المؤلفون: Anneliese J. Flatt, Elizabeth Chen, Amy J. Peleckis, Cornelia Dalton-Bakes, Huong-Lan Nguyen, Heather W. Collins, John S. Millar, Robert J. Gallop, Michael R. Rickels

المصدر: Diabetes technologytherapeutics. 24(10)

مصطلحات موضوعية: Adult, Blood Glucose, Endocrinology, Diabetes and Metabolism, Blood Glucose Self-Monitoring, Insulins, Middle Aged, Hypoglycemia, Medical Laboratory Technology, Benchmarking, Endocrinology, Diabetes Mellitus, Type 1, Glucose, Humans, Hypoglycemic Agents, Insulin

الوصف: Repeated hypoglycemia exposure leads to impaired awareness of hypoglycemia (IAH) and the development of defective counterregulatory responses. To date, only pancreas or islet transplantation has demonstrated normalization of hypoglycemia awareness and the endogenous glucose production (EGP) response to defend against insulin-induced hypoglycemia in long-standing type 1 diabetes (T1D). This study aims to validate clinical metrics of IAH (Clarke score), hypoglycemia severity (HYPO score), glycemic lability (lability index), and continuous glucose monitoring (CGM) as predictors of absent autonomic symptom (AS) recognition and defective glucose counterregulation during insulin-induced hypoglycemia, thus enabling early identification of individuals with compromised physiologic defense against clinically significant hypoglycemia. Forty-three subjects with mean ± standard deviation age 43 ± 13 years and T1D duration 28 ± 13 years, including 32 with IAH and 11 with hypoglycemia awareness (Aware), and 12 nondiabetic control subjects, underwent single-blinded randomized-paired hyperinsulinemic-euglycemic and hypoglycemic clamp experiments. Receiver operating characteristic (ROC) curves and sensitivity analyses were performed to assess metric prediction of absent AS recognition and defective EGP responses to hypoglycemia. Clarke score and CGM measures of hypoglycemia exposure demonstrated good ability to predict absent AS recognition (area under the curve ≥0.80). A composite threshold of IAH-Clarke ≥4 with ROC curve-derived thresholds for CGM measures of hypoglycemia exposure showed high specificity and predictive value in identifying an absent AS response during the hypoglycemic clamp. Metrics demonstrated poor ability to predict defective glucose counterregulation by the EGP response, which was impaired even in the Aware group. Screening for IAH alongside assessment of CGM data can increase the specificity for identifying individuals with absent hypoglycemia symptom recognition who may benefit from further intervention.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a74ce8740a634326c425c5b5ef39de38Test
https://pubmed.ncbi.nlm.nih.gov/35758724Test

المؤلفون: Huong-Lan T. Nguyen, Cornelia Dalton-Bakes, Amy J. Peleckis, Ali Naji, Melena D. Bellin, Eileen Markmann, Michael R. Rickels, Darko Stefanovski

المصدر: Diabetes. 69

مصطلحات موضوعية: Type 1 diabetes, medicine.medical_specialty, business.industry, Endocrinology, Diabetes and Metabolism, Insulin, medicine.medical_treatment, Glucagon secretion, Adrenergic, Propranolol, Hypoglycemia, medicine.disease, Transplantation, Endocrinology, Phentolamine, Internal medicine, Internal Medicine, medicine, business, medicine.drug

الوصف: Recipients of intrahepatic islet transplantation for T1D exhibit appropriate suppression of endogenous insulin and activation of glucagon secretion in response to insulin-induced hypoglycemia with restored glucose counterregulation and protection against clinically significant hypoglycemia. Whether sympathetic activation of adrenergic receptors on transplanted islets is required for these responses is not known. To evaluate the adrenergic contribution to post-transplant glucose counterregulation, we performed a randomized, double-blind crossover study of responses during a hyperinsulinemic (1 mU·kg-1·min-1) euglycemic (EU, ∼90 mg/dL)-hypoglycemic (HYPO, ∼50 mg/dL) clamp conducted under phentolamine (0.95 µg·kg-1·min-1; α-adrenergic blockage), propranolol (0.48 µg·kg-1·min-1; β-adrenergic blockage), or placebo infusion. Subjects were 5F/4M with median (range) age 53 (34 - 63) years, T1D duration 29 (18 - 56) years, post-transplant 7 (2 - 8) years, HbA1c 5.8 (4.5 - 6.8) %, insulin in-/dependent 5/4, on tacrolimus-based immunosuppression, and spent 97 (76 - 99) % time in range 70 - 180 mg/dL and 1 (0 - 3) % time with hypoglycemia < 70 mg/dL by CGM. During the EU-HYPO clamp, blood pressure was lower with phentolamine and heart rate lower with propranolol vs. placebo (P < 0.05). There was no difference in suppression of C-peptide or activation of glucagon with phentolamine or propranolol vs. placebo. Pancreatic polypeptide was greater with phentolamine vs. placebo during EU (P < 0.05), and free fatty acids were lower and the glucose infusion rate higher with propranolol vs. placebo during HYPO (P < 0.05) with no differences seen for endogenous glucose production. These results indicate physiologic α- and β-adrenergic blockage had no effect on transplanted islet responses to hypoglycemia. Sympathetic re-innervation, as occurs with re-vascularization of intrahepatic islets, may not be necessary for post-transplant recovery of glucose counterregulation in T1D. Disclosure M.R. Rickels: Consultant; Self; Semma Therapeutics, Inc. Research Support; Self; Xeris Pharmaceuticals, Inc. M. Bellin: Research Support; Self; Dexcom, Inc., Viacyte, Inc. Other Relationship; Self; Insulet Corporation. D. Stefanovski: None. A.J. Peleckis: None. C.V. Dalton-Bakes: None. E. Markmann: None. H.T. Nguyen: None. A. Naji: None. Funding National Institutes of Health (R01DK091331, UL1TR001878, P30DK19525)

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::68ff909803ec1ad3782cd58cdeff4330Test
https://doi.org/10.2337/db20-359-orTest

المؤلفون: Muredach P. Reilly, Cornelia Dalton-Bakes, Carissa Fuller, Michael R. Rickels, Karen L. Teff, Ali Naji, Jane F. Ferguson, Stephanie M. Kong

المصدر: The Journal of Clinical Endocrinology & Metabolism. 98:E1780-E1785

مصطلحات موضوعية: Adult, Graft Rejection, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Clinical Biochemistry, Islets of Langerhans Transplantation, Biochemistry, Tacrolimus, Endocrinology, Insulin resistance, Diabetes mellitus, Internal medicine, medicine, Humans, Insulin, Muscle, Skeletal, Glycated Hemoglobin, Sirolimus, Type 1 diabetes, geography, geography.geographical_feature_category, business.industry, Biochemistry (medical), Immunosuppression, JCEM Online: Brief Reports, Middle Aged, Glucose clamp technique, medicine.disease, Islet, Transplantation, Diabetes Mellitus, Type 1, Liver, Glucose Clamp Technique, Female, Insulin Resistance, business, Immunosuppressive Agents

الوصف: Context: 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 < .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 < .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.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::dd998c73a135079132c77745ea6d8e06Test
https://doi.org/10.1210/jc.2013-1764Test

المؤلفون: Malek Kamoun, Ali Naji, Cornelia Dalton-Bakes, Maral Palangian, Kumar Vivek, Zaw Min, Eline T. Luning Prak, Eileen Markmann, Michael R. Rickels, Chengyang Liu, Clyde F. Barker, Carissa Fuller, Scott A. Soleimanpour, Richard D. Shlansky-Goldberg, Allen J. Chiou

المصدر: Diabetes

مصطلحات موضوعية: Adult, Male, medicine.medical_specialty, Edmonton protocol, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Islets of Langerhans Transplantation, Urology, 030209 endocrinology & metabolism, 030230 surgery, Tacrolimus, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Insulin-Secreting Cells, Internal medicine, Diabetes mellitus, Insulin Secretion, Internal Medicine, medicine, Humans, Hypoglycemic Agents, Insulin, Original Research, Sirolimus, geography, geography.geographical_feature_category, C-Peptide, C-peptide, business.industry, Immunosuppression, Middle Aged, Islet, medicine.disease, 3. Good health, Transplantation, Diabetes Mellitus, Type 1, Treatment Outcome, Endocrinology, chemistry, Female, Immunology and Transplantation, business, Immunosuppressive Agents, medicine.drug

الوصف: The Clinical Islet Transplantation 07 (CIT07) protocol uses antithymocyte globulin and etanercept induction, islet culture, heparinization, and intensive insulin therapy with the same low-dose tacrolimus and sirolimus maintenance immunosuppression as in the Edmonton protocol. To determine whether CIT07 improves engrafted islet β-cell mass, our center measured β-cell secretory capacity from glucose-potentiated arginine tests at days 75 and 365 after transplantation and compared those results with the results previously achieved by our group using the Edmonton protocol and normal subjects. All subjects were insulin free, with CIT07 subjects receiving fewer islet equivalents from a median of one donor compared with two donors for Edmonton protocol subjects. The acute insulin response to glucose-potentiated arginine (AIRpot) was greater in the CIT07 protocol than in the Edmonton protocol and was less in both cohorts than in normal subjects, with similar findings for C-peptide. The CIT07 subjects who completed reassessment at day 365 exhibited increasing AIRpot by trend relative to that of day 75. These data indicate that engrafted islet β-cell mass is markedly improved with the CIT07 protocol, especially given more frequent use of single islet donors. Although several peritransplant differences may have each contributed to this improvement, the lack of deterioration in β-cell secretory capacity over time in the CIT07 protocol suggests that low-dose tacrolimus and sirolimus are not toxic to islets.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f158e425a50f360420bdffa1c90b5fd9Test
https://doi.org/10.2337/db12-1802Test

المؤلفون: Michael R. Rickels, Cornelia Dalton-Bakes, Ali Naji, Jane F. Ferguson, Muredach P. Reilly, Stephanie M. Kong, Carissa Fuller, Karen L. Teff

المصدر: American journal of physiology. Endocrinology and metabolism. 306(10)

مصطلحات موضوعية: Adult, Blood Glucose, Male, medicine.medical_specialty, endocrine system diseases, Physiology, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Islets of Langerhans Transplantation, Biology, Models, Biological, Insulin resistance, Physiology (medical), Internal medicine, medicine, Humans, Insulin, Type 1 diabetes, geography, Glucose tolerance test, geography.geographical_feature_category, medicine.diagnostic_test, Articles, Glucose clamp technique, Glucose Tolerance Test, Middle Aged, medicine.disease, Islet, Transplantation, Endocrinology, Diabetes Mellitus, Type 1, Metabolic control analysis, Glucose Clamp Technique, Female, Insulin Resistance

الوصف: Insulin sensitivity is impaired in type 1 diabetes (T1D) and may be enhanced by islet transplantation, an effect best explained by improved metabolic control. While the minimal model index of insulin sensitivity, SI, has been used in studies of T1D, it has not before been evaluated against gold-standard measures derived from the euglycemic clamp. We sought to determine how well minimal model SI derived from an insulin-modified frequently sampled intravenous glucose tolerance (FSIGT) test compared with total body and peripheral insulin sensitivity estimates derived from the hyperinsulinemic-euglycemic clamp in subjects with T1D and following islet transplantation. Twenty-one T1D subjects were evaluated, including a subgroup ( n = 12) studied again after intrahepatic islet transplantation, with results compared with normal controls ( n = 11 for the FSIGT). The transplant recipients received 9,648 ± 666 islet equivalents/kg with reduction in HbA1c from 7.1 ± 0.2 to 5.5 ± 0.1% ( P < 0.01) and 10/12 were insulin independent. FSIGT-derived SI was reduced in T1D pre- compared with posttransplant and with normal [1.76 ± 0.45 vs. 4.21 ± 0.34 vs. 4.45 ± 0.81 × 10−4(μU/ml)−1·min−1; P < 0.01 for both]. Similarly, clamp-derived total body, and by the isotopic dilution method with [6,6-2H2]glucose, peripheral insulin sensitivity increased in T1D from pre- to posttransplant ( P < 0.05 for both). The predictive power ( r2) between volume-corrected SIC and measures of total and peripheral insulin sensitivity was 0.66 and 0.70, respectively ( P < 0.00001 for both). That the minimal model SIC is highly correlated to the clamp-derived measures indicates that the FSIGT is an appropriate methodology for the determination of insulin sensitivity in T1D and following islet transplantation.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e94f39c63b193d661c4186209048c6e5Test
https://pubmed.ncbi.nlm.nih.gov/24691031Test