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  • American Diabetes Association  (4)
  • 1
    Online-Ressource
    Online-Ressource
    Endoplasmic Reticulum Stress Inhibits STAT3-Dependent Suppression of Hepatic Gluconeogenesis via Dephosphorylation and Deacetylation
    American Diabetes Association ; 2012
    In:  Diabetes Vol. 61, No. 1 ( 2012-01-01), p. 61-73
    Details
    In: Diabetes, American Diabetes Association, Vol. 61, No. 1 ( 2012-01-01), p. 61-73
    Kurzfassung: In the liver, signal transducer and activator of transcription 3 (STAT3) plays an important role in the suppression of gluconeogenic enzyme expression. While obesity-associated endoplasmic reticulum (ER) stress has been shown to increase hepatic gluconeogenic enzyme expression, the role of ER stress in STAT3-dependent regulation of such expression is unclear. The current study aimed to elucidate the effect of ER stress on the STAT3-dependent regulation of hepatic gluconeogenic enzyme expression. Genetically obese/diabetic db/db mice and db/db mouse–derived isolated hepatocytes were used as ER stress models. A tyrosine phosphatase inhibitor, a deacetylation inhibitor, and an acetylated mutant of STAT3 were used to examine the effect of ER stress on hepatic STAT3 action. ER stress inhibited STAT3-dependent suppression of gluconeogenic enzyme gene expression by suppressing hepatic Janus kinase (JAK)2 and STAT3 phosphorylation. A tyrosine phosphatase inhibitor restored ER stress–induced suppression of JAK2 phosphorylation but exhibited no improving effect on suppressed STAT3 phosphorylation. STAT3 acetylation is known to correlate with its phosphorylation. ER stress also decreased STAT3 acetylation. An acetylated mutant of STAT3 was resistant to ER stress–induced inhibition of STAT3-phosphorylation and STAT3-dependent suppression of hepatic gluconeogenic enzyme gene expression in vitro and in vivo. Trichostatin A, a histone deacetylase (HDAC) inhibitor, ameliorated ER stress–induced inhibition of STAT3 acetylation and phosphorylation. The current study revealed that ER stress inhibits STAT3-dependent suppression of hepatic gluconeogenic enzymes via JAK2 dephosphorylation and HDAC-dependent STAT3 deacetylation, playing an important role in the increase of hepatic glucose production in obesity and diabetes.
    Materialart: Online-Ressource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db10-1684
    Sprache: Englisch
    Verlag: American Diabetes Association
    Publikationsdatum: 2012
    ZDB Id: 1501252-9
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 2
    Online-Ressource
    Online-Ressource
    1386-P: Confirmation of the Criteria for Insulin Administration at the Start of Steroid Therapy
    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)
    Kurzfassung: Blood glucose elevates at initial high-dose steroid (HDS) administration and is prolonged by persistent amplification of glucagon-induced glycogenesis. Insulin (INS) administration at initial dose of HDS will avoid this. However, INS administration criteria regarding BS elevation are not defined. HDS were given based on COVID-treatment guidelines. HDS administration circumstances in clinical settings may clarify these criteria. The necessity of INS therapy at initial HDS administration is studied. COVID-inpatients receiving HDS, regarding a COVID-period in Japan comprising 5 waves, were sub-grouped into those requiring INS therapy and those not, and analyzed with respect to age, BMI, fasting blood glucose (FBS) , A1c, C-peptide (CPR) index, CPR/glucagon (GCG) . INS was administered, target BS level 200 mg/dL or less at 14:00, depending on BS level after HDS administration. From 396 patients, 257 received HDS as follows, 1of the 154 patients in Wave 1-3 (69.5 ± 16.7 years, BMI 23.9 ± 4.8%, A1c 6.3 ± 1.1%) , 79 of the 83 patients in Wave 4 (64.5 ± 14.6 years, BMI 24.9 ± 4.78, A1c 6.6 ± 1.1%) , and 73 of the 117 patients in Wave 5 (54.4 ± 15.2 years, BMI 25.2 ± 5.1, A1c 6.2 ± 0.8%) . Of the 257 patients above, 145 were treated with INS. In all Waves, only FBS and A1c differed significantly between INS-treated and non-INS-treated patients. ROC analysis in Wave 1-3, Wave 4 and Wave 5 showed cut-off values of A1c (sensitivity/specificity) and FBS (sensitivity/specificity) measuring 6.1% (0.85/0.62) and 121.5 mg/dL (1.00/ 0.62) , 6.5% (0.44/0.83) and133.5 mg/dL (0.40/0.93) , and 6.4% (0.49/1.0) and 112.5 mg/dL (0.81/0.85) , respectively. In patients with FBS levels of 112.5 mg/dL or higher or A1c levels of 6.3% or higher, the use of INS from the initial HDS administration reduced prolongation of hyperglycemia. Variables BMI, CPR, and GCG secretion cannot determine the need for INS therapy. It is important to use FBS and A1c levels, according to conventional practice, to ascertain if INS administration is necessary. Disclosure S.Kaneko: None. K.Motohashi: None. T.Minami: None. Y.Ueba: None. T.Osugi: None. S.Tokumoto: None. Funding Reiwa 2nd year cookie test clinical research grant
    Materialart: Online-Ressource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db22-1386-P
    Sprache: Englisch
    Verlag: American Diabetes Association
    Publikationsdatum: 2022
    ZDB Id: 1501252-9
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 3
    Online-Ressource
    Online-Ressource
    1020-P: Effects of Insulin Degludec and Insulin Glargine U300 on Interday Glycemic Variability in Individuals with Type 1 Diabetes: A Multicenter, Randomized, Crossover Study
    American Diabetes Association ; 2020
    In:  Diabetes Vol. 69, No. Supplement_1 ( 2020-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 69, No. Supplement_1 ( 2020-06-01)
    Kurzfassung: Background: Insulin degludec (IDeg) and insulin glargine U300 (IGla-300) are recently launched ultra-long-acting insulin formulations. It remains unclear whether or how their glucose-stabilizing effects differ. We now compared the effects of these insulins on parameters on glycemic variability in patients with type 1 diabetes (T1D). Methods: This multicenter, randomized, crossover, non-inferiority trial recruited 46 patients with T1D treated with basal-bolus insulin therapy at 14 facilities in Japan. Patients were randomly assigned 1:1 to IGla-300 (first period)/IDeg (second period) or IDeg (first period)/IGla-300 (second period) groups, in which subjects were treated with the corresponding basal insulin for 4-week periods. The last week of each treatment period constituted the data collection phase, during which the participants determined the plasma glucose level seven times a day using a SMBG devise and were also equipped with a CGM devise. The primary end point was comparison of day-to-day glycemic variability evaluated by the standard deviation (SD) of FPG during the last week of each treatment period. Results: The SD for FPG in the IDeg treatment period was not inferior to that in the IGla-300 treatment period (95% CI, -16.1-3.0 mg/dL). The levels (95% CI, -18.4-5.7 mg/dL) and the coefficient of variance (95% CI, -4.6-4.3 %) of FPG did not significantly differ between the two periods. Parameters obtained with CGM, including time-in-range, duration of nocturnal hypoglycemia, mean amplitude of glycemic excursion, and mean of the daily differences, as well as the doses of basal and bolus insulins also did not significantly differ between the two treatment periods. Conclusion: IDeg was not inferior to IGla-300 in terms of inter-day glycemic variability in the treatment of T1D, and the treatments with these two insulins yielded similar outcomes for various parameters related to blood glucose control. Disclosure H. Miura: None. K. Sakaguchi: Other Relationship; Self; AstraZeneca, Novartis AG, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. A. Kaneko: None. J. Ito: None. Y. Morita: None. T. Yamada: None. N. Otowa-Suematsu: None. A. So: None. T. Nakamura: None. H. Komada: None. Y. Okada: None. Y. Hirota: Other Relationship; Self; Sanofi. Y. Tamori: None. W. Ogawa: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharma GmbH & Co.KG, Eli Lilly Japan K.K., Kowa Company, Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. Other Relationship; Self; Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited.
    Materialart: Online-Ressource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db20-1020-P
    Sprache: Englisch
    Verlag: American Diabetes Association
    Publikationsdatum: 2020
    ZDB Id: 1501252-9
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 4
    Online-Ressource
    Online-Ressource
    1097-P: Disposition Index Is a Predictor of Urinary Glucose Excretion in Subjects Treated with SGLT2 Inhibitors
    American Diabetes Association ; 2020
    In:  Diabetes Vol. 69, No. Supplement_1 ( 2020-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 69, No. Supplement_1 ( 2020-06-01)
    Kurzfassung: Aims: Urinary glucose excretion (UGE) induced by SGLT2 inhibitors (SGLT2i) varies considerably by individual, and is influenced by blood glucose level and glomerular filtration rate (GFR). It is however unknown what other factors are involved in this process. We have now investigated the relation between various physiological parameters and UGE in patients treated with an SGLT2i. Methods: To minimize the influence of glycemic variability, we analyzed SGLT2i-induced UGE during a hyperinsulinemic-euglycemic clamp. OGTT and a 120 min-hyperinsulinemic-euglycemic clamp, during which plasma glucose (PG) were maintained at 90 mg/dl, were performed with type 2 diabetes subjects (n=45) within 6 days after the start of dapagliflozin (5mg/day). Relationships between UGE during the clamp and various indexes for insulin secretion/sensitivity were analyzed. Disposition index (DI) was calculated as the product of insulinogenic index (II) and insulin sensitivity index (ISI) determined by the clamp. Results: During the clamp, UGE considerably varied from 28.2 to 176.9 (mean ± SD, 87.1 ± 32.8) mg/kg/120min. In univariate analysis, UGE was not correlated with PG before the clamp, mean PG during the clamp or any indexes for insulin secretion/sensitivity determined by OGTT or the clamp (HOMA-β, II, OGTT AUCIRI/AUCPG, HOMA-IR, composite index, QUICKI and ISI). However, UGE was correlated with log-transformed DI (r = -0.338, p = 0.023) as was eGFR (r = 0.418, p = 0.004). Multivariate analysis revealed that eGFR and log-transformed DI were independent predictors of UGE (R2 = 0.267, β = 0.332, p = 0.045, and β = -0.315, p = 0.031, respectively). Conclusion: Even in euglycemic conditions, SGLT2i-induced UGE considerably varied by individuals and was correlated with DI, which represents individual capacity of glucose disposal. The present results thus suggest that SGLT2i-induced UGE is regulated by an unidentified physiological process that is related to glucose tolerance in living body. Disclosure K. Sakaguchi: Other Relationship; Self; AstraZeneca, Novartis AG, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. A. So: None. J. Ito: None. A. Kaneko: None. Y. Morita: None. T. Yamada: None. H. Miura: None. N. Otowa-Suematsu: None. T. Nakamura: None. H. Komada: None. Y. Okada: None. Y. Hirota: Other Relationship; Self; Sanofi. Y. Tamori: None. W. Ogawa: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharma GmbH & Co.KG, Eli Lilly Japan K.K., Kowa Company, Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. Other Relationship; Self; Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited.
    Materialart: Online-Ressource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db20-1097-P
    Sprache: Englisch
    Verlag: American Diabetes Association
    Publikationsdatum: 2020
    ZDB Id: 1501252-9
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
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