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1. Abatacept for Delay of Type 1 Diabetes Progression in Stage 1 Relatives at Risk: A Randomized, Double-Masked, Controlled Trial

Author

Russell, William E, Bundy, Brian N, Anderson, Mark S, Cooney, Laura A, Gitelman, Stephen E, Goland, Robin S, Gottlieb, Peter A, Greenbaum, Carla J, Haller, Michael J, Krischer, Jeffrey P, Libman, Ingrid M, Linsley, Peter S, Long, S Alice, Lord, Sandra M, Moore, Daniel J, Moore, Wayne V, Moran, Antoinette M, Muir, Andrew B, Raskin, Philip, Skyler, Jay S, Wentworth, John M, Wherrett, Diane K, Wilson, Darrell M, Ziegler, Anette-Gabriele, Herold, Kevan C, and Group, Type 1 Diabetes TrialNet Study

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Immunology, Clinical Research, Clinical Trials and Supportive Activities, Diabetes, Nutrition, Prevention, 6.1 Pharmaceuticals, Metabolic and endocrine, Humans, Abatacept, Diabetes Mellitus, Type 1, Immunosuppressive Agents, T-Lymphocytes, Regulatory, Glucose, Type 1 Diabetes TrialNet Study Group, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences, Health sciences
Abstract

ObjectivePrevious studies showed that inhibiting lymphocyte costimulation reduces declining β-cell function in individuals newly diagnosed with type 1 diabetes. We tested whether abatacept would delay or prevent progression of type 1 diabetes from normal glucose tolerance (NGT) to abnormal glucose tolerance (AGT) or to diabetes and the effects of treatment on immune and metabolic responses.Research design and methodsWe conducted a phase 2, randomized, placebo-controlled, double-masked trial of abatacept in antibody-positive participants with NGT who received monthly abatacept/placebo infusions for 12 months. The end point was AGT or diabetes, assessed by oral glucose tolerance tests.ResultsA total of 101 participants received abatacept and 111 placebo. Of these, 81 (35 abatacept and 46 placebo) met the end point of AGT or type 1 diabetes diagnosis (hazard ratio 0.702; 95% CI 0.452, 1.09; P = 0.11) The C-peptide responses to oral glucose tolerance tests were higher in the abatacept arm (P < 0.03). Abatacept reduced the frequency of inducible T-cell costimulatory (ICOS)+ PD1+ T-follicular helper (Tfh) cells during treatment (P < 0.0001), increased naive CD4+ T cells, and also reduced the frequency of CD4+ regulatory T cells (Tregs) from the baseline (P = 0.0067). Twelve months after treatment, the frequency of ICOS+ Tfh, naive CD4+ T cells, and Tregs returned to baseline.ConclusionsAlthough abatacept treatment for 1 year did not significantly delay progression to glucose intolerance in at-risk individuals, it impacted immune cell subsets and preserved insulin secretion, suggesting that costimulation blockade may modify progression of type 1 diabetes.

Published
2023

2. Multicenter, Randomized Trial of a Bionic Pancreas in Type 1 Diabetes.

Author

Russell, Steven, Beck, Roy, Damiano, Edward, El-Khatib, Firas, Ruedy, Katrina, Balliro, Courtney, Li, Zoey, Calhoun, Peter, Wadwa, R, Buckingham, Bruce, Zhou, Keren, Daniels, Mark, Raskin, Philip, White, Perrin, Lynch, Jane, Pettus, Jeremy, Hirsch, Irl, Goland, Robin, Buse, John, Kruger, Davida, Mauras, Nelly, Muir, Andrew, McGill, Janet, Cogen, Fran, Weissberg-Benchell, Jill, Sherwood, Jordan, Castellanos, Luz, Hillard, Mallory, Tuffaha, Marwa, Putman, Melissa, Sands, Mollie, Forlenza, Gregory, Slover, Robert, Messer, Laurel, Cobry, Erin, Shah, Viral, Polsky, Sarit, Lal, Rayhan, Ekhlaspour, Laya, Hughes, Michael, Basina, Marina, Hatipoglu, Betul, Olansky, Leann, Bhangoo, Amrit, Forghani, Nikta, Kashmiri, Himala, Sutton, Francoise, Choudhary, Abha, Penn, Jimmy, Jafri, Rabab, Rayas, Maria, Escaname, Elia, Kerr, Catherine, Favela-Prezas, Ruby, Trikudanathan, Subbulaxmi, Williams, Kristen, Leibel, Natasha, Kirkman, M, Bergamo, Kate, Klein, Klara, Dostou, Jean, Machineni, Sriram, Young, Laura, Diner, Jamie, Bhan, Arti, Jones, J, Benson, Matthew, Bird, Keisha, Englert, Kimberly, Permuy, Joe, Cossen, Kristina, Felner, Eric, Salam, Maamoun, Silverstein, Julie, Adamson, Samantha, Cedeno, Andrea, Meighan, Seema, Dauber, Andrew, and Boeder, Schafer

Subjects
Adolescent, Adult, Aged, Bionics, Blood Glucose, Blood Glucose Self-Monitoring, Child, Diabetes Mellitus, Type 1, Glycated Hemoglobin, Humans, Hypoglycemic Agents, Insulin, Insulin Aspart, Insulin Infusion Systems, Insulin Lispro, Middle Aged, Young Adult
Abstract

BACKGROUND: Currently available semiautomated insulin-delivery systems require individualized insulin regimens for the initialization of therapy and meal doses based on carbohydrate counting for routine operation. In contrast, the bionic pancreas is initialized only on the basis of body weight, makes all dose decisions and delivers insulin autonomously, and uses meal announcements without carbohydrate counting. METHODS: In this 13-week, multicenter, randomized trial, we randomly assigned in a 2:1 ratio persons at least 6 years of age with type 1 diabetes either to receive bionic pancreas treatment with insulin aspart or insulin lispro or to receive standard care (defined as any insulin-delivery method with unblinded, real-time continuous glucose monitoring). The primary outcome was the glycated hemoglobin level at 13 weeks. The key secondary outcome was the percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter; the prespecified noninferiority limit for this outcome was 1 percentage point. Safety was also assessed. RESULTS: A total of 219 participants 6 to 79 years of age were assigned to the bionic-pancreas group, and 107 to the standard-care group. The glycated hemoglobin level decreased from 7.9% to 7.3% in the bionic-pancreas group and did not change (was at 7.7% at both time points) in the standard-care group (mean adjusted difference at 13 weeks, -0.5 percentage points; 95% confidence interval [CI], -0.6 to -0.3; P

Published
2022

3. Islet Autoimmunity is Highly Prevalent and Associated With Diminished β-Cell Function in Patients With Type 2 Diabetes in the Grade Study.

Author

Brooks-Worrell, Barbara, Hampe, Christiane S, Hattery, Erica G, Palomino, Brenda, Zangeneh, Sahar Z, Utzschneider, Kristina, Kahn, Steven E, Larkin, Mary E, Johnson, Mary L, Mather, Kieren J, Younes, Naji, Rasouli, Neda, Desouza, Cyrus, Cohen, Robert M, Park, Jean Y, Florez, Hermes J, Valencia, Willy Marcos, Shojaie, Ali, Palmer, Jerry P, Balasubramanyam, Ashok, Crandall, Jill P, McKee, Melissa Diane, Brown-Friday, Janet, Xhori, Entila, Ballentine-Cargill, Keisha, Duran, Sally, Lukin, Jennifer, Beringher, Stephanie, Gonzalez de la Torre, Susana, Phillips, Lawrence, Burgess, Elizabeth, Olson, Darin, Rhee, Mary, Wilson, Peter, Raines, Tasha Stephanie, Costello, Julie, Gullett, Chona, Maher-Albertelli, Maxine, Morehead, Folayan, Mungara, Radhika, Person, Saranjit, Savoye, Louise, Sibymon, Mabil, Tanukonda, Sridhar, White, Carol Ann, Holloway, Leah, Adams, Cynthia, Ross, April, Gonzalez Hattery, Erica, Gaba, Ruchi, Montes, Graciela, Wright, Charlyne, Hollander, Priscilla, Roe, Erin, Uy, Analyn, Burt, Polly, Estrada, Lorie, Chionh, Kris, Ismail-Beigi, Faramarz, Falck-Ytter, Corinna, Sayyed Kassem, Laure, Sood, Ajay, Tiktin, Margaret, Cramer, Bethany, Iacoboni, Jacalyn, Kononets, Maria V, Kulow, Tanya, Newman, Cynthia, Stancil, Katherine A, Sanders, Cristina, Tucker, Lisa, Werner, Amanda, Krol, Adrienne, McPhee, Gloria, Patel, Christine, Colosimo, Linda, Goland, Robin, Pring, James, Kringas, Patricia, Tejada, Jessica, Hausheer, Camille, Schneier, Harvey, Gumpel, Kelly, Kirpitch, Amanda, Green, Jennifer B, AbouAssi, Hiba, Chatterjee, Ranee, Feinglos, Mark N, English Jones, Jennifer, Khan, Shubi A, Kimpel, Jeanne B, Zimmer, Ronna P, Furst, Mary, Satterwhite, Barbara M, Thacker, Connie, Evans Kreider, Kathryn, Lteif, Amale, and Hamilton, Tonya

Subjects
Biomedical and Clinical Sciences, Immunology, Autoimmune Disease, Clinical Research, Diabetes, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, GRADE Beta-cell Ancillary Study Network, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences
Abstract

Islet autoimmunity may contribute to β-cell dysfunction in type 2 diabetes (T2D). Its prevalence and clinical significance have not been rigorously determined. In this ancillary study to the Glycemia Reduction Approaches in Diabetes-A Comparative Effectiveness (GRADE) Study, we investigated the prevalence of cellular and humoral islet autoimmunity in patients with T2D duration 4·0±3·0 y, HbA1c 7·5±0·5% on metformin alone. We measured T cell autoreactivity against islet proteins, islet autoantibodies against GAD65, IA2, ZnT8, and β-cell function. Cellular islet autoimmunity was present in 41·3%, humoral islet autoimmunity in 13·5%, and both in 5·3%. β-cell function calculated as iAUC-CG and ΔC-peptide(0- 30)/Δglucose(0-30) from an oral glucose tolerance test was lower among T cell-positives (T+) than T cell-negatives (T-) using two different adjustments for insulin sensitivity (iAUC-CG: 13·2% [95% CI 0·3, 24·4%] or 11·4% [95% CI 0·4, 21·2%] lower; ΔC-peptide(0-30)/Δglucose(0-30)) 19% [95% CI 3·1, 32·3%] or 17·7% [95% CI 2·6, 30·5%] lower). T+ patients had 17% higher HbA1c (95% CI 0·07, 0·28) and 7·7 mg/dL higher fasting plasma glucose levels (95% CI 0·2,15·3) than T- patients. We conclude that islet autoimmunity is much more prevalent in T2D patients than previously reported. T cell-mediated autoimmunity is associated with diminished β-cell function and worse glycemic control.

Published
2022

4. IL-6 receptor blockade does not slow β cell loss in new-onset type 1 diabetes

Author

Greenbaum, Carla J, Serti, Elisavet, Lambert, Katharina, Weiner, Lia J, Kanaparthi, Sai, Lord, Sandra, Gitelman, Stephen E, Wilson, Darrell M, Gaglia, Jason L, Griffin, Kurt J, Russell, William E, Raskin, Philip, Moran, Antoinette, Willi, Steven M, Tsalikian, Eva, DiMeglio, Linda A, Herold, Kevan C, Moore, Wayne V, Goland, Robin, Harris, Mark, Craig, Maria E, Schatz, Desmond A, Baidal, David A, Rodriguez, Henry, Utzschneider, Kristina M, Nel, Hendrik J, Soppe, Carol L, Boyle, Karen D, Cerosaletti, Karen, Keyes-Elstein, Lynette, Long, S Alice, Thomas, Ranjeny, McNamara, James G, Buckner, Jane H, and Sanda, Srinath

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Diabetes, Clinical Research, Clinical Trials and Supportive Activities, Pediatric, Metabolic and endocrine, Good Health and Well Being, Adolescent, B-Lymphocyte Subsets, Child, Diabetes Mellitus, Type 1, Double-Blind Method, Female, Humans, Male, Receptors, Interleukin-6, ITN058AI EXTEND Study Team, Beta cells, Endocrinology, Immunology, T cells, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundIL-6 receptor (IL-6R) signaling drives development of T cell populations important to type 1 diabetes pathogenesis. We evaluated whether blockade of IL-6R with monoclonal antibody tocilizumab would slow loss of residual β cell function in newly diagnosed type 1 diabetes patients.MethodsWe conducted a multicenter, randomized, placebo-controlled, double-blind trial with tocilizumab in new-onset type 1 diabetes. Participants were screened within 100 days of diagnosis. Eligible participants were randomized 2:1 to receive 7 monthly doses of tocilizumab or placebo. The primary outcome was the change from screening in the mean AUC of C-peptide collected during the first 2 hours of a mixed meal tolerance test at week 52 in pediatric participants (ages 6-17 years).ResultsThere was no statistical difference in the primary outcome between tocilizumab and placebo. Immunophenotyping showed reductions in downstream signaling of the IL-6R in T cells but no changes in CD4 memory subsets, Th17 cells, Tregs, or CD4+ T effector cell resistance to Treg suppression. A DC subset decreased during therapy but regressed to baseline once therapy stopped. Tocilizumab was well tolerated.ConclusionTocilizumab reduced T cell IL-6R signaling but did not modulate CD4+ T cell phenotypes or slow loss of residual β cell function in newly diagnosed individuals with type 1 diabetes.Trial RegistrationClinicalTrials.gov NCT02293837.FundingNIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Allergy and Infectious Diseases (NIAID) UM1AI109565, UL1TR000004 from NIH/National Center for Research Resources (NCRR) Clinical and Translational Science Award (CTSA), NIH/NIDDK P30DK036836, NIH/NIDDK U01DK103266, NIH/NIDDK U01DK103266, 1UL1TR000064 from NIH/NCRR CTSA, NIH/National Center for Advancing Translational Sciences (NCATS) UL1TR001878, UL1TR002537 from NIH/CTSA; National Health and Medical Research Council Practitioner Fellowship (APP1136735), NIH/NIDDK U01-DK085476, NIH/CTSA UL1-TR002494, Indiana Clinical and Translational Science Institute Award UL1TR002529, Vanderbilt Institute for Clinical and Translational Research UL1TR000445. NIH/NCATS UL1TR003142, NIH/CTSA program UL1-TR002494, Veteran Affairs Administration, and 1R01AI132774.

Published
2021

5. Association of Glycemia, Lipids, and Blood Pressure With Cognitive Performance in People With Type 2 Diabetes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).

Author

Luchsinger, José A, Younes, Naji, Manly, Jennifer J, Barzilay, Joshua, Valencia, Willy, Larkin, Mary E, Falck-Ytter, Corinna, Krause-Steinrauf, Heidi, Pop-Busui, Rodica, Florez, Hermes, Seaquist, Elizabeth, Crandall, Jill P, McKee, Melissa Diane, Brown-Friday, Janet, Xhori, Entila, Ballentine-Cargill, Keisha, Duran, Sally, Lukin, Jennifer, Beringher, Stephanie, Gonzalez de la torre, Susana, Phillips, Lawrence, Burgess, Elizabeth, Olson, Darin, Rhee, Mary, Wilson, Peter, Raines, Tasha Stephanie, Costello, Julie, Gullett, Chona, Maher-Albertelli, Maxine, Morehead, Folayan, Mungara, Radhika, Person, Saranjit, Savoye, Louise, Sibymon, Mabil, Tanukonda, Sridhar, White, Carol Ann, Holloway, Leah, Adams, Cynthia, Ross, April, Balasubramanyam, Ashok, Gonzalez, Erica, Wright, Charlyne, Hollander, Priscilla, Roe, Erin, Uy, Analyn, Burt, Polly, Estrada, Lorie, Chionh, Kris, Ismail-Beigi, Faramarz, Sayyed Kassem, Laure, Sood, Ajay, Tiktin, Margaret, Cramer, Bethany, Iacoboni, Jacalyn, Kononets, Maria V, Kulow, Tanya, Newman, Cynthia, Stancil, Katherine A, Sanders, Cristina, Tucker, Lisa, Werner, Amanda, Krol, Adrienne, McPhee, Gloria, Patel, Christine, Colosimo, Linda, Goland, Robin, Pring, James, Kringas, Patricia, Tejada, Jessica, Hausheer, Camille, Schneier, Harvey, Gumpel, Kelly, Kirpitch, Amanda, Green, Jennifer B, AbouAssi, Hiba, Chatterjee, Ranee, Feinglos, Mark N, English Jones, Jennifer, Khan, Shubi A, Kimpel, Jeanne B, Zimmer, Ronna P, Furst, Mary, Satterwhite, Barbara M, Thacker, Connie R, Evans Kreider, Kathryn, Mather, Kieren J, Lteif, Amale, Hamilton, Tonya, Patel, Nick, Riera, Gabriela, Jackson, Marcia, Pirics, Vivian, Howard, Devin, Aguillar, Danielle, Hurt, Sloan, Bergenstal, Richard, Carlson, Anders, Martens, Thomas, and Johnson, Mary

Subjects
Biomedical and Clinical Sciences, Hypertension, Clinical Research, Clinical Trials and Supportive Activities, Diabetes, Cardiovascular, Behavioral and Social Science, Aged, Blood Pressure, Cognition, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Female, Humans, Lipids, Middle Aged, GRADE Research Group, GRADE Research Group Investigators:, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences, Health sciences
Abstract

ObjectiveType 2 diabetes is a risk factor for cognitive impairment. We examined the relation of glycemia, lipids, blood pressure (BP), hypertension history, and statin use with cognition in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).Research design and methodsCross-sectional analyses from GRADE at baseline examined the association of glycemia (hemoglobin A1c [HbA1c]), LDL, systolic BP (SBP) and diastolic BP (DBP), hypertension history, and statin use with cognition assessed by the Spanish English Verbal Learning Test, letter and animal fluency tests, and Digit Symbol Substitution Test (DSST).ResultsAmong 5,047 GRADE participants, 5,018 (99.4%) completed cognitive assessments. Their mean age was 56.7 ± 10.0 years, and 36.4% were women. Mean diabetes duration was 4.0 ± 2.7 years. HbA1c was not related to cognition. Higher LDL was related to modestly worse DSST scores, whereas statin use was related to modestly better DSST scores. SBP between 120 and 139 mmHg and DBP between 80 and 89 mmHg were related to modestly better DSST scores. Hypertension history was not related to cognition.ConclusionsIn people with type 2 diabetes of a mean duration of

Published
2021

6. Association of Baseline Characteristics With Insulin Sensitivity and β-Cell Function in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study Cohort.

Author

Rasouli, Neda, Younes, Naji, Utzschneider, Kristina M, Inzucchi, Silvio E, Balasubramanyam, Ashok, Cherrington, Andrea L, Ismail-Beigi, Faramarz, Cohen, Robert M, Olson, Darin E, DeFronzo, Ralph A, Herman, William H, Lachin, John M, Kahn, Steven E, Crandall, Jill P, McKee, Melissa Diane, Brown-Friday, Janet, Xhori, Entila, Ballentine-Cargill, Keisha, Duran, Sally, Lukin, Jennifer, Beringher, Stephanie, de la torre, Susana Gonzalez, Phillips, Lawrence, Burgess, Elizabeth, Olson, Darin, Rhee, Mary, Wilson, Peter, Raines, Tasha Stephanie, Costello, Julie, Gullett, Chona, Maher-Albertelli, Maxine, Morehead, Folayan, Mungara, Radhika, Person, Saranjit, Savoye, Louise, Sibymon, Mabil, Tanukonda, Sridhar, Ann White, Carol, Holloway, Leah, Adams, Cynthia, Ross, April, Gonzalez, Erica, Wright, Charlyne, Hollander, Priscilla, Roe, Erin, Uy, Analyn, Burt, Polly, Estrada, Lorie, Chionh, Kris, Falck-Ytter, Corinna, Kassem, Laure Sayyed, Sood, Ajay, Tiktin, Margaret, Cramer, Bethany, Iacoboni, Jacalyn, Kononets, Maria V, Kulow, Tanya, Newman, Cynthia, Stancil, Katherine A, Sanders, Cristina, Tucker, Lisa, Werner, Amanda, Krol, Adrienne, McPhee, Gloria, Patel, Christine, Colosimo, Linda, Goland, Robin, Pring, James, Kringas, Patricia, Tejada, Jessica, Hausheer, Camille, Schneier, Harvey, Gumpel, Kelly, Kirpitch, Amanda, Green, Jennifer B, AbouAssi, Hiba, Chatterjee, Ranee, Feinglos, Mark N, Jones, Jennifer English, Khan, Shubi A, Kimpel, Jeanne B, Zimmer, Ronna P, Furst, Mary, Satterwhite, Barbara M, Thacker, Connie R, Kreider, Kathryn Evans, Mather, Kieren J, Lteif, Amale, Hamilton, Tonya, Patel, Nick, Riera, Gabriela, Jackson, Marcia, Pirics, Vivian, Howard, Devin, Aguillar, Danielle, Hurt, Sloan, Bergenstal, Richard, and Carlson, Anders

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Prevention, Diabetes, Metabolic and endocrine, Blood Glucose, C-Peptide, Child, Child, Preschool, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Female, Humans, Infant, Insulin, Insulin Resistance, Male, GRADE Research Group, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences, Health sciences
Abstract

ObjectiveWe investigated sex and racial differences in insulin sensitivity, β-cell function, and glycated hemoglobin (HbA1c) and the associations with selected phenotypic characteristics.Research design and methodsThis is a cross-sectional analysis of baseline data from 3,108 GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) participants. All had type 2 diabetes diagnosed

Published
2021

7. A Randomized Clinical Trial Assessing Continuous Glucose Monitoring (CGM) Use With Standardized Education With or Without a Family Behavioral Intervention Compared With Fingerstick Blood Glucose Monitoring in Very Young Children With Type 1 Diabetes.

Author

Laffel, Lori, Harrington, Kara, Hanono, Anat, Naik, Nisha, Ambler-Osborn, Louise, Schultz, Alan, DiMeglio, Linda, Woerne, Stephanie, Jolivette, Heather, Ismail, Heba, Tebbe, Megan, Newman, America, Legge, Megan, Tamborlane, William, Van Name, Michelle, Weyman, Kate, Finnegan, Jennifer, Steffen, Amy, Zgorski, Melinda, DeSalvo, Daniel, Hilliard, Marisa, DeLaO, Kylie, Xie, Cicilyn, Levy, Wendy, Wadwa, R Paul, Forlenza, Greg, Majidi, Shideh, Alonso, Guy, Weber, Isabel, Clay, Michelle, Simmons, Emily, Nathan, Brandon, Sunni, Muna, Sweet, Jessica, Pappenfus, Beth, Kogler, Anne, Ludwig, Marrissa, Nelson, Brittney, Street, Anne, Weingartner, Darcy, Albanese-O’Neill, Anastasia, Haller, Michael, Adams, Janey, Cintron, Miriam, Thomas, Nicole, Kelley, Jennifer, Simmons, Jill, William, George, Brendle, Faith, Goland, Robin, Williams, Kristen, Gandica, Rachelle, Pollak, Sarah, Casciano, Emily, Robinson, Elizabeth, Willi, Steven, Minnock, Pantea, Olivos, Diana, Carchidi, Cathy, Grant, Brian, Wong, Jenise C, Adi, Saleh, Corathers, Sarah, Sheanon, Nicole, Fox, Cathy, Weis, Tammy, MacLeish, Sarah, Wood, Jamie, Casey, Terri, Campbell, Wendy, McGuigan, Paul, Wintergerst, Kupper, Watson, Sara, Kingery, Suzanne, Pierce, Gwen, Ruch, Heather, Rayborn, Lauren, Rodriguez-Luna, Manuel, and Deuser, Amy

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Clinical Trials and Supportive Activities, Pediatric, Diabetes, Prevention, Metabolic and endocrine, Adolescent, Blood Glucose, Blood Glucose Self-Monitoring, Child, Child, Preschool, Diabetes Mellitus, Type 1, Glycated Hemoglobin, Humans, Hypoglycemic Agents, Quality of Life, Strategies to Enhance New CGM Use in Early Childhood (SENCE) Study Group, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences, Health sciences
Abstract

ObjectiveThis study evaluated the effects of continuous glucose monitoring (CGM) combined with family behavioral intervention (CGM+FBI) and CGM alone (Standard-CGM) on glycemic outcomes and parental quality of life compared with blood glucose monitoring (BGM) in children ages 2 to

Published
2021

8. Optimization of Metformin in the GRADE Cohort: Effect on Glycemia and Body Weight

Author

Sivitz, William I, Phillips, Lawrence S, Wexler, Deborah J, Fortmann, Stephen P, Camp, Anne W, Tiktin, Margaret, Perez, Magalys, Craig, Jacqueline, Hollander, Priscilla A, Cherrington, Andrea, Aroda, Vanita R, Tan, Meng Hee, Krakoff, Jonathan, Rasouli, Neda, Butera, Nicole M, Younes, Naji, Crandall, Jill P, Diane McKee, Melissa, Brown-Friday, Janet, Xhori, Entila, Ballentine-Cargill, Keisha, Duran, Sally, Lukin, Jennifer, Beringher, Stephanie, Gonzalez de la torre, Susana, Phillips, Lawrence, Burgess, Elizabeth, Olson, Darin, Rhee, Mary, Wilson, Peter, Stephanie Raines, Tasha, Costello, Julie, Gullett, Chona, Maher-Albertelli, Maxine, Morehead, Folayan, Mungara, Radhika, Person, Saranjit, Savoye, Louise, Sibymon, Mabil, Tanukonda, Sridhar, Ann White, Carol, Holloway, Leah, Adams, Cynthia, Ross, April, Balasubramanyam, Ashok, Gonzalez, Erica, Wright, Charlyne, Hollander, Priscilla, Roe, Erin, Uy, Analyn, Burt, Polly, Estrada, Lorie, Chionh, Kris, Ismail-Beigi, Faramarz, Falck-Ytter, Corinna, Sayyed Kassem, Laure, Sood, Ajay, Cramer, Bethany, Iacoboni, Jacalyn, Kononets, Maria V, Kulow, Tanya, Newman, Cynthia, Stancil, Katherine A, Sanders, Cristina, Tucker, Lisa, Werner, Amanda, Krol, Adrienne, McPhee, Gloria, Patel, Christine, Colosimo, Linda, Goland, Robin, Pring, James, Kringas, Patricia, Tejada, Jessica, Hausheer, Camille, Schneier, Harvey, Gumpel, Kelly, Kirpitch, Amanda, Green, Jennifer B, AbouAssi, Hiba, Chatterjee, Ranee, Feinglos, Mark N, English Jones, Jennifer, Khan, Shubi A, Kimpel, Jeanne B, Zimmer, Ronna P, Furst, Mary, Satterwhite, Barbara M, Thacker, Connie R, Evans Kreider, Kathryn, Mather, Kieren J, Lteif, Amale, Hamilton, Tonya, Patel, Nick, Riera, Gabriela, Jackson, Marcia, Pirics, Vivian, Howard, Devin, and Aguillar, Danielle

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Prevention, Clinical Research, Diabetes, Nutrition, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Metabolic and endocrine, Adult, Aged, Blood Glucose, Body Weight, Calibration, Comparative Effectiveness Research, Diabetes Mellitus, Type 2, Dose-Response Relationship, Drug, Drug Therapy, Combination, Female, Glycated Hemoglobin, Humans, Hypoglycemic Agents, Insulin, Liraglutide, Male, Maximum Tolerated Dose, Metformin, Middle Aged, Sitagliptin Phosphate, Sulfonylurea Compounds, Weight Loss, GRADE Research Group, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences, Health sciences
Abstract

ObjectiveWe evaluated the effect of optimizing metformin dosing on glycemia and body weight in type 2 diabetes.Research design and methodsThis was a prespecified analysis of 6,823 participants in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) taking metformin as the sole glucose-lowering drug who completed a 4- to 14-week (mean ± SD 7.9 ± 2.4) run-in in which metformin was adjusted to 2,000 mg/day or a maximally tolerated lower dose. Participants had type 2 diabetes for

Published
2020

9. Rationale and Design for a GRADE Substudy of Continuous Glucose Monitoring

Author

Larkin, Mary E, Nathan, David M, Bebu, Ionut, Krause-Steinrauf, Heidi, Herman, William H, Higgins, John M, Tiktin, Margaret, Cohen, Robert M, Lund, Claire, Bergenstal, Richard M, Johnson, Mary L, Arends, Valerie, Crandall, Jill P, McKee, Melissa Diane, Brown-Friday, Janet, Xhori, Entila, Ballentine-Cargill, Keisha, Duran, Sally, Lukin, Jennifer, Beringher, Stephanie, de la torre, Susana Gonzalez, Phillips, Lawrence, Burgess, Elizabeth, Olson, Darin, Rhee, Mary, Wilson, Peter, Raines, Tasha Stephanie, Costello, Julie, Gullett, Chona, Maher-Albertelli, Maxine, Morehead, Folayan, Mungara, Radhika, Person, Saranjit, Savoye, Louise, Sibymon, Mabil, Tanukonda, Sridhar, White, Carol Ann, Holloway, Leah, Adams, Cynthia, Ross, April, Balasubramanyam, Ashok, Gonzalez, Erica, Wright, Charlyne, Hollander, Priscilla, Roe, Erin, Uy, Analyn, Burt, Polly, Estrada, Lorie, Chionh, Kris, Ismail-Beigi, Faramarz, Falck-Ytter, Corinna, Kassem, Laure Sayyed, Sood, Ajay, Cramer, Bethany, Iacoboni, Jacalyn, Kononets, Maria V, Kulow, Tanya, Newman, Cynthia, Stancil, Katherine A, Sanders, Cristina, Tucker, Lisa, Werner, Amanda, Krol, Adrienne, McPhee, Gloria, Patel, Christine, Colosimo, Linda, Goland, Robin, Pring, James, Kringas, Patricia, Tejada, Jessica, Hausheer, Camille, Schneier, Harvey, Gumpel, Kelly, Kirpitch, Amanda, Green, Jennifer B, AbouAssi, Hiba, Chatterjee, Ranee, Feinglos, Mark N, Jones, Jennifer English, Khan, Shubi A, Kimpel, Jeanne B, Zimmer, Ronna P, Furst, Mary, Satterwhite, Barbara M, Thacker, Connie R, Kreider, Kathryn Evans, Mather, Kieren J, Lteif, Amale, Hamilton, Tonya, Patel, Nick, Riera, Gabriela, Jackson, Marcia, Pirics, Vivian, Howard, Devin, Aguillar, Danielle, Hurt, Sloan, Bergenstal, Richard, Carlson, Anders, Martens, Thomas, and Johnson, Mary

Subjects
Diabetes, Clinical Research, Metabolic and endocrine, Black or African American, Blood Glucose, Blood Glucose Self-Monitoring, Diabetes Mellitus, Type 2, Glycated Hemoglobin, Hispanic or Latino, Humans, Hypoglycemic Agents, Randomized Controlled Trials as Topic, Research Design, White People, Type 2 diabetes, Glycated hemoglobin, Interracial differences, Continuous glucose monitoring, Average glucose, GRADE Research Group, Clinical Sciences, Medical Physiology, Endocrinology & Metabolism
Abstract

Background: The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) study has enrolled a racially and ethnically diverse population with type 2 diabetes, performed extensive phenotyping, and randomly assigned the participants to one of four second-line diabetes medications. The continuous glucose monitoring (CGM) substudy has been added to determine whether there are racial/ethnic differences in the relationship between average glucose (AG) and hemoglobin A1c (HbA1c). CGM will also be used to compare time in target range, glucose variability, and the frequency and duration of hypoglycemia across study groups. Methods: The observational CGM substudy will enroll up to 1800 of the 5047 GRADE study participants from the four treatment groups, including as many as 450 participants from each of 4 racial/ethnic minority groups to be compared: Hispanic White, non-Hispanic White, non-Hispanic African American, and non-Hispanic Other. CGM will be performed for 2 weeks in proximity to a GRADE annual visit, during which an oral glucose tolerance test will be performed and HbA1c and glycated albumin measured. Indicators of interindividual variation in red blood cell turnover, based on specialized erythrocyte measurements, will also be measured to explore the potential causes of interindividual HbA1c variations. Conclusions: The GRADE CGM substudy will provide new insights into whether differences exist in the relationship between HbA1c and AG among different racial/ethnic groups and whether glycemic profiles differ among frequently used diabetes medications and their potential clinical implications. Understanding such differences is important for clinical care and adjustment of diabetes medications in patients of different races or ethnicities.

Published
2019

10. Low-Dose Anti-Thymocyte Globulin Preserves C-Peptide, Reduces HbA1c, and Increases Regulatory to Conventional T-Cell Ratios in New-Onset Type 1 Diabetes: Two-Year Clinical Trial Data

Author

Haller, Michael J, Long, S Alice, Blanchfield, J Lori, Schatz, Desmond A, Skyler, Jay S, Krischer, Jeffrey P, Bundy, Brian N, Geyer, Susan M, Warnock, Megan V, Miller, Jessica L, Atkinson, Mark A, Becker, Dorothy J, Baidal, David A, DiMeglio, Linda A, Gitelman, Stephen E, Goland, Robin, Gottlieb, Peter A, Herold, Kevan C, Marks, Jennifer B, Moran, Antoinette, Rodriguez, Henry, Russell, William E, Wilson, Darrell M, Greenbaum, Carla J, Battaglia, Manuela, Becker, Dorothy, Bingley, Penelope, Bosi, Emanuele, Buckner, Jane, Clements, Mark, Colman, Peter G, DiMeglio, Linda, Evans-Molina, Carmella, Gottlieb, Peter, Herold, Kevan, Knip, Mikael, Lernmark, Ake, Moore, Wayne, Muir, Andrew, Palmer, Jerry, Peakman, Mark, Philipson, Louis, Raskin, Philip, Redondo, Maria, Russell, William, Sosenko, Jay M, Spain, Lisa, Wentworth, John, Wherrett, Diane, Winter, William, Ziegler, Anette, Anderson, Mark, Antinozzi, Peter, Insel, Richard, Kay, Thomas, Pugliese, Alberto, Roep, Bart, Toppari, Jorma, Leschek, Ellen, Bourcier, Katarzyna, Ridge, John, Rafkin, Lisa, Santiago, Irene, Bundy, Brian, Abbondondolo, Michael, Adams, Timothy, Asif, Ilma, Bjellquist, Jenna, Boonstra, Matthew, Burroughs, Cristina, Cleves, Mario, Cuthbertson, David, DeSalvatore, Meagan, Eberhard, Christopher, Fiske, Steve, Ford, Julie, Garmeson, Jennifer, Geyer, Susan, and Hays, Brian

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Immunology, Clinical Trials and Supportive Activities, Clinical Research, Diabetes, 6.1 Pharmaceuticals, Metabolic and endocrine, Adolescent, Adult, Antilymphocyte Serum, C-Peptide, CD4-CD8 Ratio, Child, Diabetes Mellitus, Type 1, Double-Blind Method, Female, Flow Cytometry, Glycated Hemoglobin, Granulocyte Colony-Stimulating Factor, Humans, Immunologic Factors, Male, T-Lymphocytes, Regulatory, Young Adult, Type 1 Diabetes TrialNet ATG-GCSF Study Group, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences
Abstract

A three-arm, randomized, double-masked, placebo-controlled phase 2b trial performed by the Type 1 Diabetes TrialNet Study Group previously demonstrated that low-dose anti-thymocyte globulin (ATG) (2.5 mg/kg) preserved β-cell function and reduced HbA1c for 1 year in new-onset type 1 diabetes. Subjects (N = 89) were randomized to 1) ATG and pegylated granulocyte colony-stimulating factor (GCSF), 2) ATG alone, or 3) placebo. Herein, we report 2-year area under the curve (AUC) C-peptide and HbA1c, prespecified secondary end points, and potential immunologic correlates. The 2-year mean mixed-meal tolerance test-stimulated AUC C-peptide, analyzed by ANCOVA adjusting for baseline C-peptide, age, and sex (n = 82) with significance defined as one-sided P < 0.025, was significantly higher in subjects treated with ATG versus placebo (P = 0.00005) but not ATG/GCSF versus placebo (P = 0.032). HbA1c was significantly reduced at 2 years in subjects treated with ATG (P = 0.011) and ATG/GCSF (P = 0.022) versus placebo. Flow cytometry analyses demonstrated reduced circulating CD4:CD8 ratio, increased regulatory T-cell:conventional CD4 T-cell ratios, and increased PD-1+CD4+ T cells following low-dose ATG and ATG/GCSF. Low-dose ATG partially preserved β-cell function and reduced HbA1c 2 years after therapy in new-onset type 1 diabetes. Future studies should determine whether low-dose ATG might prevent or delay the onset of type 1 diabetes.

Published
2019

12. Low-Dose Anti-Thymocyte Globulin (ATG) Preserves β-Cell Function and Improves HbA1c in New-Onset Type 1 Diabetes

Author

Haller, Michael J, Schatz, Desmond A, Skyler, Jay S, Krischer, Jeffrey P, Bundy, Brian N, Miller, Jessica L, Atkinson, Mark A, Becker, Dorothy J, Baidal, David, DiMeglio, Linda A, Gitelman, Stephen E, Goland, Robin, Gottlieb, Peter A, Herold, Kevan C, Marks, Jennifer B, Moran, Antoinette, Rodriguez, Henry, Russell, William, Wilson, Darrell M, Greenbaum, Carla J, Greenbaum, C, Atkinson, M, Baidal, D, Battaglia, M, Becker, D, Bingley, P, Bosi, E, Buckner, J, Clements, M, Colman, P, DiMeglio, L, Evans-Molina, C, Gitelman, S, Goland, R, Gottlieb, P, Herold, K, Knip, M, Krischer, J, Lernmark, A, Moore, W, Moran, A, Muir, A, Palmer, J, Peakman, M, Philipson, L, Raskin, P, Redondo, M, Rodriguez, H, Russell, W, Spain, L, Schatz, DA, Sosenko, J, Wherrett, D, Wilson, D, Winter, W, Ziegler, A, Anderson, M, Antinozzi, P, Benoist, C, Blum, J, Bourcier, K, Chase, P, Clare-Salzler, M, Clynes, R, Cowie, C, Eisenbarth, G, Fathman, CG, Grave, G, Harrison, L, Hering, B, Insel, R, Jordan, S, Kaufman, F, Kay, T, Kenyon, N, Klines, R, Lachin, J, Leschek, E, Mahon, J, Marks, JB, Monzavi, R, Nanto-Salonen, K, Nepom, G, Orban, T, Parkman, R, Pescovitz, M, Peyman, J, Pugliese, A, Ridge, J, Roep, B, Roncarolo, M, Savage, P, Simell, O, Sherwin, R, Siegelman, M, Skyler, JS, Steck, A, Thomas, J, Trucco, M, and Wagner, J

Subjects
Pediatric, Diabetes, Clinical Trials and Supportive Activities, Clinical Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Metabolic and endocrine, Adolescent, Adult, Antilymphocyte Serum, C-Peptide, Child, Cytoprotection, Diabetes Mellitus, Type 1, Dose-Response Relationship, Drug, Double-Blind Method, Drug Therapy, Combination, Female, Glycated Hemoglobin, Granulocyte Colony-Stimulating Factor, Humans, Insulin-Secreting Cells, Male, Pilot Projects, Polyethylene Glycols, Recombinant Proteins, Young Adult, Type 1 Diabetes TrialNet ATG-GCSF Study Group
Abstract

ObjectiveA pilot study suggested that combination therapy with low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte colony-stimulating factor (GCSF) preserves C-peptide in established type 1 diabetes (T1D) (duration 4 months to 2 years). We hypothesized that 1) low-dose ATG/GCSF or 2) low-dose ATG alone would slow the decline of β-cell function in patients with new-onset T1D (duration

Published
2018

14. Glycemia reduction in type 2 diabetes—Hypoglycemia outcomes: A randomized clinical trial.

Author

Seaquist, Elizabeth R., Phillips, Lawrence S., Ghosh, Alokananda, Baker, Chelsea, Bergenstal, Richard M., Crandall, Jill P., Goland, Robin S., Gramzinski, Michaela R., Hox, Sophia H., Hsia, Daniel S., Johnson, Mary L., Lachin, John M., Raskin, Philip, Valencia, Willy M., Waltje, Andrea H., and Younes, Naji

Subjects
TYPE 2 diabetes, CLINICAL trials, HYPOGLYCEMIA, SITAGLIPTIN, GLYCOSYLATED hemoglobin
Abstract

Objective: Hypoglycemia is a major concern in type 2 diabetes (T2DM), but little is known about its likelihood compared across common therapies. We compared the likelihood of hypoglycemia among metformin-treated patients with T2DM randomized to the addition of one of 4 common therapies. Research design & methods: Randomized, controlled trial of 5,047 participants with T2DM of <10 years' duration, hemoglobin A1c (HbA1c) 6.8–8.5% (50.8–69.4 mmol/mol). Randomization to addition of glargine U100, glimepiride, liraglutide, or sitagliptin over 5.0 ± 1.3 (mean ± SD) years. HbA1c was measured quarterly; if a level >7.5% (>58.5 mmol/mol) was confirmed, rescue glargine and/or aspart insulin was added. We conducted a per-protocol analysis of 4,830, who attended at least one post-baseline visit and took at least one dose of assigned study medication. We assessed severe hypoglycemia events reported throughout the entire study. At quarterly visits, all participants were asked about hypoglycemic symptoms within the last 30 days, and those in the glargine and glimepiride groups were asked for any measured glucose <70 mg/dL (3.9 mmol/L) within this time period. Results: While participants were taking their assigned medications, severe hypoglycemia occurred in 10 (0.8%), 16 (1.3%), 6 (0.5%), and 4 (0.3%), (p<0.05) and hypoglycemic symptoms in 659 (54.2%), 833 (68.3%), 375 (32.4%), and 361 (29.1%) of participants following randomization to glargine, glimepiride, liraglutide, and sitagliptin, respectively (p<0.001). Conclusions: In metformin-treated patients with T2DM who add a second medication, hypoglycemia is most likely with addition of glimepiride, less with glargine, and least likely with liraglutide and sitagliptin. Trial registration: ClinicalTrials.gov Identifier: NCT01794143. [ABSTRACT FROM AUTHOR]

Published
2024
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18. Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials

Author

Moran, Antoinette, Bundy, Brian, Becker, Dorothy J, DiMeglio, Linda A, Gitelman, Stephen E, Goland, Robin, Greenbaum, Carla J, Herold, Kevan C, Marks, Jennifer B, Raskin, Philip, Sanda, Srinath, Schatz, Desmond, Wherrett, Diane K, Wilson, Darrell M, Krischer, Jeffrey P, Skyler, Jay S, Group, for the Type 1 Diabetes TrialNet Canakinumab Study, Pickersgill, Linda, de Koning, Eelco, Ziegler, Anette-G, Böehm, Bernhard, Badenhoop, Klaus, Schloot, Nanette, Bak, Jens Friis, Pozzilli, Paolo, Mauricio, Didac, Donath, Marc Y, Castaño, Luis, Wägner, Ana, Lervang, Hans Henrik, Perrild, Hans, Mandrup-Poulsen, Thomas, and Group, for the AIDA Study

Subjects
Clinical Trials and Supportive Activities, Clinical Research, Diabetes, Autoimmune Disease, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Metabolic and endocrine, Adolescent, Adult, Analysis of Variance, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, C-Peptide, Child, Diabetes Mellitus, Type 1, Double-Blind Method, Female, Humans, Hypoglycemic Agents, Immunologic Factors, Insulin-Secreting Cells, Interleukin 1 Receptor Antagonist Protein, Interleukin-1, Male, Treatment Outcome, Young Adult, Type 1 Diabetes TrialNet Canakinumab Study Group, AIDA Study Group, Medical and Health Sciences, General & Internal Medicine
Abstract

BackgroundInnate immunity contributes to the pathogenesis of autoimmune diseases, such as type 1 diabetes, but until now no randomised, controlled trials of blockade of the key innate immune mediator interleukin-1 have been done. We aimed to assess whether canakinumab, a human monoclonal anti-interleukin-1 antibody, or anakinra, a human interleukin-1 receptor antagonist, improved β-cell function in recent-onset type 1 diabetes.MethodsWe did two randomised, placebo-controlled trials in two groups of patients with recent-onset type 1 diabetes and mixed-meal-tolerance-test-stimulated C peptide of at least 0·2 nM. Patients in the canakinumab trial were aged 6-45 years and those in the anakinra trial were aged 18-35 years. Patients in the canakinumab trial were enrolled at 12 sites in the USA and Canada and those in the anakinra trial were enrolled at 14 sites across Europe. Participants were randomly assigned by computer-generated blocked randomisation to subcutaneous injection of either 2 mg/kg (maximum 300 mg) canakinumab or placebo monthly for 12 months or 100 mg anakinra or placebo daily for 9 months. Participants and carers were masked to treatment assignment. The primary endpoint was baseline-adjusted 2-h area under curve C-peptide response to the mixed meal tolerance test at 12 months (canakinumab trial) and 9 months (anakinra trial). Analyses were by intention to treat. These studies are registered with ClinicalTrials.gov, numbers NCT00947427 and NCT00711503, and EudraCT number 2007-007146-34.FindingsPatients were enrolled in the canakinumab trial between Nov 12, 2010, and April 11, 2011, and in the anakinra trial between Jan 26, 2009, and May 25, 2011. 69 patients were randomly assigned to canakinumab (n=47) or placebo (n=22) monthly for 12 months and 69 were randomly assigned to anakinra (n=35) or placebo (n=34) daily for 9 months. No interim analyses were done. 45 canakinumab-treated and 21 placebo-treated patients in the canakinumab trial and 25 anakinra-treated and 26 placebo-treated patients in the anakinra trial were included in the primary analyses. The difference in C peptide area under curve between the canakinumab and placebo groups at 12 months was 0·01 nmol/L (95% CI -0·11 to 0·14; p=0·86), and between the anakinra and the placebo groups at 9 months was 0·02 nmol/L (-0·09 to 0·15; p=0·71). The number and severity of adverse events did not differ between groups in the canakinumab trial. In the anakinra trial, patients in the anakinra group had significantly higher grades of adverse events than the placebo group (p=0·018), which was mainly because of a higher number of injection site reactions in the anakinra group.InterpretationCanakinumab and anakinra were safe but were not effective as single immunomodulatory drugs in recent-onset type 1 diabetes. Interleukin-1 blockade might be more effective in combination with treatments that target adaptive immunity in organ-specific autoimmune disorders.FundingNational Institutes of Health and Juvenile Diabetes Research Foundation.

Published
2013

19. Rapamycin/IL-2 Combination Therapy in Patients With Type 1 Diabetes Augments Tregs yet Transiently Impairs β-Cell Function

Author

Long, S Alice, Rieck, Mary, Sanda, Srinath, Bollyky, Jennifer B, Samuels, Peter L, Goland, Robin, Ahmann, Andrew, Rabinovitch, Alex, Aggarwal, Sudeepta, Phippard, Deborah, Turka, Laurence A, Ehlers, Mario R, Bianchine, Peter J, Boyle, Karen D, Adah, Steven A, Bluestone, Jeffrey A, Buckner, Jane H, and Greenbaum, Carla J

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Immunology, Autoimmune Disease, Clinical Trials and Supportive Activities, Clinical Research, Pediatric, Diabetes, 5.2 Cellular and gene therapies, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Metabolic and endocrine, Animals, Diabetes Mellitus, Type 1, Drug Therapy, Combination, Humans, Insulin-Secreting Cells, Interleukin-2, Mice, Mice, Inbred NOD, Sirolimus, T-Lymphocytes, Regulatory, Diabetes TrialNet and the Immune Tolerance Network, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences
Abstract

Rapamycin/interleukin-2 (IL-2) combination treatment of NOD mice effectively treats autoimmune diabetes. We performed a phase 1 clinical trial to test the safety and immunologic effects of rapamycin/IL-2 combination therapy in type 1 diabetic (T1D) patients. Nine T1D subjects were treated with 2-4 mg/day rapamycin orally for 3 months and 4.5 × 10(6) IU IL-2 s.c. three times per week for 1 month. β-Cell function was monitored by measuring C-peptide. Immunologic changes were monitored using flow cytometry and serum analyses. Regulatory T cells (Tregs) increased within the first month of therapy, yet clinical and metabolic data demonstrated a transient worsening in all subjects. The increase in Tregs was transient, paralleling IL-2 treatment, whereas the response of Tregs to IL-2, as measured by STAT5 phosphorylation, increased and persisted after treatment. No differences were observed in effector T-cell subset frequencies, but an increase in natural killer cells and eosinophils occurred with IL-2 therapy. Rapamycin/IL-2 therapy, as given in this phase 1 study, resulted in transient β-cell dysfunction despite an increase in Tregs. Such results highlight the difficulties in translating therapies to the clinic and emphasize the importance of broadly interrogating the immune system to evaluate the effects of therapy.

Published
2012

20. HSC extrinsic sex-related and intrinsic autoimmune disease–related human B-cell variation is recapitulated in humanized mice

Author

Borsotti, Chiara, Danzl, Nichole M., Nauman, Grace, Hölzl, Markus A., French, Clare, Chavez, Estefania, Khosravi-Maharlooei, Mohsen, Glauzy, Salome, Delmotte, Fabien R., Meffre, Eric, Savage, David G., Campbell, Sean R., Goland, Robin, Greenberg, Ellen, Bi, Jing, Satwani, Prakash, Yang, Suxiao, Bathon, Joan, Winchester, Robert, and Sykes, Megan

Published
2017
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22. Bardet-Biedl syndrome proteins regulate intracellular signaling and neuronal function in patient-specific iPSC-derived neurons

Author

Wang, Liheng, Liu, Yang, Stratigopoulos, George, Panigrahi, Sunil, Sui, Lina, Zhang, Yiying, Leduc, Charles A., Glover, Hannah J., De Rosa, Maria Caterina, Burnett, Lisa C., Williams, Damian J., Shang, Linshan, Goland, Robin, Tsang, Stephen H., Wardlaw, Sharon, Egli, Dieter, Zheng, Deyou, Doege, Claudia A., and Leibel, Rudolph L.

Subjects
Complications and side effects, Usage, Models, Health aspects, Obesity -- Complications and side effects, Cellular proteins -- Health aspects, Gene mutation -- Health aspects, Bardet-Biedl syndrome -- Models, Stem cells -- Usage, Gene mutations -- Health aspects
Abstract

Introduction Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder characterized by severe, early-onset obesity, as well as an array of other diagnostic features typical of ciliopathies including polydactyly, retinal degeneration, [...], Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder caused by mutations in genes encoding components of the primary cilium and is characterized by hyperphagic obesity. To investigate the molecular basis of obesity in human BBS, we developed a cellular model of BBS using induced pluripotent stem cell-derived (iPSC-derived) hypothalamic arcuate-like neurons. BBS mutations [BBS1.sup.M390R] and BBS[10.sup.C91fsX95] did not affect neuronal differentiation efficiency but caused morphological defects, including impaired neurite outgrowth and longer primary cilia. Single-cell RNA sequencing of [BBS1.sup.M390R] hypothalamic neurons identified several downregulated pathways, including insulin and cAMP signaling and axon guidance. Additional studies demonstrated that [BBS1.sup.M390R] and BBS[10.sup.C91fsX95] mutations impaired insulin signaling in both human fibroblasts and iPSC-derived neurons. Overexpression of intact BBS10 fully restored insulin signaling by restoring insulin receptor tyrosine phosphorylation in BBS[10.sup.C91fsX95] neurons. Moreover, mutations in BBS1 and BBS10 impaired leptin-mediated p-STAT3 activation in iPSC-derived hypothalamic neurons. Correction of the BBS mutation by CRISPR rescued leptin signaling. POMC expression and neuropeptide production were decreased in [BBS1.sup.M390R] and BBS[10.sup.C91fsX95] iPSC-derived hypothalamic neurons. In the aggregate, these data provide insights into the anatomic and functional mechanisms by which components of the BBSome in CNS primary cilia mediate effects on energy homeostasis.

Published
2021
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23. Abatacept for Delay of Type 1 Diabetes Progression in Stage 1 Relatives at Risk: A Randomized, Double-Masked, Controlled Trial

Author

E. Russell, William, primary, Bundy, Brian N., primary, S. Anderson, Mark, primary, Cooney, Laura A., primary, Gitelman, Stephen E., primary, Goland, Robin S., primary, Gottlieb, Peter A., primary, J. Greenbaum, Carla, primary, Haller, Michael J., primary, Krischer, Jeffrey P, primary, Libman, Ingrid M., primary, Linsley, Peter S., primary, Alice Long, S., primary, Lord, Sandra M., primary, J. Moore, Daniel, primary, Moore, Wayne V, primary, Moran, Antoinette M., primary, Muir, Andrew B., primary, Raskin, Phillip, primary, Skyler, Jay S., primary, Wentworth, John M, primary, Wherrett, Diane K., primary, Wilson, Darrell M., primary, Ziegler, Anette-Gabriele, primary, and C. Herold, Kevan, primary

Published
2023
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24. Obesity in Youth with Type 1 Diabetes in Germany, Austria, and the United States

Author

Willi, Steven, Lipman, Terri, Calvano, Tammy, Kucheruk, Olena, Minnock, Pantea, Nguyen, Chau, Klingensmith, Georgeanna, Banion, Carolyn, Barker, Jennifer, Cain, Cindy, Chase, Peter, Hoops, Sandy, Kelsy, Megan, Maahs, David, Mowry, Cathy, Nadeau, Kristen, Raymond, Jennifer, Rewers, Marian, Rewers, Arleta, Slover, Robert, Steck, Andrea, Wadwa, Paul, Walravens, Philippe, Zeitler, Philip, Haro, Heidi, Manseau, Katherine, Weinstock, Ruth, Izquierdo, Roberto, Sheikh, Umair, Conboy, Patricia, Bulger, Jane, Bzdick, Suzan, Goland, Robin, Gandica, Rachelle, Weiner, Lindsay, Cook, Steve, Greenberg, Ellen, Kohm, Kevin, Pollack, Sarah, Lee, Joyce, Gregg, Brigid, Tan, Meng, Burgh, Kimberly, Eason, Ashley, Garg, Satish, Michels, Aaron, Myers, Lisa, DiMeglio, Linda, Hannon, Tamara, Orr, Donald, Cruz, Christy, Woerner, Stephanie, Wolfsdorf, Joseph, Quinn, Maryanne, Tawa, Olivia, Ahmann, Andrew, Castle, Jessica, Joarder, Farahnaz, Bogan, Chris, Cady, Nancy, Cox, Jennifer, Pitts, Amy, Fitch, Rebecca, White, Brad, Wollam, Bethany, Bode, Bruce, Lindmark, Katie, Hosey, RaShonda, Bethin, Kathleen, Quattrin, Teresa, Ecker, Michelle, Wood, Jamie, Chao, Lily, Cheung, Clement, Fisher, Lynda, Jeandron, Debra, Kaufman, Francine, Kim, Mimi, Miyazaki, Brian, Monzavi, Roshanak, Patel, Payal, Pitukcheewanont, Pisit, Sandstrom, Anna, Cohen, Marisa, Ichihara, Brian, Lipton, Megan, Cemeroglu, Ayse, Appiagyei-Dankah, Yaw, Daniel, Maala, Postellon, Daniel, Racine, Michael, Wood, Michael, Kleis, Lora, Hirsch, Irl, DeSantis, Anthony, Dugdale, D.C., Failor, R. Alan, Gilliam, Lisa, Greenbaum, Carla, Janci, Mary, Odegard, Peggy, Trence, Dace, Wisse, Brent, Batts, Emily, Dove, Angela, Hefty, Deborah, Khakpour, Dori, Klein, Jani, Kuhns, Kristen, McCulloch-Olson, Marli, Peterson, Christina, Ramey, Mary, Marie, Marissa St., Thomson, Pam, Webber, Christine, Liljenquist, David, Sulik, Mark, Vance, Carl, Coughenour, Tiffany, Brown, Chris, Halford, Jean, Prudent, Andrea, Rigby, Shanda, Robison, Brandon, Starkman, Harold, Berry, Tymara, Cerame, Barbara, Chin, Daisy, Ebner-Lyon, Laurie, Guevarra, Frances, Sabanosh, Kristen, Silverman, Lawrence, Wagner, Christine, Fox, Marie, Buckingham, Bruce, Shah, Avni, Caswell, Kimberly, Harris, Breanne, Bergenstal, Richard, Criego, Amy, Damberg, Greg, Matfin, Glenn, Powers, Margaret, Tridgell, David, Burt, Cassie, Olson, Beth, Thomas, LeeAnn, Mehta, Sanjeev, Katz, Michelle, Laffel, Lori, Hathway, Joanne, Phillips, Roxanne, Cengiz, Eda, Tamborlane, William, Cappiello, Darryll, Steffen, Amy, Zgorski, Melinda, Peters, Anne, Ruelas, Valerie, Benjamin, Robert, Adkins, Deanna, Cuffee, Juanita, Spruill, Amber, Aleppo-Kacmarek, Grazia, Derby, Teresa, Massaro, Elaine, Webb, Kimberly, Burt Solorzano, Christine, DeBoer, Mark, Madison, Helen, McGill, Janet, Buechler, Lori, Clifton, Mary Jane, Hurst, Stacy, Kissel, Sarah, Recklein, Carol, Tsalikian, Eva, Tansey, Michael, Cabbage, Joanne, Coffey, Julie, Salamati, Sarah, Clements, Mark, Raman, Sripriya, Turpin, Angela, Bedard, Jennifer, Cohoon, Cyndy, Elrod, Aliza, Fridlington, Amanda, Hester, Lois, Kruger, Davida, Schatz, Desmond, Clare-Salzler, Michael, Cusi, Kenneth, Digman, Colleen, Fudge, Becky, Haller, Mike, Meehan, Collette, Rohrs, Henry, Silverstein, Janet, Wagh, Sujata, Cintron, Miriam, Sheehan, Eleni, Thomas, Jamie, Daniels, Mark, Clark, Susan, Flannery, Timothy, Forghani, Nikta, Naidu, Ajanta, Reh, Christina, Scoggin, Peggy, Trinh, Lien, Ayala, Natalie, Quintana, Rebeca, Speer, Heather, Zipf, William, Seiple, Diane, Kittelsrud, Julie, Gupta, Ashutosh, Peterson, Vikki, Stoker, Ashley, Gottschalk, Michael, Hashiguchi, Marla, Smith, Katheryn, Rodriguez, Henry, Bobik, Craig, Henson, Danielle, Simmons, Jill, Potter, Amy, Black, Margo, Brendle, Faith, Gubitosi-Klug, Rose, Kaminski, Beth, Bergant, Susan, Campbell, Wendy, Tasi, Catherine, Copeland, Kenneth, Beck, Joni, Less, Joane, Schanuel, Jill, Tolbert, Jennifer, Adi, Saleh, Gerard-Gonzalez, Andrea, Gitelman, Stephen, Chettout, Nassim, Torok, Christine, Pihoker, Catherine, Yi-Frazier, Joyce, Kearns, Susan, Libman, Ingrid, Bills, Vicky, Diaz, Ana, Duke, Julie, Nathan, Brandon, Moran, Antoinette, Bellin, Melena, Beasley, Shannon, Kogler, Anne, Leschyshyn, Janice, Schmid, Kara, Street, Anne, Nelson, Bryce, Frost, Carrie, Reifeis, Erin, Haymond, Morey, Bacha, Fida, Caldas-Vasquez, Maria, Klinepeter, Sara, Redondo, Maria, Berlanga, Rosa, Falk, Teresa, Garnes, Elizabeth, Gonzalez, Janette, Martinez, Cecilia, Pontifes, Mariam, Yulatic, Ronald, Arnold, Kathleen, Evans, Traci, Sellers, Sharon, Raman, Vandana, Foster, Carol, Murray, Mary, Brown, Trina, Slater, Hillarie, Wheeler, Karen, Harlan, David, Lee, Mary, Lock, John-Paul, Hartigan, Celia, Hubacz, Lisa, Buse, John, Calikoglu, Ali, Largay, Joseph, Young, Laura, Brown, Helen, Duncan, Vinnie, Duclos, Michelle, Tricome, Julie, Brandenburg, Verdayne, Blehm, Julie, Hallanger-Johnson, Julie, Hanson, Dawn, Miller, Corliss, Weiss, Jennifer, Hoffman, Robert, Chaudhari, Monika, Repaske, David, Gilson, Elizabeth, Haines, Jesse, Rudolph, Justen, McClave, Charles, Biersdorf, Doris, Tello, Anthony, Amundson, Donna, Ward, Rhonda, Rickels, Michael, Dalton-Bakes, Cornelia, Markman, Eileen, Peleckis, Amy, Rosenfeld, Nora, Dolan, Lawrence, Corathers, Sarah, Kichler, Jessica, Baugh, Holly, Standiford, Debbie, Hassing, Jeanne, Jones, Jennifer, Willis, Stephen, Wysham, Carol, Davis, Lisa, Blackman, Scott, Abel, Kimber-Lee, Clark, Loretta, Jonas, Andrea, Kagan, Ellie, Sosenko, Jay, Blashke, Carlos, Matheson, Della, Edelen, Rachel, Repas, Thomas, Baldwin, Denise, Borgwardt, Trista, Conroy, Christina, DeGrote, Kelly, Marchiando, Rod, Wasson, Michelle, Fox, Larry, Mauras, Nelly, Damaso, Ligeia, Englert, Kim, Hamaty, Marwan, Kennedy, Laurence, Schweiger, Michelle, Konstantinopoulos, Pantelis, Mawhorter, Carolyn, Orasko, Amy, Rose, Denise, Deeb, Larry, Rohrbacher, Kim, Schroeder, Leroy, Roark, Amanda, Ali, Omar, Kramer, Joanna, Whitson-Jones, Donna, Gassner, Heidi, Kollipara, Sobha, Harwood, Katerina, Prasad, Vijaya, Brault, Judy, DuBose, Stephanie N., Hermann, Julia M., Tamborlane, William V., Beck, Roy W., Dost, Axel, DiMeglio, Linda A., Schwab, Karl Otfried, Holl, Reinhard W., Hofer, Sabine E., and Maahs, David M.

Published
2015
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29. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial

Author

Orban, Tihamer, Bundy, Brian, Becker, Dorothy J, DiMeglio, Linda A, Gitelman, Stephen E, Goland, Robin, Gottlieb, Peter A, Greenbaum, Carla J, Marks, Jennifer B, Monzavi, Roshanak, Moran, Antoinette, Raskin, Philip, Rodriguez, Henry, Russell, William E, Schatz, Desmond, Wherrett, Diane, Wilson, Darrell M, Krischer, Jeffrey P, and Skyler, Jay S

Published
2011
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30. Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial

Author

Wherrett, Diane K, Bundy, Brian, Becker, Dorothy J, DiMeglio, Linda A, Gitelman, Stephen E, Goland, Robin, Gottlieb, Peter A, Greenbaum, Carla J, Herold, Kevan C, Marks, Jennifer B, Monzavi, Roshanak, Moran, Antoinette, Orban, Tihamer, Palmer, Jerry P, Raskin, Philip, Rodriguez, Henry, Schatz, Desmond, Wilson, Darrell M, Krischer, Jeffrey P, and Skyler, Jay S

Published
2011
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31. Differentiation of hypothalamic-like neurons from human pluripotent stem cells

Author

Wang, Liheng, Meece, Kana, Williams, Damian J., Lo, Kinyui Alice, Zimmer, Matthew, Heinrich, Garrett, Carli, Jayne Martin, Leduc, Charles A., Sun, Lei, Zeltser, Lori M., Freeby, Matthew, Goland, Robin, Tsang, Stephen H., Wardlaw, Sharon L., Egli, Dieter, and Leibel, Rudolph L.

Subjects
Physiological aspects, Research, Properties, Cell differentiation -- Research, Embryonic stem cells -- Properties, Cytological research, Neurons -- Physiological aspects, Cell research
Abstract

Introduction The mediobasal hypothalamus is a functional integrator of homeostatic processes, including food intake, energy expenditure, neuroendocrine regulation, body temperature, and circadian rhythms (1). Constituent cell bodies with distinct physiological [...], The hypothalamus is the central regulator of systemic energy homeostasis, and Its dysfunction can result In extreme body weight alterations. Insights into the complex cellular physiology of this region are critical to the understanding of obesity pathogenesis; however, human hypothalamic cells are largely inaccessible for direct study. Here, we developed a protocol for efficient generation of hypothalamic neurons from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) obtained from patients with monogenetic forms of obesity. Combined early activation of sonic hedgehog signaling followed by timed NOTCH inhibition in human ESCs/iPSCs resulted in efficient conversion into hypothalamic [NKX2.1.sup.+] precursors. Application of a NOTCH inhibitor and brain-derived neurotrophic factor (BDNF) further directed the cells into arcuate nucleus hypothalamic-like neurons that express hypothalamic neuron markers proopiomelanocortin (POMC), neuropeptide Y (NPY), agouti-related peptide (AGRP), somatostatin, and dopamine. These hypothalamic-like neurons accounted for over 90% of differentiated cells and exhibited transcriptional profiles defined by a hypothalamic-specific gene expression signature that lacked pituitary markers. Importantly, these cells displayed hypothalamic neuron characteristics, including production and secretion of neuropeptides and increased p-AKT and p-STAT3 in response to insulin and leptin. Our results suggest that these hypothalamic-like neurons have potential for further investigation of the neurophysiology of body weight regulation and evaluation of therapeutic targets for obesity.

Published
2015
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32. Islet Autoimmunity is Highly Prevalent and Associated With Diminished β-Cell Function in Patients With Type 2 Diabetes in the Grade Study

Author

Brooks-Worrell, Barbara, Hampe, Christiane S., Hattery, Erica G., Palomino, Brenda, Zangeneh, Sahar Z., Utzschneider, Kristina, Kahn, Steven E., Larkin, Mary E., Johnson, Mary L., Mather, Kieren J., Younes, Naji, Rasouli, Neda, Desouza, Cyrus, Cohen, Robert M., Park, Jean Y., Florez, Hermes J., Valencia, Willy Marcos, Shojaie, Ali, Palmer, Jerry P., Balasubramanyam, Ashok, Crandall, Jill P., McKee, Melissa Diane, Brown-Friday, Janet, Xhori, Entila, Ballentine-Cargill, Keisha, Duran, Sally, Lukin, Jennifer, Beringher, Stephanie, Gonzalez de la Torre, Susana, Phillips, Lawrence, Burgess, Elizabeth, Olson, Darin, Rhee, Mary, Wilson, Peter, Raines, Tasha Stephanie, Costello, Julie, Gullett, Chona, Maher-Albertelli, Maxine, Morehead, Folayan, Mungara, Radhika, Person, Saranjit, Savoye, Louise, Sibymon, Mabil, Tanukonda, Sridhar, White, Carol Ann, Holloway, Leah, Adams, Cynthia, Ross, April, Gonzalez Hattery, Erica, Gaba, Ruchi, Montes, Graciela, Wright, Charlyne, Hollander, Priscilla, Roe, Erin, Uy, Analyn, Burt, Polly, Estrada, Lorie, Chionh, Kris, Ismail-Beigi, Faramarz, Falck-Ytter, Corinna, Sayyed Kassem, Laure, Sood, Ajay, Tiktin, Margaret, Cramer, Bethany, Iacoboni, Jacalyn, Kononets, Maria V., Kulow, Tanya, Newman, Cynthia, Stancil, Katherine A., Sanders, Cristina, Tucker, Lisa, Werner, Amanda, Krol, Adrienne, McPhee, Gloria, Patel, Christine, Colosimo, Linda, Goland, Robin, Pring, James, Kringas, Patricia, Tejada, Jessica, Hausheer, Camille, Schneier, Harvey, Gumpel, Kelly, Kirpitch, Amanda, Green, Jennifer B., AbouAssi, Hiba, Chatterjee, Ranee, Feinglos, Mark N., English Jones, Jennifer, Khan, Shubi A., Kimpel, Jeanne B., Zimmer, Ronna P., Furst, Mary, Satterwhite, Barbara M., Thacker, Connie, Evans Kreider, Kathryn, Lteif, Amale, Hamilton, Tonya, Patel, Nick, Riera, Gabriela, Jackson, Marcia, Pirics, Vivian, Howard, Devin, Aguillar, Danielle, Hurt, Sloan, Bergenstal, Richard, Carlson, Anders, Martens, Thomas, Johnson, Mary, Hill, Renae, Hyatt, Jamie, Jensen, Connie, Madden, Marcia, Martin, Dianna, Willis, Holly, Konerza, Wanda, Passi, Rebecca, Kleeberger, Kathleen, Fortmann, Stephen, Herson, Michael, Mularski, Karen, Glauber, Harry, Prihoda, James, Ash, Britt, Carlson, Christina, Ramey, Phyllis Anne, Schield, Emily, Torgrimson-Ojerio, Britta, Arnold, Kathy, Kauffman, Bryan, Panos, Elease, Sahnow, Samantha, Bays, Kristi, Cook, Jennifer, Gluth, Jennifer, Sasaki, Debra, Schell, Katrina, Criscola, Jennifer, Friason, Camille, Jones, Suzi, Nazarov, Sergey, Barzilay, Joshua, Rassouli, Negah, Puttnam, Rachel, Curtis, Michelle, Stokes, Kia, Hollis, Bonita, Sanders-Jones, Cynthia, Nelson, Roslin, El-Haqq, Zakiah, Kolli, Abby, Tran, Tu, Wexler, Deborah, Larkin, Mary, Meigs, James, Dushkin, Amy, Rocchio, Gianna, Chambers, Brittany, Yepes, Mike, Steiner, Barbara, Dulin, Hilary, Cayford, Melody, DeManbey, Andrea, Gurry, Lindsey, Hillard, Mallory, Martin, Kimberly, Stevens, Christine, Thangthaeng, Nopporn, Kochis, Raquel, Raymond, Elyse, Ripley, Valerie, Park, Jean, Aroda, Vanita, Ghazi, Adline, Loveland, Amy, Hurtado, Maria, Kuhn, Alexander, Mofor, Florence, Marks, Jennifer, Oropesa-Gonzalez, Lisset, Riccio Veliz, Ana K., Nieto-Martinez, Ramfis, Gutt, Miriam, Ahmann, Andrew, Aby-Daniel, Diana, Joarder, Farahnaz, Morimoto, Victoria, Sprague, Carol, Yamashita, Daisuke, Cady, Nancy, Kirchhoff, Patricia, Rivera-Eschright, Nadia, Adducci, Joseph, Morales Gomez, Brianna, Goncharova, Alina, Hox, Sophia H., Petrovitch, Helen, Matwichyna, Michael, Jenkins, Victoria, Bermudez, Nina O., Ishii, Renée R., Hsia, Daniel S., Cefalu, William T., Greenway, Frank L., Waguespack, Celeste, King, Erin, Haynes, Natalie, Thomassie, Amy, Bourgeois, Brandi, Hazlett, Claire, Henry, Robert, Mudaliar, Sunder, Boeder, Schafer, Pettus, Jeremy, Diaz, Elsa, DeLue, Catherine, Castro, Erick, Hernandez, Sylvia, Krakoff, Jonathan, Curtis, Jeffrey M., Killean, Tina, Joshevama, Erica, Diaz, Enrique, Martin, Denelle, Karshner, Tracey, Albu, Jeanine, Pi-Sunyer, F. Xavier, Frances, Sylvaine, Maggio, Carol, Ellis, Emily, Bastawrose, Joseph, Gong, Xiuqun, Banerji, Mary Ann, August, Phyllis, Lorber, Daniel, Brown, Necole M., Josephson, Debra H., Thomas, Lorraine L., Tsovian, Mari, Cherian, Ajini, Jacobson, Marlo H., Mishko, Motria M., Kirkman, M. Sue, Bergamo, Katherine, Buse, John B., Dostou, Jean, Young, Laura, Goley, April, Kerr, Jeffrey, Largay, Joseph F., Guarda, Sonia, Cuffee, Juanita, Culmer, Dawn, Fraser, Rachael, Almeida, Hope, Coffer, Samantha, Debnam, Elizabeth, Kiker, Lauren, Morton, Sarah, Josey, Kim, Fuller, Gail, Garvey, W. Timothy, Cherrington, Andrea, Golson, Dana, Griffith, Olivia, Robertson, Mary Catherine, Agne, April, McCullars, Steve, Craig, Jacqueline, Kersey, Kimberly, Rogge, M. Colleen, Wilson, Carla, Burton, Kathryn, Lipp, Sonia, Vonder Meulen, Mary Beth, Schroeder, Emily, Steiner, Stephanie, Baker, Chelsea, Underkofler, Chantal, Douglass, Sara, Sivitz, William, Cline, Erin, Knosp, Laura, McConnell, Jennifer, Lowe, Tamara, Herman, William H., Pop-Busui, Rodica, Tan, Meng H., Martin, Catherine, Waltje, Andrea, Goodhall, Lynn, Eggleston, Rebecca, Kuo, Shihchen, Bule, Stephanie, Kessler, Nancy, LaSalle, Elizabeth, Seaquist, Elizabeth R., Bantle, Anne, Kumar, Anjali, Redmon, Bruce, Bantle, John, Harindhanavudhi, Tasma, Coe, Mary, Mech, Michael, Taddese, Abdisa, Lesne, Lesia, Smith, Shannon, Kuechenmeister, Lisa, Shivaswamy, Vijay, Morales, Ana Laura, Rodriguez, Maria Grace, Seipel, Kris, Alfred, Alissa, Eggert, Jenna, Lord, Grace, Taylor, William, Tillson, Renee, Schade, David S., Adolphe, Allen, Burge, Mark, Duran-Valdez, Elizabeth, Martinez, Janae, Hernandez McGinnis, Doris, Pucchetti, Benjamin, Scripsick, Elizabeth, DeFronzo, Ralph A., Cersosimo, Eugenio, Abdul-Ghani, Muhammad, Triplitt, Curtis, Verastiqui, Hector, Garza, Rosa Irene, Wright, Kathryn, Puckett, Curtiss, Raskin, Philip, Rhee, Chanhaeng, Abraham, Soma, Jordan, Lin Fan, Sao, Serey, Morton, Luisa, Smith, Oralenda, Osornio Walker, Laura, Schnurr-Breen, Laura, Ayala, Rosa, Kraymer, Robert, Sturgess, Daytheon, Utzschneider, Kristina M., Alarcon-Casas Wright, Lorena, Boyko, Edward, Tsai, Elaine C., Trence, Dace L., Fattaleh, Basma N., Montgomery, Brenda K., Atkinson, Karen M., Concepcion, Tessa, Kozedub, Alexandra, Moak, Cameron, Rhothisen, Samantha, Elasy, Tom A., Martin, Stephanie, Shackelford, Laura, Goidel, Rita, Hinkle, Nina, Lipps Hogan, Janie, Lovell, Cynthia, Myers, Janet, McGill, Janet B., Salam, Maamoun, Kissel, Sarah, Schweiger, Toni, Recklein, Carol, Tamborlane, William, Gatcomb, Patricia, Camp, Anne, Gulanski, Barbara, Inzucchi, Silvio, Pham, Kim, Alguard, Michele, Lessard, Katarzyna, Perez, Magalys, Magenheimer, Elizabeth, Montoza, Abmaridel, Nathan, David M., Lachin, John, Krause-Steinrauf, Heidi, Burch, Henry, Linder, Barbara, Bremer, Andrew, Backman, Michael, Bebu, Ionut, Buys, C.J., Fagan Murphy, Anna, Gao, Yuping, Gramzinski, Michaela, Hall, Stephanie, Legowski, Elizabeth, Arey, Alyssa, Bethepu, Joel, Lund, Claire, Mangat Dhaliwal, Pam, McGee, Paula, Mesimer, Emily, Ngo, Lisa, Steffes, Michael, Seegmiller, Jesse, Saenger, Amy, Arends, Valerie, Gabrielson, Deanna, Conner, Todd, Stuart, Warren, Day, Jolene, Scrymgeour, Alexandra, Soliman, Elsayed Z., Zhang, Zhu-Ming, Campbell, Charles, Hu, Julie, Keasler, Lisa, Hensley, Susan, Li, Yabing, Herman, William, Mihalcea, Rada, Perez-Rosas, Veronica, Prosser, Lisa, Resnicow, Kenneth, Ye, Wen, Shao, Hui, Zhang, Ping, Luchsinger, Jose, Sanchez, Danurys, Burch, Henry B., Fradkin, Judith, Groessl, Erik, Chong, Helen, Hillery, Naomi, Abdouch, Ivan, Brantley, Paula, Broyles, Frances E., Canaris, Gay, Copeland, Paul, Craine, Jeri J., Fein, Warren L., Lee, Melissa S., Meiners, Rebecca, Meiners, Vaughn, O’Neal, Hollis, Park, James E., Sledge, Edward, Steppel-Resnick, Jeanne, Turchin, Alexander, Higgins, John, Fischer, Lawrence, Golden, Sherita, Gonzalez, Jeffrey, Naik, Aanand, Walker, Elizabeth, Doner Lotenberg, Lynne, Gallivan, Joanne M., Lim, Joanne, Tuncer, Diane M., and Behringer-Massera, Stephanie

Subjects
endocrine system diseases, Diabetes Mellitus, Type 2, Endocrinology, Diabetes and Metabolism, Smoke, T-Lymphocytes, Internal Medicine, Humans, Pathophysiology, Fires
Abstract

Islet autoimmunity may contribute to β-cell dysfunction in type 2 diabetes (T2D). Its prevalence and clinical significance have not been rigorously determined. In this ancillary study to the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE), we investigated the prevalence of cellular and humoral islet autoimmunity in patients with T2D duration of 4.0 ± 3.0 years (HbA1c 7.5 ± 0.5% on metformin alone). We measured T-cell autoreactivity against islet proteins, islet autoantibodies against 65-kDa GAD antigen, IA-2, and zinc transporter-8, and β-cell function. Cellular islet autoimmunity was present in 41.3%, humoral islet autoimmunity in 13.5%, and both in 5.3%. β-Cell function calculated as incremental area under the curve of glucose from 0–120 min (iAUC-CG) and ΔC-peptide(0–30)/Δglucose(0–30) from an oral glucose tolerance test was lower among T-cell–positive (T+) than T-cell–negative (T−) individuals using two different adjustments for insulin sensitivity (iAUC-CG: 13.2% [95% CI 0.3, 24.4] or 11.4% [95% CI 0.4, 21.2] lower; ΔC-peptide[0–30]/Δglucose[0–30]: 19% [95% CI 3.1, 32.3] or 17.7% [95% CI 2.6, 30.5%] lower). T+ patients had 17% higher HbA1c (95% CI 0.07, 0.28) and 7.7 mg/dL higher fasting plasma glucose levels (95% CI 0.2, 15.3) than T− patients. We conclude that islet autoimmunity is much more prevalent in patients with T2D than previously reported. T-cell–mediated autoimmunity is associated with diminished β-cell function and worse glycemic control.

Published
2021

33. A Randomized Trial Comparing Telemedicine Case Management with Usual Care in Older, Ethnically Diverse, Medically Underserved Patients with Diabetes Mellitus: 5 Year Results of the IDEATel Study

Author

Shea, Steven, Weinstock, Ruth S., Teresi, Jeanne A., Palmas, Walter, Starren, Justin, Cimino, James J., Lai, Albert M., Field, Lesley, Morin, Philip C., Goland, Robin, Izquierdo, Roberto E., Ebner, Susana, Silver, Stephanie, Petkova, Eva, Kong, Jian, and Eimicke, Joseph P.

Published
2009
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37. iPSC-derived β cells model diabetes due to glucokinase deficiency

Author

Hua, Haiqing, Shang, Linshan, Martinez, Hector, Freeby, Matthew, Gallagher, Mary Pat, Ludwig, Thomas, Deng, Liyong, Greenberg, Ellen, LeDuc, Charles, Chung, Wendy K., Goland, Robin, Leibel, Rudolph L., and Egli, Dieter

Subjects
Research, Methods, Health aspects, Diabetes mellitus -- Research, Glucokinase -- Health aspects, Stem cell transplantation -- Methods, Diabetes -- Research, Stem cells -- Transplantation
Abstract

Diabetes is a disorder characterized by loss of β cell mass and/or β cell function, leading to deficiency of insulin relative to metabolic need. To determine whether stem cell-derived β [...]

Published
2013
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39. Adult-Onset Type 1 Diabetes: Current Understanding and Challenges

Author

Leslie, R. David, primary, Evans-Molina, Carmella, additional, Freund-Brown, Jacquelyn, additional, Buzzetti, Raffaella, additional, Dabelea, Dana, additional, Gillespie, Kathleen M., additional, Goland, Robin, additional, Jones, Angus G., additional, Kacher, Mark, additional, Phillips, Lawrence S., additional, Rolandsson, Olov, additional, Wardian, Jana L., additional, and Dunne, Jessica L., additional

Published
2021
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40. Nuclear genome transfer in human oocytes eliminates mitochondrial DNA variants

Author

Paull, Daniel, Emmanuele, Valentina, Weiss, Keren A., Treff, Nathan, Stewart, Latoya, Hua, Haiqing, Zimmer, Matthew, Kahler, David J., Goland, Robin S., Noggle, Scott A., Prosser, Robert, Hirano, Michio, Sauer, Mark V., and Egli, Dieter

Subjects
Research, Genetic aspects, Oocytes -- Genetic aspects, Genomes -- Research, Mitochondrial DNA -- Research
Abstract

A crucial determinant of the phenotypic severity in most maternally inherited mitochondrial diseases is heteroplasmy, that is, the proportion of mutant, relative to total, mitochondrial DNA (mtDNA) in a cell. [...], Mitochondrial DNA mutations transmitted maternally within the oocyte cytoplasm often cause life-threatening disorders. Here we explore the use of nuclear genome transfer between unfertilized oocytes of two donors to prevent the transmission of mitochondrial mutations. Nuclear genome transfer did not reduce developmental efficiency to the blastocyst stage, and genome integrity was maintained provided that spontaneous oocyte activation was avoided through the transfer of incompletely assembled spindle-chromosome complexes. Mitochondrial DNA transferred with the nuclear genome was initially detected at levels below 1%, decreasing in blastocysts and stem-cell lines to undetectable levels, and remained undetectable after passaging for more than one year, clonal expansion, differentiation into neurons, cardiomyocytes or β-cells, and after cellular reprogramming. Stem cells and differentiated cells had mitochondrial respiratory chain enzyme activities and oxygen consumption rates indistinguishable from controls. These results demonstrate the potential of nuclear genome transfer to prevent the transmission of mitochondrial disorders in humans.

Published
2013
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41. Human oocytes reprogram somatic cells to a pluripotent state

Author

Noggle, Scott, Fung, Ho-Lim, Gore, Athurva, Martinez, Hector, Satriani, Kathleen Crumm, Prosser, Robert, Oum, Kiboong, Paull, Daniel, Druckenmiller, Sarah, Freeby, Matthew, Greenberg, Ellen, Zhang, Kun, Goland, Robin, Sauer, Mark V., Leibel, Rudolph L., and Egli, Dieter

Subjects
Physiological aspects, Research, Genetic aspects, Risk factors, DNA damage -- Physiological aspects -- Research, Oocytes -- Genetic aspects -- Physiological aspects -- Research, Genetic disorders -- Risk factors -- Research
Abstract

The generation of animals by transfer of the genome from an adult cell into an unfertilized oocyte (1), and the isolation of pluripotent stem cells from human blastocysts (2), raised [...], The exchange of the oocyte's genome with the genome of a somatic cell, followed by the derivation of pluripotent stem cells, could enable the generation of specific cells affected in degenerative human diseases. Such cells, carrying the patient's genome, might be useful for cell replacement. Here we report that the development of human oocytes after genome exchange arrests at late cleavage stages in association with transcriptional abnormalities. In contrast, if the oocyte genome is not removed and the somatic cell genome is merely added, the resultant triploid cells develop to the blastocyst stage. Stem cell lines derived from these blastocysts differentiate into cell types of all three germ layers, and a pluripotent gene expression program is established on the genome derived from the somatic cell. This result demonstrates the feasibility of reprogramming human cells using oocytes and identifies removal of the oocyte genome as the primary cause of developmental failure after genome exchange.

Published
2011
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42. Costimulation modulation with abatacept in patients with recent-onset type 1 diabetes: follow-up 1 year after cessation of treatment

Author

Orban, Tihamer, Bundy, Brian, Becker, Dorothy J., DiMeglio, Linda A., Gitelman, Stephen E., Goland, Robin, Gottlieb, Peter A., Greenbaum, Carla J., Marks, Jennifer B., Monzavi, Roshanak, Moran, Antoinette, Peakman, Mark, Raskin, Philip, Russell, William E., Schatz, Desmond, Wherrett, Diane K., Wilson, Darrell M., Krischer, Jeffrey P., and Skyler, Jay S.

Subjects
Bristol-Myers Squibb Co., Care and treatment, Development and progression, Peptides, Diabetes therapy, Pharmaceutical industry, Type 1 diabetes -- Care and treatment -- Development and progression
Abstract

OBJECTIVE We previously reported that 2 years of costimulation modulation with abatacept slowed decline of β-cell function in recent-onset type 1 diabetes (T1D). Subsequently, abatacept was discontinued and subjects were [...]

Published
2014
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43. β-cell dysfunction due to increased ER stress in a stem cell model of Wolfram syndrome

Author

Shang, Linshan, Hua, Haiqing, Foo, Kylie, Martinez, Hector, Watanabe, Kazuhisa, Zimmer, Matthew, Kahler, David J., Freeby, Matthew, Chung, Wendy, LeDuc, Charles, Goland, Robin, Leibel, Rudolph L., and Egli, Dieter

Subjects
Physiological aspects, Research, Pancreatic beta cells -- Physiological aspects, Ear diseases -- Physiological aspects, Cell regulation -- Research, Cytological research, Cell research, Cellular control mechanisms -- Research
Abstract

All forms of diabetes are ultimately the result of an inability of pancreatic β-cells to provide sufficient insulin in response to ambient blood glucose concentrations. Stem cell-based models of diabetes [...], Wolfram syndrome is an autosomal recessive disorder caused by mutations in WFS1 and is characterized by insulin-dependent diabetes mellitus, optic atrophy, and deafness. To investigate the cause of β-cell failure, we used induced pluripotent stem cells to create insulin-producing cells from individuals with Wolfram syndrome. WFS1-deficient β-cells showed increased levels of endoplasmic reticulum (ER) stress molecules and decreased insulin content. Upon exposure to experimental ER stress, Wolfram β-cells showed impaired insulin processing and failed to increase insulin secretion in response to glucose and other secretagogues. Importantly, 4-phenyl butyric acid, a chemical protein folding and trafficking chaperone, restored normal insulin synthesis and the ability to upregulate insulin secretion. These studies show that ER stress plays a central role in β-cell failure in Wolfram syndrome and indicate that chemical chaperones might have therapeutic relevance under conditions of ER stress in Wolfram syndrome and other forms of diabetes. Diabetes 2014;63:923-933 | DOI: 10.2337/db13-0717

Published
2014
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45. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function

Author

Pescovitz, Mark D., Greenbaum, Carla J., Krause-Steinrauf,Heidi, Becker, Dorothy J., Gitelman, Stephen E., Goland, Robin, Gottlieb, Peter A., Marks, Jennifer B., McGee, Paula F., Moran, Antoinette M., Raskin, Philip, Rodriguez, Henry, Schatz, Desmond A., Wherrett, Diane, Wilson, Darrell M., Lachin, John M., and Skyler, Jay S.

Subjects
Antibodies -- Health aspects, Viral antibodies -- Health aspects, B cells -- Health aspects, Type 1 diabetes -- Diagnosis, Type 1 diabetes -- Drug therapy
Abstract

The study examines if selective depletion of B-lymphocytes with rituximab decreases immune-mediated destruction of beta cells and lead to preserved beta-cell function in patients with type 1 diabetes. Results show a four-dose course of rituximab partially preserves beta-cell function over a period of one year.

Published
2009

46. HNF1A deficiency causes reduced calcium levels, accumulation of abnormal insulin granules and uncoupled insulin to C-peptide secretion in a stem cell model of MODY3

Author

Gonzalez, Bryan, primary, Zhao, Haoquan, additional, Niu, Jacqueline, additional, Williams, Damian, additional, Lee, Jaeyop, additional, Goulbourne, Christopher, additional, Xing, Yuan, additional, Wang, Yong, additional, Oberholzer, Jose, additional, Chen, Xiajuan, additional, LeDuc, Charles, additional, Chung, Wendy K, additional, Colecraft, Henry, additional, Gromada, Jesper, additional, Shen, Yufeng, additional, Goland, Robin, additional, Leibel, Rudolph, additional, and Egli, Dieter, additional

Published
2021
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47. Adult-Onset Type 1 Diabetes : Current Understanding and Challenges

Author

Leslie, R. David, Evans-Molina, Carmella, Freund-Brown, Jacquelyn, Buzzetti, Raffaella, Dabelea, Dana, Gillespie, Kathleen M., Goland, Robin, Jones, Angus G., Kacher, Mark, Phillips, Lawrence S., Rolandsson, Olov, Wardian, Jana L., Dunne, Jessica L., Leslie, R. David, Evans-Molina, Carmella, Freund-Brown, Jacquelyn, Buzzetti, Raffaella, Dabelea, Dana, Gillespie, Kathleen M., Goland, Robin, Jones, Angus G., Kacher, Mark, Phillips, Lawrence S., Rolandsson, Olov, Wardian, Jana L., and Dunne, Jessica L.

Abstract

Recent epidemiological data have shown that more than half of all new cases of type 1 diabetes occur in adults. Key genetic, immune, and metabolic differences exist between adult- and childhood-onset type 1 diabetes, many of which are not well understood. A substantial risk of misclassification of diabetes type can result. Notably, some adults with type 1 diabetes may not require insulin at diagnosis, their clinical disease can masquerade as type 2 diabetes, and the consequent misclassification may result in inappropriate treatment. In response to this important issue, JDRF convened a workshop of international experts in November 2019. Here, we summarize the current understanding and unanswered questions in the field based on those discussions, highlighting epidemiology and immunogenetic and metabolic characteristics of adult-onset type 1 diabetes as well as disease-associated comorbidities and psychosocial challenges. In adult-onset, as compared with childhood-onset, type 1 diabetes, HLA-associated risk is lower, with more protective genotypes and lower genetic risk scores; multiple diabetes-associated autoantibodies are decreased, though GADA remains dominant. Before diagnosis, those with autoantibodies progress more slowly, and at diagnosis, serum C-peptide is higher in adults than children, with ketoacidosis being less frequent. Tools to distinguish types of diabetes are discussed, including body phenotype, clinical course, family history, autoantibodies, comorbidities, and C-peptide. By providing this perspective, we aim to improve the management of adults presenting with type 1 diabetes.

Published
2021
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49. Longitudinal noninvasive PET-based [beta] cell mass estimates in a spontaneous diabetes rat model

Author

Souza, Fabiola, Simpson, Norman, Raffo, Anthony, Saxena, Chitra, Maffei, Antonella, Hardy, Mark, Kilbourn, Michael, Goland, Robin, Leibel, Rudolph, Mann, J. John, Van Heertum, Ronald, and Harris, Paul E.

Subjects
Diabetes -- Research, Diabetes -- Development and progression, Mice -- Research, Pancreatic diseases -- Research, Medical research, Medicine, Experimental
Abstract

Diabetes results from an absolute or relative reduction in pancreatic [beta] cell mass (BCM) leading to insufficient insulin secretion and hyperglycemia. Measurement of insulin secretory capacity is currently used as [...]

Published
2006

50. Reduced replication fork speed promotes pancreatic endocrine differentiation and controls graft size

Author

Sui, Lina, primary, Xin, Yurong, additional, Du, Qian, additional, Georgieva, Daniela, additional, Diedenhofen, Giacomo, additional, Haataja, Leena, additional, Su, Qi, additional, Zuccaro, Michael V., additional, Kim, Jinrang, additional, Fu, Jiayu, additional, Xing, Yuan, additional, He, Yi, additional, Baum, Danielle, additional, Goland, Robin S., additional, Wang, Yong, additional, Oberholzer, Jose, additional, Barbetti, Fabrizio, additional, Arvan, Peter, additional, Kleiner, Sandra, additional, and Egli, Dieter, additional

Published
2021
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