Medicine. Consultant; Sanofi. Research Support; Servier Laboratories. Consultant; Viatris Inc. Research Support; Merck & Co., Inc. Stock/Shareholder; GemVCare Ltd. Board Member; Asia Diabetes Foundation. Speaker's Bureau; Zuellig Pharma Holdings Pte. Ltd. Advisory Panel; Bayer Inc. Speaker's Bureau; Boehringer-Ingelheim. Funding Health and Medical Research Fund, Health Bureau, the HKSAR Government (CFS-CUHK2); Research Impact Fund, the Research Grants Council Hong Kong (R4012-18); Hong Kong Genome Institute
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db24-1477-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2024
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