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  • 1
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    Long-term Outcomes With Islet-Alone and Islet-After-Kidney Transplantation for Type 1 Diabetes in the Clinical Islet Transplantation Consortium: The CIT-08 Study
    American Diabetes Association ; 2022
    In:  Diabetes Care Vol. 45, No. 12 ( 2022-12-01), p. 2967-2975
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 45, No. 12 ( 2022-12-01), p. 2967-2975
    Abstract: To determine long-term outcomes for islet-alone and islet-after-kidney transplantation in adults with type 1 diabetes complicated by impaired awareness of hypoglycemia. RESEARCH DESIGN AND METHODS This was a prospective interventional and observational cohort study of islet-alone (n = 48) and islet-after-kidney (n = 24) transplant recipients followed for up to 8 years after intraportal infusion of one or more purified human pancreatic islet products under standardized immunosuppression. Outcomes included duration of islet graft survival (stimulated C-peptide ≥0.3 ng/mL), on-target glycemic control (HbA1c & lt;7.0%), freedom from severe hypoglycemia, and insulin independence. RESULTS Of the 48 islet-alone and 24 islet-after-kidney transplantation recipients, 26 and 8 completed long-term follow-up with islet graft function, 15 and 7 withdrew from follow-up with islet graft function, and 7 and 9 experienced islet graft failure, respectively. Actuarial islet graft survival at median and final follow-up was 84% and 56% for islet-alone and 69% and 49% for islet-after-kidney (P = 0.007) with 77% and 49% of islet-alone and 57% and 35% of islet-after-kidney transplantation recipients maintaining posttransplant HbA1c & lt;7.0% (P = 0.0017); freedom from severe hypoglycemia was maintained at & gt;90% in both cohorts. Insulin independence was achieved by 74% of islet-alone and islet-after-kidney transplantation recipients, with more than one-half maintaining insulin independence during long-term follow-up. Kidney function remained stable during long-term follow-up in both cohorts, and rates of sensitization against HLA were low. Severe adverse events occurred at 0.31 per patient-year for islet-alone and 0.43 per patient-year for islet-after-kidney transplantation. CONCLUSIONS Islet transplantation results in durable islet graft survival permitting achievement of glycemic targets in the absence of severe hypoglycemia for most appropriately indicated recipients having impaired awareness of hypoglycemia, with acceptable safety of added immunosuppression for both islet-alone and islet-after-kidney transplantation.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc21-2688
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2022
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  • 2
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    Biopsychobehavioral model of severe hypoglycemia. II. Understanding the risk of severe hypoglycemia.
    American Diabetes Association ; 1999
    In:  Diabetes Care Vol. 22, No. 12 ( 1999-12-01), p. 2018-2025
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 22, No. 12 ( 1999-12-01), p. 2018-2025
    Abstract: OBJECTIVE: To evaluate the clinical/research utility of the biopsycho-behavioral model of severe hypoglycemia in differentiating patients with and without a history of severe hypoglycemia and in predicting occurrence of future severe hypoglycemia. RESEARCH DESIGN AND METHODS: A total of 93 adults with type 1 diabetes (mean age 35.8 years, duration of diabetes 16 +/- 10 years, HbA1 8.6 +/- 1.8%), 42 of whom had a recent history of recurrent severe hypoglycemia (SH) and 51 who did not (NoSH), used a handheld computer for 70 trials during 1 month recording cognitive-motor functioning, symptoms, blood glucose (BG) estimates, judgments concerning self-treatment of BG, actual BG readings, and actual treatment of low BG. For the next 6 months, patients recorded occurrence of severe hypoglycemia. RESULTS: SH patients demonstrated significantly more frequent and extreme low BG readings (low BG index), greater cognitive-motor impairments during hypoglycemia, fewer perceived symptoms of hypoglycemia, and poorer detection of hypoglycemia. SH patients were also less likely to treat their hypoglycemia with glucose and more likely to treat with general foods. Low BG index, magnitude of hypoglycemia-impaired ability to do mental subtraction, and awareness of neuroglycopenia, neurogenic symptoms, and hypoglycemia correlated separately with number of SH episodes in the subsequent 6 months. However, only low BG index, hypoglycemia-impaired ability to do mental subtraction, and awareness of hypoglycemia entered into a regression model predicting future severe hypoglycemia (R2 = 0.25, P & lt; 0.001). CONCLUSIONS: Patients with a history of severe hypoglycemia differed on five of the seven steps of the biopsychobehavioral model of severe hypoglycemia. Helping patients with a recent history of severe hypoglycemia to reduce the frequency of their low-BG events, become more sensitive to early signs of neuroglycopenia and neurogenic symptoms, better recognize occurrence of low BG, and use fast-acting glucose more frequently in the treatment of low BG, may reduce occurrence of future severe hypoglycemia.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/diacare.22.12.2018
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 1999
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  • 3
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    Progressive hypoglycemia's impact on driving simulation performance. Occurrence, awareness and correction.
    American Diabetes Association ; 2000
    In:  Diabetes Care Vol. 23, No. 2 ( 2000-02-01), p. 163-170
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 23, No. 2 ( 2000-02-01), p. 163-170
    Abstract: OBJECTIVE: Progressive hypoglycemia leads to cognitive-motor and driving impairments. This study evaluated the blood glucose (BG) levels at which driving was impaired, impairment was detected, and corrective action was taken by subjects, along with the mechanisms underlying these three issues. RESEARCH DESIGN AND METHODS: There were 37 adults with type 1 diabetes who drove a simulator during continuous euglycemia and progressive hypoglycemia. During testing, driving performance, EEG, and corrective behaviors (drinking a soda or discontinuing driving) were continually monitored, and BG, symptom perception, and judgement concerning impairment were assessed every 5 min. Mean +/- SD euglycemia performance was used to quantify z scores for performance in three hypoglycemic ranges (4.0-3.4, 3.3-2.8, and & lt;2.8 mmol/l). RESULTS: During all three hypoglycemic BG ranges, driving was significantly impaired, and subjects were aware of their impaired driving. However, corrective actions did not occur until BG was & lt;2.8 mmol/l. Driving impairment was related to increased neurogenic symptoms and increased theta-wave activity. Awareness of impaired driving was associated with neuroglycopenic symptoms. increased beta-wave activity, and awareness of hypoglycemia. High beta and low theta activity and awareness of both hypoglycemia and the need to treat low BG influenced corrective behavior. CONCLUSIONS: Driving performance is significantly disrupted at relatively mild hypoglycemia, yet subjects demonstrated a hesitation to take corrective action. The longer treatment is delayed, the greater the neuroglycopenia (increased theta), which precludes corrective behaviors. Patients should treat themselves while driving as soon as low BG and/or impaired driving is suspected and should not begin driving when their BG is in the 5.0-4.0 mmol/l range without prophylactic treatment.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/diacare.23.2.163
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2000
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  • 4
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    National Institutes of Health–Sponsored Clinical Islet Transplantation Consortium Phase 3 Trial: Manufacture of a Complex Cellular Product at Eight Processing Facilities
    American Diabetes Association ; 2016
    In:  Diabetes Vol. 65, No. 11 ( 2016-11-01), p. 3418-3428
    Details
    In: Diabetes, American Diabetes Association, Vol. 65, No. 11 ( 2016-11-01), p. 3418-3428
    Abstract: Eight manufacturing facilities participating in the National Institutes of Health–sponsored Clinical Islet Transplantation (CIT) Consortium jointly developed and implemented a harmonized process for the manufacture of allogeneic purified human pancreatic islet (PHPI) product evaluated in a phase 3 trial in subjects with type 1 diabetes. Manufacturing was controlled by a common master production batch record, standard operating procedures that included acceptance criteria for deceased donor organ pancreata and critical raw materials, PHPI product specifications, certificate of analysis, and test methods. The process was compliant with Current Good Manufacturing Practices and Current Good Tissue Practices. This report describes the manufacturing process for 75 PHPI clinical lots and summarizes the results, including lot release. The results demonstrate the feasibility of implementing a harmonized process at multiple facilities for the manufacture of a complex cellular product. The quality systems and regulatory and operational strategies developed by the CIT Consortium yielded product lots that met the prespecified characteristics of safety, purity, potency, and identity and were successfully transplanted into 48 subjects. No adverse events attributable to the product and no cases of primary nonfunction were observed.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db16-0234
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2016
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  • 5
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    Erratum. National Institutes of Health–Sponsored Clinical Islet Transplantation Consortium Phase 3 Trial: Manufacture of a Complex Cellular Product at Eight Processing Facilities. Diabetes 2016;65:3418–3428
    American Diabetes Association ; 2017
    In:  Diabetes Vol. 66, No. 9 ( 2017-09), p. 2531.1-2531
    Details
    In: Diabetes, American Diabetes Association, Vol. 66, No. 9 ( 2017-09), p. 2531.1-2531
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db17-er09a
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2017
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  • 6
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    Higher Rates of Celiac Disease Serology and Biopsy Positivity in Adults with Type 1 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: Background: Celiac Disease (CD) is more common in individuals with type 1 diabetes (T1D) and is frequently asymptomatic. Despite this association, evidence as to the impact and diagnostic accuracy of CD screening is limited in asymptomatic patients with T1D. Objective: To describe CD serology and biopsy positivity rates in T1D patients screened as part of the Celiac Disease and Diabetes Dietary Intervention and Evaluation Trial (CD-DIET). Methods: Prospective data from patients, aged 8-45 years, with T1D screened at 22 sites across Ontario, Canada as part of CD-DIET were analyzed with respect to demographics, clinical symptoms and CD status. Serological and biopsy-confirmed rates of CD were evaluated. Results: Overall, 2585 patients were approached and 2386 patients completed serological testing using tissue transglutaminase antibodies. The sample included 1298 (54.4%) adults, aged 19-45 years, and 1088 (45.6%) pediatric subjects, aged 8-18 years. Mean age was 23.1 ± 10.3 years, 49.2% female, with mean duration of diabetes 12.2 ± 9.0 years. A small number of screened patients (N=45) were symptomatic for CD as per study criteria with clinical GI symptoms (n=39), osteoporosis (n=2), apthous ulcers (n=1), weight loss (n=1), and/or anemia (n=2). Overall, 140 asymptomatic patients were serologically positive for CD. A positive CD serology rate of 7.2% (94/1298) was seen in adults as compared to 4.2% (46/1088) in pediatric subjects (p=0.0064). Endoscopy was completed in 104 patients and CD was subsequently confirmed using duodenal biopsy in 54/71 adults (76.1%) and 28/33 pediatric patients (84.8%), with overall biopsy positivity rates of 4.2% and 2.6% respectively (p=0.034). Conclusions: Significant differences were observed in CD serology and biopsy positivity, with higher rates seen in adults as compared with children with T1D, which may be due to increasing risk of autoimmune co-morbidities with age as well as many adults being naïve to celiac disease screening. Disclosure F.H. Mahmud: None. A.B. Clarke: None. K.C. Joachim: None. E. Assor: None. A. Parikh: None. A. Advani: Research Support; Self; AstraZeneca, Boehringer Ingelheim GmbH. Other Relationship; Self; Boehringer Ingelheim GmbH. B.A. Perkins: Advisory Panel; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH, Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc., Abbott. Speaker's Bureau; Self; Abbott, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Insulet Corporation. Speaker's Bureau; Self; Insulet Corporation, Dexcom, Inc.. B.R. Shah: None. C.S. Zuijdwijk: None. C. McDonald: None. D. Mack: None. D. Koltin: None. E. Hsieh: None. E.M. Szentgyorgyi: None. F. Saibil: None. G. Mukerji: None. H.A. Lochnan: Research Support; Self; Amylin Pharmaceuticals, Boston Therapeutics, Inc., Sanofi. J. Gilbert: Other Relationship; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Sanofi. K. Bax: None. M.L. Lawson: None. M.D. Beaton: Advisory Panel; Self; Takeda Canada Inc., Janssen Pharmaceuticals, Inc., AbbVie Inc.. N.A. Saloojee: None. O. Lou: None. P.H. Gallego: None. R.L. Houlden: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc., AstraZeneca, Eli Lilly and Company. R. Aronson: Other Relationship; Self; Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Sanofi, AstraZeneca. Research Support; Self; Eli Lilly and Company, Becton, Dickinson and Company, Merck & Co., Inc., Senseonics, Boehringer Ingelheim Pharmaceuticals, Inc.. S.E. Kirsch: None. W.G. Paterson: None. Z. Punthakee: Research Support; Self; Amgen, Astra Zeneca/Bristol Myers Squibb, Lexicon, Merck, NovoNordisk, Sanofi. Speaker's Bureau; Self; Abbott, Astra Zeneca/Bristol Myers Squibb, Boehringer Ingelheim/Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Sanofi. Advisory Panel; Self; Astra Zeneca/Bristol Myers Squibb, Boehringer Ingelheim/Eli Lilly, Dexcom, Janssen, Medtronic, NovoNordisk, Pfizer, Sanofi. M.A. Marcon: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-1550-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 7
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    Improved Health-Related Quality of Life in a Phase 3 Islet Transplantation Trial in Type 1 Diabetes Complicated by Severe Hypoglycemia
    American Diabetes Association ; 2018
    In:  Diabetes Care Vol. 41, No. 5 ( 2018-05-01), p. 1001-1008
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 41, No. 5 ( 2018-05-01), p. 1001-1008
    Abstract: Attaining glycemic targets without severe hypoglycemic events (SHEs) is a challenging treatment goal for patients with type 1 diabetes complicated by impaired awareness of hypoglycemia (IAH). The CIT Consortium Protocol 07 (CIT-07) trial showed islet transplantation to be an effective treatment for subjects with IAH and intractable SHEs. We evaluated health-related quality of life (HRQOL), functional health status, and health utility before and after pancreatic islet transplantation in CIT-07 trial participants. RESEARCH DESIGN AND METHODS Four surveys, the Diabetes Distress Scale (DDS), the Hypoglycemic Fear Survey (HFS), the Short Form 36 Health Survey (SF-36), and the EuroQoL 5 Dimensions (EQ-5D), were administered repeatedly before and after islet transplantation. Summary statistics and longitudinal modeling were used to describe changes in survey scores from baseline and to characterize change in relation to a minimally important difference (MID) threshold of half an SD. RESULTS Improvements in condition-specific HRQOL met the MID threshold. Reductions from baseline in the DDS total score and its four DDS subscales (all P ≤ 0.0013) and in the HFS total score and its two subscales (all P & lt; 0.0001) were observed across all time points. Improvements were observed after both 1 and 2 years for the EQ-5D visual analog scale (both P & lt; 0.0001). CONCLUSIONS In CIT-07, 87.5% of the subjects achieved the primary end point of freedom from SHE along with glycemic control (HbA1c & lt;7% [ & lt;53 mmol/mol]) at 1 year post–initial islet transplantation. The same subjects reported consistent, statistically significant, and clinically meaningful improvements in condition-specific HRQOL as well as self-assessments of overall health.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc17-1779
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 8
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    Biopsychobehavioral model of risk of severe hypoglycemia. Self-management behaviors.
    American Diabetes Association ; 1999
    In:  Diabetes Care Vol. 22, No. 4 ( 1999-04-01), p. 580-584
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 22, No. 4 ( 1999-04-01), p. 580-584
    Abstract: OBJECTIVE: To identify self-management antecedents of low blood glucose (BG) ( & lt; 3.9 mmol/l) that might be easily recognized, treated, or avoided altogether. RESEARCH DESIGN AND METHODS: Ninety-three adults with type 1 diabetes (age, 35.8 +/- 8 years [mean +/- SD]; duration of diabetes, 17.0 +/- 11 years; daily insulin dose, 0.58 +/- 0.18 U/kg; and HbAlc, 8.6 +/- 1.8%) were recruited to participate in the study. Of the 93 subjects, 42 had a history of severe hypoglycemia (SH), defined as two or more hypoglycemic episodes in the preceding 12 months, and 51 subjects had no history of SH (No-SH) in the same time period. Before each of 70 BG measurements obtained over a 3-week period, subjects used a handheld computer to record whether their most recent insulin, food, and exercise was more than, less than, or the same as usual. Associations among self-management behaviors preceding BG readings & lt; 3.9 mmol/l versus those preceding BG readings of 5.6-7.8 mmol/l were determined using chi 2 tests, analyses of variance, and logistic regression analyses. RESULTS: Analysis of 6,425 self-management/self-monitoring of BG events revealed that the usual amounts of insulin, food, and exercise preceded the events 58.3% of the time. No significant differences were observed for changes in insulin before readings of BG & lt; 3.9 mmol/l versus 7.8 & lt; BG & gt; 5.6 mmol/l, but significantly less food (P & lt; 0.01) was eaten and more exercise (P & lt; 0.001) was performed before the low BG measurement. No interactions between SH and No-SH groups and management behaviors were observed. However, each of the three management variables entered significantly in a logistic model that predicted 61% of all readings of BG & lt; 3.9 mmol/l. CONCLUSIONS: Subjects with a history of SH did not report managing their diabetes differently from those with no such history. Specifically, when low BG occurred, the preceding management behaviors, although predictive of low BG, were not different in SH and No-SH subjects. Overall, self-management behaviors did not distinguish SH from No-SH subjects. Thus, even though it might be beneficial for all patients to review their food and exercise management decisions to reduce their frequency of low BG, an educational intervention whose content stresses insulin, food, and exercise would be unlikely by itself to be sufficient to reduce the frequency of SH.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/diacare.22.4.580
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 1999
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  • 9
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    Diagnostic Accuracy of Serologic Screening Tests for Celiac Disease in Asymptomatic Adults and Children with Type 1 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: Background: As related autoimmune conditions, celiac disease (CD) is more common in individuals with type 1 diabetes (T1D) and is frequently asymptomatic. Despite this association, evidence as to the diagnostic accuracy of screening as well as the potential benefits or harms of screening for CD is limited in asymptomatic patients with T1D. Methods: T1D patients, aged 8-45 years, were serologically screened for CD at multiple centers across Ontario, Canada as part of the Celiac Disease and Diabetes Dietary Intervention and Evaluation Trial (CD-DIET). Patients were deemed asymptomatic on the basis of the absence of GI symptoms, weight changes, anemia and other CD-related clinical features. Screening was conducted in 2,386 patients using chemiluminescent (CL, BioFlash™) and/or ELISA (Celikey™) tissue transglutaminase (TTG) IgA assays, yielding 140 positives. Of these, 104 patients had a duodenal biopsy with CD confirmation (Marsh ≥2). Receiver operating characteristic (ROC) curve analysis was conducted and positive predictive values (PPV) of available screening tests for CD were evaluated. Results: CL and ELISA data were available for 100/104 and 36/104 patients, respectively. The area under the curve of the ROC for CL TTG was 0.918, while the PPV using the manufacturer referenced upper limit (RUL) of 30 CU was 85.9% (95% CI: 82.3-90.8%). According to our data, an optimal cut-off of 156.5 CU, or 5.2 times the RUL, showed an improved PPV of 95.8% (95% CI: 92.4-100.0%). With respect to ELISA TTG, the PPV was 94.4% at the RUL of 8 U/ml and reached to 100% at the optimal cut-off determined by our analysis of 58.7 U/ml, which translates to 7.3 times the RUL. Conclusion: Results from serologic CL and ELISA TTG assays that were greater than 5 times the reported upper limit showed a high PPV for biopsy-confirmed CD in asymptomatic adult and pediatric T1D patients, which may help guide diagnostic evaluation in this population. Disclosure M. Gould: None. F.H. Mahmud: None. A.B. Clarke: None. E. Assor: None. A. Parikh: None. A. Advani: Research Support; Self; AstraZeneca, Boehringer Ingelheim GmbH. Other Relationship; Self; Boehringer Ingelheim GmbH. B.A. Perkins: Advisory Panel; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH, Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc., Abbott. Speaker's Bureau; Self; Abbott, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Insulet Corporation. Speaker's Bureau; Self; Insulet Corporation, Dexcom, Inc.. B.R. Shah: None. C.S. Zuijdwijk: None. C. McDonald: None. D. Mack: None. D. Koltin: None. E. Hsieh: None. E.M. Szentgyorgyi: None. F. Saibil: None. G. Mukerji: None. H.A. Lochnan: Research Support; Self; Amylin Pharmaceuticals, Boston Therapeutics, Inc., Sanofi. J. Gilbert: Other Relationship; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Sanofi. K. Bax: None. M.L. Lawson: None. M.D. Beaton: Advisory Panel; Self; Takeda Canada Inc., Janssen Pharmaceuticals, Inc., AbbVie Inc.. N.A. Saloojee: None. O. Lou: None. P.H. Gallego: None. R.L. Houlden: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc., AstraZeneca, Eli Lilly and Company. R. Aronson: Other Relationship; Self; Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Sanofi, AstraZeneca. Research Support; Self; Eli Lilly and Company, Becton, Dickinson and Company, Merck & Co., Inc., Senseonics, Boehringer Ingelheim Pharmaceuticals, Inc.. S.E. Kirsch: None. W.G. Paterson: None. Z. Punthakee: Research Support; Self; Amgen, Astra Zeneca/Bristol Myers Squibb, Lexicon, Merck, NovoNordisk, Sanofi. Speaker's Bureau; Self; Abbott, Astra Zeneca/Bristol Myers Squibb, Boehringer Ingelheim/Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Sanofi. Advisory Panel; Self; Astra Zeneca/Bristol Myers Squibb, Boehringer Ingelheim/Eli Lilly, Dexcom, Janssen, Medtronic, NovoNordisk, Pfizer, Sanofi. M.A. Marcon: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-1579-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 10
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    Impaired insulin secretion and increased insulin sensitivity in familial maturity-onset diabetes of the young 4 (insulin promoter factor 1 gene).
    American Diabetes Association ; 2000
    In:  Diabetes Vol. 49, No. 11 ( 2000-11-01), p. 1856-1864
    Details
    In: Diabetes, American Diabetes Association, Vol. 49, No. 11 ( 2000-11-01), p. 1856-1864
    Abstract: Diabetes resulting from heterozygosity for an inactivating mutation of the homeodomain transcription factor insulin promoter factor 1 (IPF-1) is due to a genetic defect of beta-cell function referred to as maturity-onset diabetes of the young 4. IPF-1 is required for the development of the pancreas and mediates glucose-responsive stimulation of insulin gene transcription. To quantitate islet cell responses in a family harboring a Pro63fsdelC mutation in IPF-1, we performed a five-step (1-h intervals) hyperglycemic clamp on seven heterozygous members (NM) and eight normal genotype members (NN). During the last 30 min of the fifth glucose step, glucagon-like peptide 1 (GLP-1) was also infused (1.5 pmol x kg(-1) x min(-1)). Fasting plasma glucose levels were greater in the NM group than in the NN group (9.2 vs. 5.9 mmol/l, respectively; P & lt; 0.05). Fasting insulin levels were similar in both groups (72 vs. 105 pmol/l for NN vs. NM, respectively). First-phase insulin and C-peptide responses were absent in individuals in the NM group, who had markedly attenuated insulin responses to glucose alone compared with the NN group. At a glucose level of 16.8 mmol/l above fasting level, GLP-1 augmented insulin secretion equivalently (fold increase) in both groups, but the insulin and C-peptide responses to GLP-1 were sevenfold less in the NM subjects than in the NN subjects. In both groups, glucagon levels fell during each glycemic plateau, and a further reduction occurred during the GLP-1 infusion. Sigmoidal dose-response curves of glucose clearance versus insulin levels during the hyperglycemic clamp in the two small groups showed both a left shift and a lower maximal response in the NM group compared with the NN group, which is consistent with an increased insulin sensitivity in the NM subjects. A sharp decline occurred in the dose-response curve for suppression of nonesterified fatty acids versus insulin levels in the NM group. We conclude that the Pro63fsdelC IPF-1 mutation is associated with a severe impairment of beta-cell sensitivity to glucose and an apparent increase in peripheral tissue sensitivity to insulin and is a genetically determined cause of beta-cell dysfunction.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/diabetes.49.11.1856
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2000
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