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  • American Diabetes Association  (5)
  • 1
    Online Resource
    Online Resource
    Identification of a Common Variant for Coronary Heart Disease at PDE1A Contributes to Individualized Treatment Goals and Risk Stratification of Cardiovascular Complications in Chinese Patients With Type 2 Diabetes
    American Diabetes Association ; 2023
    In:  Diabetes Care Vol. 46, No. 6 ( 2023-06-01), p. 1271-1281
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 46, No. 6 ( 2023-06-01), p. 1271-1281
    Abstract: In this study we aim to unravel genetic determinants of coronary heart disease (CHD) in type 2 diabetes (T2D) and explore their applications. RESEARCH DESIGN AND METHODS We performed a two-stage genome-wide association study for CHD in Chinese patients with T2D (3,596 case and 8,898 control subjects), followed by replications in European patients with T2D (764 case and 4,276 control subjects) and general populations (n = 51,442–547,261). Each identified variant was examined for its association with a wide range of phenotypes and its interactions with glycemic, blood pressure (BP), and lipid controls in incident cardiovascular diseases. RESULTS We identified a novel variant (rs10171703) for CHD (odds ratio 1.21 [95% CI 1.13–1.30]; P = 2.4 × 10−8) and BP (β ± SE 0.130 ± 0.017; P = 4.1 × 10−14) at PDE1A in Chinese T2D patients but found only a modest association with CHD in general populations. This variant modulated the effects of BP goal attainment (130/80 mmHg) on CHD (Pinteraction = 0.0155) and myocardial infarction (MI) (Pinteraction = 5.1 × 10−4). Patients with CC genotype of rs10171703 had & gt;40% reduction in either cardiovascular events in response to BP control (2.9 × 10−8 & lt; P & lt; 3.6 × 10−5), those with CT genotype had no difference (0.0726 & lt; P & lt; 0.2614), and those with TT genotype had a threefold increase in MI risk (P = 6.7 × 10−3). CONCLUSIONS We discovered a novel CHD- and BP-related variant at PDE1A that interacted with BP goal attainment with divergent effects on CHD risk in Chinese patients with T2D. Incorporating this information may facilitate individualized treatment strategies for precision care in diabetes, only when our findings are validated.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc22-2331
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
    detail.hit.zdb_id: 1490520-6
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  • 2
    Online Resource
    Online Resource
    Efficacy and Safety of Dapagliflozin in Patients With Inadequately Controlled Type 1 Diabetes (the DEPICT-2 Study): 24-Week Results From a Randomized Controlled Trial
    American Diabetes Association ; 2018
    In:  Diabetes Care Vol. 41, No. 9 ( 2018-09-01), p. 1938-1946
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 41, No. 9 ( 2018-09-01), p. 1938-1946
    Abstract: This 24-week, double-blinded, phase 3 clinical trial (DEPICT-2; ClinicalTrials.gov, NCT02460978) evaluated efficacy and safety of dapagliflozin as adjunct therapy to adjustable insulin in patients with inadequately controlled type 1 diabetes (HbA1c 7.5–10.5%). RESEARCH DESIGN AND METHODS Patients were randomized 1:1:1 to dapagliflozin 5 mg (n = 271), dapagliflozin 10 mg (n = 270), or placebo (n = 272) plus insulin. Insulin dose was adjusted by investigators according to self-monitored glucose readings, local guidance, and individual circumstances. RESULTS Baseline characteristics were balanced between treatment groups. At week 24, dapagliflozin significantly decreased HbA1c (primary outcome; difference vs. placebo: dapagliflozin 5 mg −0.37% [95% CI −0.49, −0.26], dapagliflozin 10 mg –0.42% [−0.53, −0.30] ), total daily insulin dose (−10.78% [−13.73, −7.72] and −11.08% [−14.04, −8.02] , respectively), and body weight (−3.21% [−3.96, −2.45] and −3.74% [−4.49, −2.99] , respectively) (P & lt; 0.0001 for all). Mean interstitial glucose, amplitude of glucose excursion, and percent of readings within target glycemic range ( & gt;70 to ≤180 mg/dL) versus placebo were significantly improved. More patients receiving dapagliflozin achieved a reduction in HbA1c ≥0.5% without severe hypoglycemia compared with placebo. Adverse events were reported for 72.7%, 67.0%, and 63.2% of patients receiving dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo, respectively. Hypoglycemia, including severe hypoglycemia, was balanced between groups. There were more adjudicated definite diabetic ketoacidosis (DKA) events with dapagliflozin: 2.6%, 2.2%, and 0% for dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo, respectively. CONCLUSIONS Dapagliflozin as adjunct therapy to adjustable insulin in patients with type 1 diabetes was well tolerated and improved glycemic control with no increase in hypoglycemia versus placebo but with more DKA events.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc18-0623
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
    detail.hit.zdb_id: 1490520-6
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  • 3
    Online Resource
    Online Resource
    A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. 7 ( 2018-07-01), p. 1414-1427
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. 7 ( 2018-07-01), p. 1414-1427
    Abstract: Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10−8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db17-0914
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
    detail.hit.zdb_id: 1501252-9
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  • 4
    Online Resource
    Online Resource
    Aldose Reductase–Deficient Mice Are Protected From Delayed Motor Nerve Conduction Velocity, Increased c-Jun NH2-Terminal Kinase Activation, Depletion of Reduced Glutathione, Increased Superoxide Accumulation, and DNA Damage
    American Diabetes Association ; 2006
    In:  Diabetes Vol. 55, No. 7 ( 2006-07-01), p. 1946-1953
    Details
    In: Diabetes, American Diabetes Association, Vol. 55, No. 7 ( 2006-07-01), p. 1946-1953
    Abstract: The exaggerated flux through polyol pathway during diabetes is thought to be a major cause of lesions in the peripheral nerves. Here, we used aldose reductase (AR)-deficient (AR−/−) and AR inhibitor (ARI)-treated mice to further understand the in vivo role of polyol pathway in the pathogenesis of diabetic neuropathy. Under normal conditions, there were no obvious differences in the innervation patterns between wild-type AR (AR+/+) and AR−/− mice. Under short-term diabetic conditions, AR−/− mice were protected from the reduction of motor and sensory nerve conduction velocities observed in diabetic AR+/+ mice. Sorbitol levels in the sciatic nerves of diabetic AR+/+ mice were increased significantly, whereas sorbitol levels in the diabetic AR−/− mice were significantly lower than those in diabetic AR+/+ mice. In addition, signs of oxidative stress, such as increased activation of c-Jun NH2-terminal kinase (JNK), depletion of reduced glutathione, increase of superoxide formation, and DNA damage, observed in the sciatic nerves of diabetic AR+/+ mice were not observed in the diabetic AR−/− mice, indicating that the diabetic AR−/− mice were protected from oxidative stress in the sciatic nerve. The diabetic AR−/− mice also excreted less 8-hydroxy-2′-deoxyguanosine in urine than diabetic AR+/+ mice. The structural abnormalities observed in the sural nerve of diabetic AR+/+ mice were less severe in the diabetic AR−/− mice, although it was only mildly protected by AR deficiency under short-term diabetic conditions. Signs of oxidative stress and functional and structural abnormalities were also inhibited by the ARI fidarestat in diabetic AR+/+ nerves, similar to those in diabetic AR−/− mice. Taken together, increased polyol pathway flux through AR is a major contributing factor in the early signs of diabetic neuropathy, possibly through depletion of glutathione, increased superoxide accumulation, increased JNK activation, and DNA damage.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db05-1497
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2006
    detail.hit.zdb_id: 1501252-9
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  • 5
    Online Resource
    Online Resource
    Sustained Antidiabetic Effects of a Berberine-Containing Chinese Herbal Medicine Through Regulation of Hepatic Gene Expression
    American Diabetes Association ; 2012
    In:  Diabetes Vol. 61, No. 4 ( 2012-04-01), p. 933-943
    Details
    In: Diabetes, American Diabetes Association, Vol. 61, No. 4 ( 2012-04-01), p. 933-943
    Abstract: Diabetes and obesity are complex diseases associated with insulin resistance and fatty liver. The latter is characterized by dysregulation of the Akt, AMP-activated protein kinase (AMPK), and IGF-I pathways and expression of microRNAs (miRNAs). In China, multicomponent traditional Chinese medicine (TCM) has been used to treat diabetes for centuries. In this study, we used a three-herb, berberine-containing TCM to treat male Zucker diabetic fatty rats. TCM showed sustained glucose-lowering effects for 1 week after a single-dose treatment. Two-week treatment attenuated insulin resistance and fatty degeneration, with hepatocyte regeneration lasting for 1 month posttreatment. These beneficial effects persisted for 1 year after 1-month treatment. Two-week treatment with TCM was associated with activation of AMPK, Akt, and insulin-like growth factor-binding protein (IGFBP)1 pathways, with downregulation of miR29-b and expression of a gene network implicated in cell cycle, intermediary, and NADPH metabolism with normalization of CYP7a1 and IGFBP1 expression. These concerted changes in mRNA, miRNA, and proteins may explain the sustained effects of TCM in favor of cell survival, increased glucose uptake, and lipid oxidation/catabolism with improved insulin sensitivity and liver regeneration. These novel findings suggest that multicomponent TCM may be a useful tool to unravel genome regulation and expression in complex diseases.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db11-1164
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2012
    detail.hit.zdb_id: 1501252-9
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