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1. 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

2. Transcription Factor 7-Like 2 (TCF7L2) Gene Polymorphism and Progression From Single to Multiple Autoantibody Positivity in Individuals at Risk for Type 1 Diabetes

Author

Redondo, Maria J, Steck, Andrea K, Sosenko, Jay, Anderson, Mark, Antinozzi, Peter, Michels, Aaron, Wentworth, John M, Atkinson, Mark A, Pugliese, Alberto, Geyer, Susan, and Group, the Type 1 Diabetes TrialNet Study

Subjects
Biomedical and Clinical Sciences, Health Sciences, Prevention, Genetics, Autoimmune Disease, Nutrition, Diabetes, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Adolescent, Adult, Antibody Specificity, Autoantibodies, Autoimmunity, Child, Child, Preschool, Cohort Studies, Diabetes Mellitus, Type 1, Disease Progression, Female, Gene Frequency, Genetic Predisposition to Disease, Humans, Infant, Male, Middle Aged, Obesity, Overweight, Polymorphism, Single Nucleotide, Risk Factors, Transcription Factor 7-Like 2 Protein, Young Adult, Type 1 Diabetes TrialNet Study Group, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences, Health sciences
Abstract

ObjectiveThe type 2 diabetes-associated alleles at the TCF7L2 locus mark a type 1 diabetes phenotype characterized by single islet autoantibody positivity as well as lower glucose and higher C-peptide measures. Here, we studied whether the TCF7L2 locus influences progression of islet autoimmunity, from single to multiple (≥2) autoantibody positivity, in relatives of patients with type 1 diabetes.Research design and methodsWe evaluated 244 participants in the Type 1 Diabetes TrialNet Pathway to Prevention study with confirmed single autoantibody positivity at screening and Immunochip single nucleotide polymorphism data (47.5% male; median age 12.8 years, range 1.2-45.9; 90.2% white). We analyzed risk allele frequency at TCF7L2 rs4506565 (in linkage disequilibrium with rs7903146). Altogether, 62.6% participants carried ≥1 risk allele. Univariate and multivariable Cox proportional hazards models and Kaplan-Meier statistical methods were used.ResultsDuring follow-up (median 5.2 years, range 0.2-12.6), 62% of the single autoantibody-positive participants developed multiple autoantibody positivity. In the overall cohort, the TCF7L2 locus did not significantly predict progression to multiple autoantibody positivity. However, among single GAD65 autoantibody-positive participants (n = 158), those who carried ≥1 risk allele had a lower rate of progression to multiple autoantibody positivity (hazard ratio [HR] 0.65, P = 0.033) than those who did not, after adjustment for HLA risk haplotypes and age. Among subjects who were either IA-2 or insulin autoantibody positive only, carrying ≥1 TCF7L2 risk allele was not a significant factor overall, but in overweight or obese participants, it increased the risk of progression to multiple autoantibody positivity (HR 3.02, P = 0.016) even with adjustment for age.ConclusionsThe type 2 diabetes-associated TCF7L2 locus influences progression of islet autoimmunity, with differential effects by autoantibody specificity and interaction by obesity/overweight.

Published
2018

3. 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

4. TCF7L2 Genetic Variants Contribute to Phenotypic Heterogeneity of Type 1 Diabetes

Author

Redondo, Maria J, Geyer, Susan, Steck, Andrea K, Sosenko, Jay, Anderson, Mark, Antinozzi, Peter, Michels, Aaron, Wentworth, John, Xu, Ping, and Pugliese, Alberto

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Diabetes, Prevention, Autoimmune Disease, Clinical Research, Nutrition, Genetics, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Adolescent, Adult, Alleles, Child, Child, Preschool, Cohort Studies, Diabetes Mellitus, Type 1, Female, Genetic Heterogeneity, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Transcription Factor 7-Like 2 Protein, Young Adult, Type 1 Diabetes TrialNet Study Group, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences, Health sciences
Abstract

ObjectiveThe phenotypic diversity of type 1 diabetes suggests heterogeneous etiopathogenesis. We investigated the relationship of type 2 diabetes-associated transcription factor 7 like 2 (TCF7L2) single nucleotide polymorphisms (SNPs) with immunologic and metabolic characteristics at type 1 diabetes diagnosis.Research design and methodsWe studied TrialNet participants with newly diagnosed autoimmune type 1 diabetes with available TCF7L2 rs4506565 and rs7901695 SNP data (n = 810; median age 13.6 years; range 3.3-58.6). We modeled the influence of carrying a TCF7L2 variant (i.e., having 1 or 2 minor alleles) on the number of islet autoantibodies and oral glucose tolerance test (OGTT)-stimulated C-peptide and glucose measures at diabetes diagnosis. All analyses were adjusted for known confounders.ResultsThe rs4506565 variant was a significant independent factor of expressing a single autoantibody, instead of multiple autoantibodies, at diagnosis (odds ratio [OR] 1.66 [95% CI 1.07, 2.57], P = 0.024). Interaction analysis demonstrated that this association was only significant in participants ≥12 years old (n = 504; OR 2.12 [1.29, 3.47], P = 0.003) but not younger ones (n = 306, P = 0.73). The rs4506565 variant was independently associated with higher C-peptide area under the curve (AUC) (P = 0.008) and lower mean glucose AUC (P = 0.0127). The results were similar for the rs7901695 SNP.ConclusionsIn this cohort of individuals with new-onset type 1 diabetes, type 2 diabetes-linked TCF7L2 variants were associated with single autoantibody (among those ≥12 years old), higher C-peptide AUC, and lower glucose AUC levels during an OGTT. Thus, carriers of the TCF7L2 variant had a milder immunologic and metabolic phenotype at type 1 diabetes diagnosis, which could be partly driven by type 2 diabetes-like pathogenic mechanisms.

Published
2018

5. Identical and Nonidentical Twins: Risk and Factors Involved in Development of Islet Autoimmunity and Type 1 Diabetes

Author

Triolo, T.M., Fouts, A., Pyle, L., Yu, L., Gottlieb, P.A., Steck, A.K., Greenbaum, C.J., Atkinson, M., Baidal, D., Battaglia, M., Becker, D., Bingley, P., Bosi, E., Buckner, J., Clements, M., Colman, P., DiMeglio, L., 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, D.A., Sosenko, J., Wentworth, 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., Eisenbarth, G., Fathman, C.G., Grave, G., Hering, B., Insel, R., Kaufman, F., Kay, T., Leschek, E., Mahon, J., Marks, J.B., Nanto-Salonen, K., Nepom, G., Orban, T., Parkman, R., Pescovitz, M., Peyman, J., Pugliese, A., Roep, B., Roncarolo, M., Savage, P., Simell, O., Sherwin, R., Siegelman, M., Skyler, J.S., Steck, A., Thomas, J., Trucco, M., Wagner, J., Krischer, J.P., Rafkin, L., Cowie, C., Foulkes, M., Krause-Steinrauf, H., Lachin, J.M., Malozowski, S., Ridge, J., Zafonte, S.J., Sosenko, J.M., Kenyon, N.S., Santiago, I., Bundy, B., Abbondondolo, M., Adams, T., Amado, D., Asif, I., Boonstra, M., Burroughs, C., Cuthbertson, D., Deemer, M., Eberhard, C., Fiske, S., Ford, J., Garmeson, J., Guillette, H., Geyer, S., Hays, B., Henderson, C., Henry, M., Heyman, K., Hsiao, B., Karges, C., Keaton, N., Kinderman, A., Law, P., Leinbach, A., Liu, S., Lloyd, J., Malloy, J., Maddox, K., Martin, J., Miller, J., Milliot, E., Moore, M., Muller, S., Nguyen, T., O'Donnell, R., Roberts, A., Sadler, K., Stavros, T., Tamura, R., Wood, K., Xu, P., Young, K., Alies, P., Badias, F., Baker, A., Bassi, M., Beam, C., Boulware, D., Bounmananh, L., Bream, S., Freeman, D., Gough, J., Ginem, J., Granger, M., Kieffer, M.H.M., Lane, P., Linton, C., Nallamshetty, L., Oduah, V., Parrimon, Y., Paulus, K., Pilger, J., Ramiro, J., Ritzie, A.L., Sharma, A., Shor, A., Song, X., Terry, A., Weinberger, J., Wootten, M., Harding, P., McDonough, S., Mcgee, P.F., Hess, K.O., Phoebus, D., Quinlan, S., Raiden, E., Batts, E., Buddy, C., Kirpatrick, K., Ramey, M., Shultz, A., Webb, C., Romesco, M., Fradkin, J., Aas, S., Blumberg, E., Beck, G., Brillon, D., Gubitosi-Klug, R., Laffel, L., Vigersky, R., Wallace, D., Braun, J., B. lo, Mitchell, H., Naji, A., Nerup, J., Orchard, T., Steffes, M., Tsiatis, A., Veatch, R., Zinman, B., Loechelt, B., Baden, L., Green, M., Weinberg, A., Marcovina, S., Palmer, J.P., Babu, S., Eisenbarth, G.S., Marks, J., Matheson, D., Gomez, D., McDonald, A., Pena, S., Pietropaolo, M., Shippy, K., Brown, T., Dove, A., Hammond, M., Hefty, D., Klein, J., Kuhns, K., Letlau, M., Lord, S., McCulloch-Olson, M., Miller, L., Odegard, J., Sachter, E., St Marie, M., Stickney, K., VanBuecken, D., Vellek, B., Webber, C., Allen, L., Bollyk, J., Hilderman, N., Ismail, H., Lamola, S., Sanda, S., Vendettuoli, H., Tridgell, D., Monzavi, R., Bock, M., Fisher, L., Halvorson, M., Jeandron, D., Kim, M., Wood, J., Geffner, M., Salazar, C., Cook, S., Freeby, M., Gallagher, M.P., Gandica, R., Greenberg, E., Kurland, A., Pollak, S., Wolk, A., Chan, M., Koplimae, L., Levine, E., Smith, K., Trast, J., Evans-Molina, C., Hufferd, R., Jagielo, B., Kruse, C., Patrick, V., Rigby, M., Spall, M., Swinney, K., Terrell, J., Christner, L., Ford, L., Lynch, S., Menendez, M., Merrill, P., and Pesc

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, Concordance, Twins, Autoimmunity, 030209 endocrinology & metabolism, Type 2 diabetes, Environment, medicine.disease_cause, Islets of Langerhans, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Seroepidemiologic Studies, Diabetes mellitus, Internal medicine, Diseases in Twins, Twins, Dizygotic, Internal Medicine, medicine, Genetic predisposition, Humans, Insulin, Mass Screening, Genetic Predisposition to Disease, 030212 general & internal medicine, Child, Mass screening, Autoantibodies, Advanced and Specialized Nursing, Type 1 diabetes, Glutamate Decarboxylase, business.industry, Siblings, Autoantibody, Twins, Monozygotic, Predicting Diabetes Using Genetic Risk Scores, medicine.disease, Diabetes Mellitus, Type 1, Endocrinology, Child, Preschool, Disease Progression, Female, business
Abstract

OBJECTIVE There are variable reports of risk of concordance for progression to islet autoantibodies and type 1 diabetes in identical twins after one twin is diagnosed. We examined development of positive autoantibodies and type 1 diabetes and the effects of genetic factors and common environment on autoantibody positivity in identical twins, nonidentical twins, and full siblings. RESEARCH DESIGN AND METHODS Subjects from the TrialNet Pathway to Prevention Study (N = 48,026) were screened from 2004 to 2015 for islet autoantibodies (GAD antibody [GADA], insulinoma-associated antigen 2 [IA-2A], and autoantibodies against insulin [IAA]). Of these subjects, 17,226 (157 identical twins, 283 nonidentical twins, and 16,786 full siblings) were followed for autoantibody positivity or type 1 diabetes for a median of 2.1 years. RESULTS At screening, identical twins were more likely to have positive GADA, IA-2A, and IAA than nonidentical twins or full siblings (all P < 0.0001). Younger age, male sex, and genetic factors were significant factors for expression of IA-2A, IAA, one or more positive autoantibodies, and two or more positive autoantibodies (all P ≤ 0.03). Initially autoantibody-positive identical twins had a 69% risk of diabetes by 3 years compared with 1.5% for initially autoantibody-negative identical twins. In nonidentical twins, type 1 diabetes risk by 3 years was 72% for initially multiple autoantibody–positive, 13% for single autoantibody–positive, and 0% for initially autoantibody-negative nonidentical twins. Full siblings had a 3-year type 1 diabetes risk of 47% for multiple autoantibody–positive, 12% for single autoantibody–positive, and 0.5% for initially autoantibody-negative subjects. CONCLUSIONS Risk of type 1 diabetes at 3 years is high for initially multiple and single autoantibody–positive identical twins and multiple autoantibody–positive nonidentical twins. Genetic predisposition, age, and male sex are significant risk factors for development of positive autoantibodies in twins.

Published
2019
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6. Effect of Oral Insulin on Prevention of Diabetes in Relatives of Patients With Type 1 Diabetes A Randomized Clinical Trial

Author

Greenbaum, C., Atkinson, M., Baidal, D., Battaglia, M., 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, D.A., 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, C.G., 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, J.B., 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, J.S., Thomas, J., Trucco, M., Wagner, J., Greenbaum, C.J., Krischer, J.P., Rafkin, L., Foulkes, M., Krause-Steinrauf, H., Lachin, J.M., Malozowski, S., Zafonte, S.J., Kenyon, N.S., Santiago, I., Bundy, B., Abbondondolo, M., Adams, T., Asif, D.A.I., Boonstra, M., Boulware, D., Burroughs, C., Cuthbertson, D., Eberhard, C., Fiske, S., Ford, J., Garmeson, J., Guillette, H., Geyer, S., Hays, B., Henderson, C., Henry, M., Heyman, K., Hsiao, B., Karges, C., Kinderman, A., Lane, L., Leinbach, A., Liu, S., Lloyd, J., Malloy, J., Maddox, K., Martin, J., Miller, J., Moore, M., Muller, S., Nguyen, T., O'Donnell, R., Parker, M., Pereyra, M.J., Reed, N., Roberts, A., Sadler, K., Stavros, T., Tamura, R., Wood, K., Xu, P., Young, K., Alies, P., Badias, F., Baker, A., Bassi, M., Beam, C., Bounmananh, L., Bream, S., Deemer, M., Freeman, D., Gough, J., Ginem, J., Granger, M., Holloway, M., Kieffer, M., Lane, P., Law, P., Linton, C., Nallamshetty, L., Oduah, V., Parrimon, Y., Paulus, K., Pilger, J., Ramiro, J., Ritzie, A.Q.L., Sharma, A., Shor, A., Song, X.H., Terry, A., Weinberger, J., Wootten, M., Harding, M.F.P., McDonough, S., Mcgee, P.F., Hess, K.O., Phoebus, D., Quinlan, S., Raiden, E., Fradkin, J., Beck, G., Blumberg, E., Gubitosi-Klug, R., Laffel, L., Veatch, R., Wallace, D., Braun, J., Brillon, D., B. lo, Mitchell, H., Naji, A., Nerup, J., Orchard, T., Steffes, M., Tsiatis, A., Zinman, B., Loechelt, B., Baden, L., Green, M., Weinberg, A., Marcovina, S., Palmer, J.P., Yu, L.P., Shultz, A., Batts, E., Fitzpatrick, K., Ramey, M., Guerra, R., Webb, C., Caffey, F., Carr, L., Ergun-Longmire, B., Fenton, C., Giebner, D., Johnson, J., Maglionico, D., Marinelli, M., Martin, K., Minnozzi, E., Riley, W., Wilson, M., Gougeon, C., Ho, J., Huang, C., Pacaud, D., Virtanen, H., Craig, C., Ghatak, A., Henderson, T., Leyland, H., Padmore, K., Paul, P., Brickman, W., Halsey-Lyda, M., Petrie, P., Rizzo, D., Steuer, R., Suchyta, K., Torchen, L., Zimmerman, D., Bode, B., Dial, M., Gazaway, K., Hosey, R., Alkanani, A., Barker, J., Barr, M., Blau, A., Burdick, P., Burke, B., Chase, H., Drye, M., Escobar, E., Fitzgerald-Miller, L., Fouts, A., Gage, V., Gall, E., Goettle, H., Harris, S., Ketchum, K., King, M., Klingensmith, G., Lehr, D., Lehr, J., Lewis, L., Logsden-Sackett, N., Lykens, J., Maahs, D., Michels, A., Pelletier, S., Rihanek, M., Rodriguez, P., Schauwecker, A., Simmons, K., Smith, J., Steck, A., Tran, B., Tran, T., Wadwa, P., Wagner, R., Wright, H., Betancourt, J., Bui, V., DeSalvo, D., Gomez, D., Jake, K., Lynds, J., McCartney, T., McDonald, A., Pena, S., Pietropaolo, M., 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, D. A., Sosenko, J., Wherrett, D., Wilson, D., Winter, W., and Ziegler, A.

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Adolescent, medicine.medical_treatment, Administration, Oral, 030209 endocrinology & metabolism, Placebo, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Interquartile range, law, Internal medicine, Diabetes mellitus, medicine, Humans, Hypoglycemic Agents, Insulin, Family, Treatment Failure, Child, Original Investigation, Autoantibodies, Type 1 diabetes, Glucose tolerance test, medicine.diagnostic_test, business.industry, General Medicine, ta3121, Glucose Tolerance Test, medicine.disease, 030104 developmental biology, Diabetes Mellitus, Type 1, Child, Preschool, Cohort, Female, business, Follow-Up Studies
Abstract

Importance Type 1 diabetes requires major lifestyle changes and carries increased morbidity and mortality. Prevention or delay of diabetes would have major clinical effect. Objective To determine whether oral insulin delays onset of type 1 diabetes in autoantibody-positive relatives of patients with type 1 diabetes. Design, Setting, and Participants Between March 2, 2007, and December 21, 2015, relatives with at least 2 autoantibodies, including insulin autoantibodies and normal glucose tolerance, were enrolled in Canada, the United States, Australia, New Zealand, the United Kingdom, Italy, Sweden, Finland, and Germany. The main study group (n = 389) had first-phase insulin release on an intravenous glucose tolerance test that was higher than the threshold. The 55 patients in the secondary stratum 1 had an identical antibody profile as the main study group except they had first-phase insulin release that was lower than the threshold. Secondary strata 2 (n = 114) and strata 3 (n = 3) had different autoantibody profiles and first-phase insulin release threshold combinations. Follow-up continued through December 31, 2016. Interventions Randomization to receive 7.5 mg/d of oral insulin (n = 283) or placebo (n = 277), including participants in the main study group who received oral insulin (n = 203) or placebo (n = 186). Main Outcome and Measures The primary outcome was time to diabetes in the main study group. Significance was based on a 1-sided threshold of .05, and 1-sided 95% CIs are reported. Results Of a total of 560 randomized participants (median enrollment age, 8.2 years; interquartile range [IQR], 5.7-12.1 years; 170 boys [60%]; 90.7% white non-Hispanic; 57.6% with a sibling with type 1 diabetes), 550 completed the trial including 389 participants (median age, 8.4 years; 245 boys [63%]), 382 (96%) in the main study group. During a median follow-up of 2.7 years (IQR, 1.5-4.6 years) in the main study group, diabetes was diagnosed in 58 participants (28.5%) in the oral insulin group and 62 (33%) in the placebo group. Time to diabetes was not significantly different between the 2 groups (hazard ratio [HR], 0.87; 95% CI, 0-1.2;P = .21). In secondary stratum 1 (n = 55), diabetes was diagnosed in 13 participants (48.1%) in the oral insulin group and in 19 participants (70.3%) in the placebo group. The time to diabetes was significantly longer with oral insulin (HR, 0.45; 95% CI, 0-0.82;P = .006). The HR for time to diabetes for the between-group comparisons for the 116 participants in the other secondary stratum was 1.03 (95% CI, 0-2.11;P = .53) and for the entire cohort of 560 participants was 0.83 (95% CI, 0-1.07;P = .11), which were not significantly different. The most common adverse event was infection (n = 254), with 134 events in the oral insulin group and 120 events in the placebo group, but no significant study-related adverse events occurred. Conclusions and Relevance Among autoantibody-positive relatives of patients with type 1 diabetes, oral insulin at a dose of 7.5 mg/d, compared with placebo, did not delay or prevent the development of type 1 diabetes over 2.7 years. These findings do not support oral insulin as used in this study for diabetes prevention. Trial Registration clinicaltrials.gov Identifier:NCT00419562

Published
2017

7. Effect of 0.005% latanoprost once daily on intraocular pressure in glaucomatous patients not adequately controlled by beta-blockers twice daily: a 3-year follow-up. Experience and incidence of side effects in a prospective study on 76 patients

Author

Francesco Parmeggiani, Antonio Del Prete, Ciro Costagliola, Leonardo Mastropasqua, Paolo Pio Antinozzi, Rosa Fusco, M Verolino, Costagliola, Ciro, DEL PRETE, A, Verolino, M, Antinozzi, P, Fusco, R, Parmeggiani, F, and Mastropasqua, L.

Subjects
Adult, Male, Intraocular pressure, genetic structures, medicine.medical_treatment, Adrenergic beta-Antagonists, Timolol, Glaucoma, Cellular and Molecular Neuroscience, chemistry.chemical_compound, medicine, Humans, Prospective Studies, Latanoprost, Prospective cohort study, Antihypertensive Agents, Intraocular Pressure, Aged, Chemotherapy, business.industry, Incidence (epidemiology), Eye drop, Middle Aged, medicine.disease, eye diseases, Sensory Systems, Ophthalmology, chemistry, Anesthesia, Prostaglandins F, Synthetic, Female, sense organs, Ophthalmic Solutions, Safety, Visual Fields, business, Glaucoma, Open-Angle, medicine.drug, Follow-Up Studies
Abstract

To assess the efficacy and side effects of 0.005% latanoprost once daily during 3 years of treatment in glaucomatous patients in whom intraocular pressure (IOP) was not adequately controlled by beta-blockers twice daily.An unmasked prospective study was performed on 76 glaucomatous patients (145 eyes) treated with 0.005% latanoprost at bedtime, after a 21-day wash-out period from beta-blockers. IOP measurement and visual field examination were recorded over the follow-up period.Latanoprost significantly reduced IOP from 26.5+/-6.6 mmHg (mean +/- SD) to 17.4+/-2.7 mmHg after 36 months of treatment in 48 patients (63.1%), who completed the trial. Twenty-eight patients (36.8%) discontinued the therapy. In 12 patients (15.8%) the treatment did not obtain a satisfactory target IOP. In two subjects (2.6%), despite the IOP reduction, visual field damage progressed. The remaining 10 patients (13.1%) discontinued the treatment because of the following side effects: microfollicular conjunctivitis (seven cases); severe oedema of conjunctiva and eyelids (one case); corneal punctate erosion (one case); cystoid macular oedema (one case). No flare or pigmentary changes of iris and eyelash were observed.Latanoprost 0.005% once daily significantly reduces IOP in the majority of glaucomatous patients uncontrolled by beta-blockers. The reduction of IOP was statistically significant during 3 years of follow-up, confirming the clinical efficacy of this compound. The ocular side effects requiring cessation of therapy were mainly allergic reactions. The most severe adverse effects were one case of corneal punctate erosion and one case of cystoid macular oedema in a pseudophakic patient.

Published
2001

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