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  • 1
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    Online Resource
    Improvement in Insulin Sensitivity After Human Islet Transplantation for Type 1 Diabetes
    The Endocrine Society ; 2013
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 98, No. 11 ( 2013-11-01), p. E1780-E1785
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 98, No. 11 ( 2013-11-01), p. E1780-E1785
    Abstract: Islet transplantation can improve metabolic control for type 1 diabetes (T1D), an effect anticipated to improve insulin sensitivity. However, current immunosuppression regimens containing tacrolimus and sirolimus have been shown to induce insulin resistance in rodents. Objective: The objective of the study was to evaluate the effect of islet transplantation on insulin sensitivity in T1D using euglycemic clamps with the isotopic dilution method to distinguish between effects at the liver and skeletal muscle. Design, Setting, and Participants: Twelve T1D subjects underwent evaluation in the Clinical and Translational Research Center before and between 6 and 7 months after the transplant and were compared with normal control subjects. Intervention: The intervention included intrahepatic islet transplantation according to a Clinical Islet Transplantation Consortium protocol under low-dose tacrolimus and sirolimus immunosuppression. Main Outcome Measures: Total body (M/Δinsulin), hepatic (1/endogenous glucose production ·basal insulin) and peripheral [(Rd − endogenous glucose production)/Δinsulin] insulin sensitivity assessed by hyperinsulinemic (1 mU·kg−1·min−1) euglycemic (∼90 mg/dL) clamps with 6,6-2H2-glucose tracer infusion were measured. Results: Glycosylated hemoglobin was reduced in the transplant recipients from 7.0% ± 0.3% to 5.6% ± 0.1% (P & lt; .01). There were increases in total (0.11 ± 0.01 to 0.15 ± 0.02 dL/min·kg per microunit per milliliter), hepatic [2.3 ± 0.1 to 3.7 ± 0.4 × 102 ([milligrams per kilogram per minute]−1·(microunits per milliliter)−1)] , and peripheral (0.08 ± 0.01 to 0.12 ± 0.02 dL/min·kg per microunit per milliliter) insulin sensitivity from before to after transplantation (P & lt; .05 for all). All insulin sensitivity measures were less than normal in T1D before (P ≤ .05) and not different from normal after transplantation. Conclusions: Islet transplantation results in improved insulin sensitivity mediated by effects at both the liver and skeletal muscle. Modern dosing of glucocorticoid-free immunosuppression with low-dose tacrolimus and sirolimus does not induce insulin resistance in this population.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jc.2013-1764
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2013
    detail.hit.zdb_id: 2026217-6
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  • 2
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    Long-Term Improvement in Glucose Control and Counterregulation by Islet Transplantation for Type 1 Diabetes
    The Endocrine Society ; 2016
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 101, No. 11 ( 2016-11-01), p. 4421-4430
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 101, No. 11 ( 2016-11-01), p. 4421-4430
    Abstract: Islet transplantation has been shown to improve glucose counterregulation and hypoglycemia symptom recognition in patients with type 1 diabetes (T1D) complicated by severe hypoglycemia episodes and symptom unawareness, but long-term data are lacking. Objective: To assess the long-term durability of glucose counterregulation and hypoglycemia symptom responses 18 months after intrahepatic islet transplantation and associated measures of glycemic control during a 24-month follow-up period. Design, Setting, and Participants: Ten patients with T1D disease duration of approximately 27 years were studied longitudinally before and 6 and 18 months after transplant in the Clinical & Translational Research Center of the University of Pennsylvania and were compared to 10 nondiabetic control subjects. Intervention: All 10 patients underwent intrahepatic islet transplantation according to the CIT07 protocol at the Hospital of the University of Pennsylvania. Main Outcome Measures: Counterregulatory hormone, endogenous glucose production, and autonomic symptom responses derived from stepped hyperinsulinemic-hypoglycemic and paired hyperinsulinemic-euglycemic clamps with infusion of 6,6-2H2-glucose. Results: Near-normal glycemia (HbA1c ≤ 6.5%; time 70–180 mg/dL ≥ 95%) was maintained for 24 months in all patients, with one returning to low-dose insulin therapy. In response to insulin-induced hypoglycemia, glucagon secretion was incompletely restored at 6 and 18 months, epinephrine was improved at 6 months and normalized at 18 months, and endogenous glucose production and symptoms, absent before, were normalized at 6 and 18 months after transplant. Conclusions: In patients with T1D experiencing problematic hypoglycemia, intrahepatic islet transplantation can lead to long-term improvement of glucose counterregulation and hypoglycemia symptom recognition, physiological effects that likely contribute to glycemic stability after transplant.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jc.2016-1649
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2016
    detail.hit.zdb_id: 2026217-6
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  • 3
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    Evidence for Allograft Rejection in an Islet Transplant Recipient and Effect on β-Cell Secretory Capacity
    The Endocrine Society ; 2007
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 7 ( 2007-07-01), p. 2410-2414
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 92, No. 7 ( 2007-07-01), p. 2410-2414
    Abstract: Context: The majority of islet transplant recipients experience a gradual decline in islet graft function, but the identification of islet-specific immune responses remains uncommon. Objectives: The aim was to present a case in which decline in islet graft function was accompanied by the appearance of islet donor-specific alloantibodies and demonstrate the effect on β-cell secretory capacity, an estimate of functional β-cell mass. Setting: The study was conducted at the Transplant Center and General Clinical Research Center of the University of Pennsylvania. Results: A 42-yr-old woman with type 1 diabetes who had a living-related kidney transplant received two intraportal islet infusions of a total 17,525 islet equivalents per kg body weight under daclizumab, prednisone, tacrolimus, and rapamycin immunosuppression. She became insulin independent, but 4 months later, the rapamycin was discontinued for associated colitis. She remained normoglycemic for another 6 months before manifesting impaired fasting glucose and requiring 5–10 U insulin daily. The decline in clinical islet graft function coincided with the detection of islet donor-specific human leukocyte antigen class I antibodies. β-Cell function and secretory capacity were assessed by the insulin secretory responses to iv glucose, arginine (AIRarg), and glucose-potentiated arginine (AIRpot) before and at alloantibody detection. The acute insulin response to glucose was almost entirely lost, whereas the AIRarg and AIRpot both decreased by approximately 50%. Conclusions: Because the AIRpot, a measure of β-cell secretory capacity, provides an estimate of functional β-cell mass, this case documents that islet graft loss can coincide with donor human leukocyte antigen sensitization and that the effect on β-cell mass may be best estimated from the AIRarg or AIRpot.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jc.2007-0172
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2007
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  • 4
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    Online Resource
    Overexpression of Hepatocyte Nuclear Factor-4α Initiates Cell Cycle Entry, but Is not Sufficient to Promote β-Cell Expansion in Human Islets
    The Endocrine Society ; 2012
    In:  Molecular Endocrinology Vol. 26, No. 9 ( 2012-09-01), p. 1590-1602
    Details
    In: Molecular Endocrinology, The Endocrine Society, Vol. 26, No. 9 ( 2012-09-01), p. 1590-1602
    Abstract: The transcription factor HNF4α (hepatocyte nuclear factor-4α) is required for increased β-cell proliferation during metabolic stress in vivo. We hypothesized that HNF4α could induce proliferation of human β-cells. We employed adenoviral-mediated overexpression of an isoform of HNF4α (HNF4α8) alone, or in combination with cyclin-dependent kinase (Cdk)6 and Cyclin D3, in human islets. Heightened HNF4α8 expression led to a 300-fold increase in the number of β-cells in early S-phase. When we overexpressed HNF4α8 together with Cdk6 and Cyclin D3, β-cell cycle entry was increased even further. However, the punctate manner of bromodeoxyuridine incorporation into HNF4αHigh β-cells indicated an uncoupling of the mechanisms that control the concise timing and execution of each cell cycle phase. Indeed, in HNF4α8-induced bromodeoxyuridine+,punctate β-cells we observed signs of dysregulated DNA synthesis, cell cycle arrest, and activation of a double stranded DNA damage-associated cell cycle checkpoint mechanism, leading to the initiation of loss of β-cell lineage fidelity. However, a substantial proportion of β-cells stimulated to enter the cell cycle by Cdk6 and Cyclin D3 alone also exhibited a DNA damage response. HNF4α8 is a mitogenic signal in the human β-cell but is not sufficient for completion of the cell cycle. The DNA damage response is a barrier to efficient β-cell proliferation in vitro, and we suggest its evaluation in all attempts to stimulate β-cell replication as an approach to diabetes treatment.
    Type of Medium: Online Resource
    ISSN: 0888-8809 , 1944-9917
    URL: Article
    DOI: 10.1210/me.2012-1019
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2012
    detail.hit.zdb_id: 1492112-1
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  • 5
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    Online Resource
    β-Cell Secretory Capacity and Demand in Recipients of Islet, Pancreas, and Kidney Transplants
    The Endocrine Society ; 2010
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 95, No. 3 ( 2010-03-01), p. 1238-1246
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 95, No. 3 ( 2010-03-01), p. 1238-1246
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jc.2009-2289
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2010
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  • 6
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    The Effect of Ethnicity in the Rate of Beta-Cell Functional Loss in the First 3 Years After Type 1 Diabetes Diagnosis
    The Endocrine Society ; 2020
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 105, No. 12 ( 2020-12-01), p. e4393-e4406
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 105, No. 12 ( 2020-12-01), p. e4393-e4406
    Abstract: We set forth to compare ethnicities for metabolic and immunological characteristics at the clinical diagnosis of type 1 diabetes (T1D) and assess the effect of ethnicity on beta-cell functional loss within 3 years after clinical diagnosis. Research Methods and Design We studied participants in TrialNet New Onset Intervention Trials (n = 624, median age = 14.4 years, 58% male, 8.7% Hispanic) and followed them prospectively for 3 years. Mixed meal tolerance tests (MMTT) were performed within 6 months following clinical diagnosis and repeated semiannually. Unless otherwise indicated, analyses were adjusted for age, sex, BMI Z-score, and diabetes duration. Results At T1D clinical diagnosis, Hispanics, compared with non-Hispanic whites (NHW), had a higher frequency of diabetic ketoacidosis (DKA) (44.7% vs 25.3%, OR = 2.36, P = 0.01), lower fasting glucose (97 vs 109 mg/dL, P = 0.02) and higher fasting C-peptide (1.23 vs 0.94 ng/mL, P = 0.02) on the first MMTT, and higher frequency of ZnT8 autoantibody positivity (n = 201, 94.1% vs 64%, OR = 7.98, P = 0.05). After exclusion of participants in experimental arms of positive clinical trials, C-peptide area under the curve (AUC) trajectories during the first 3 years after clinical diagnosis were not significantly different between Hispanics and NHW after adjusting for age, sex, BMI-z score, and DKA (n = 413, P = 0.14). Conclusion Despite differences in the metabolic and immunological characteristics at clinical diagnosis of T1D between Hispanics and NHW, C-peptide trajectories did not differ significantly in the first 3 years following clinical diagnosis after adjustment for body mass index and other confounders. These findings may inform the design of observational studies and intervention trials in T1D.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/clinem/dgaa348
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2020
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  • 7
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    Online Resource
    Glycemic Thresholds for Activation of Counterregulatory Hormone and Symptom Responses in Islet Transplant Recipients
    The Endocrine Society ; 2007
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 3 ( 2007-03-01), p. 873-879
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 92, No. 3 ( 2007-03-01), p. 873-879
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jc.2006-2426
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2007
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  • 8
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    Accumulation of Intrahepatic Islet Amyloid in a Nonhuman Primate Transplant Model
    The Endocrine Society ; 2012
    In:  Endocrinology Vol. 153, No. 4 ( 2012-04-01), p. 1673-1683
    Details
    In: Endocrinology, The Endocrine Society, Vol. 153, No. 4 ( 2012-04-01), p. 1673-1683
    Type of Medium: Online Resource
    ISSN: 0013-7227 , 1945-7170
    URL: Article
    DOI: 10.1210/en.2011-1560
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2012
    detail.hit.zdb_id: 2011695-0
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  • 9
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    Research Resource: The Pdx1 Cistrome of Pancreatic Islets
    The Endocrine Society ; 2012
    In:  Molecular Endocrinology Vol. 26, No. 3 ( 2012-03-01), p. 521-533
    Details
    In: Molecular Endocrinology, The Endocrine Society, Vol. 26, No. 3 ( 2012-03-01), p. 521-533
    Abstract: The homeodomain transcription factor pancreas duodenal homeobox 1 (Pdx1, also known as insulin promoter factor 1) is a master regulator of pancreas development, as mice or humans lacking Pdx1 function are a pancreatic. Importantly, heterozygous mutations in Pdx1 cause early and late onset forms of diabetes in humans. Despite these central roles in development and adult β-cell function, we have only rudimentary knowledge of the transcriptome targets of Pdx1 that mediate these phenotypes. Therefore, we performed global location analysis of Pdx1 occupancy in pancreatic islets. We used evolutionary conservation of target genes to identify the most relevant Pdx1 targets by performing chromatin immunoprecipitation sequencing on both human and mouse islets. Remarkably, the conserved target set is highly enriched for genes annotated to function in endocrine system and metabolic disorders, various signaling pathways, and cell survival, providing a molecular explanation for many of the phenotypes resulting from Pdx1 deficiency.
    Type of Medium: Online Resource
    ISSN: 0888-8809 , 1944-9917
    URL: Article
    DOI: 10.1210/me.2011-1231
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2012
    detail.hit.zdb_id: 1492112-1
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  • 10
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    GAD65Abs Are Not Associated With Beta-Cell Dysfunction in Patients With T2D in the GRADE Study
    The Endocrine Society ; 2024
    In:  Journal of the Endocrine Society Vol. 8, No. 3 ( 2024-01-16)
    Details
    In: Journal of the Endocrine Society, The Endocrine Society, Vol. 8, No. 3 ( 2024-01-16)
    Abstract: Autoantibodies directed against the 65-kilodalton isoform of glutamic acid decarboxylase (GAD65Abs) are markers of autoimmune type 1 diabetes (T1D) but are also present in patients with Latent Autoimmune Diabetes of Adults and autoimmune neuromuscular diseases, and also in healthy individuals. Phenotypic differences between these conditions are reflected in epitope-specific GAD65Abs and anti-idiotypic antibodies (anti-Id) against GAD65Abs. We previously reported that 7.8% of T2D patients in the GRADE study have GAD65Abs but found that GAD65Ab positivity was not correlated with beta-cell function, glycated hemoglobin (HbA1c), or fasting glucose levels. Context In this study, we aimed to better characterize islet autoantibodies in this T2D cohort. This is an ancillary study to NCT01794143. Methods We stringently defined GAD65Ab positivity with a competition assay, analyzed GAD65Ab-specific epitopes, and measured GAD65Ab-specific anti-Id in serum. Results Competition assays confirmed that 5.9% of the patients were GAD65Ab positive, but beta-cell function was not associated with GAD65Ab positivity, GAD65Ab epitope specificity or GAD65Ab-specific anti-Id. GAD65-related autoantibody responses in GRADE T2D patients resemble profiles in healthy individuals (low GAD65Ab titers, presence of a single autoantibody, lack of a distinct epitope pattern, and presence of anti-Id to diabetes-associated GAD65Ab). In this T2D cohort, GAD65Ab positivity is likely unrelated to the pathogenesis of beta-cell dysfunction. Conclusion Evidence for islet autoimmunity in the pathophysiology of T2D beta-cell dysfunction is growing, but T1D-associated autoantibodies may not accurately reflect the nature of their autoimmune process.
    Type of Medium: Online Resource
    ISSN: 2472-1972
    URL: Article
    DOI: 10.1210/jendso/bvad179
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2024
    detail.hit.zdb_id: 2881023-5
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