Effects of exenatide alone and in combination with daclizumab on beta-cell function in long-standing type 1 diabetes.
OBJECTIVE
In patients with long-standing type 1 diabetes, we investigated whether improved beta-cell function can be achieved by combining intensive insulin therapy with agents that may 1) promote beta-cell growth and/or limit beta-cell apoptosis and 2) weaken the anti-beta-cell autoimmunity.


METHODS
For this study, 20 individuals (mean age 39.5 +/- 11.1 years) with long-standing type 1 diabetes (21.3 +/- 10.7 years) were enrolled in this prospective open-label crossover trial. After achieving optimal blood glucose control, 16 subjects were randomized to exenatide with or without daclizumab. Endogenous insulin production was determined by repeatedly measuring serum C-peptide.


RESULTS
In 85% of individuals with long-standing type 1 diabetes who were screened for participation in this trial, C-peptide levels >or=0.05 ng/ml (0.02 nmol/l) were found. Residual beta-cells responded to physiological (mixed-meal) and pharmacological (arginine) stimuli. During exenatide treatment, patients lost 4.1 +/- 2.9 kg body wt and insulin requirements declined significantly (total daily dose on exenatide 0.48 +/- 0.11 vs. 0.55 +/- 0.13 units x kg(-1) x day(-1) without exenatide; P = 0.0062). No signs of further activation of the underlying autoimmune disease were observed. Exenatide delayed gastric emptying, suppressed endogenous incretin levels, but did not increase C-peptide secretion.


CONCLUSIONS
In long-standing type 1 diabetes, which remains an active autoimmune disease even decades after its onset, surviving beta-cells secrete insulin in a physiologically regulated manner. However, the combination of intensified insulin therapy, exenatide, and daclizumab did not induce improved function of these remaining beta-cells.
Rother
Kristina I
KI
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA. kristina.rother@nih.gov
Spain
Lisa M
LM
Wesley
Robert A
RA
Digon
Benigno J
BJ
Baron
Alain
A
Chen
Kim
K
Nelson
Patric
P
Dosch
H-Michael
HM
Palmer
Jerry P
JP
Brooks-Worrell
Barbara
B
Ring
Michael
M
Harlan
David M
DM
D000328:Adult; D017668:Age of Onset; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015551:Autoimmunity / Q000187:drug effects; D018592:Cross-Over Studies; D000077561:Daclizumab; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D004359:Drug Therapy, Combination; D000077270:Exenatide; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006684:HLA-DR Antigens / Q000032:analysis; D059811:HLA-DRB1 Chains; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007328:Insulin / Q000627:therapeutic use; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008297:Male; D010455:Peptides / Q000627:therapeutic use*; D012107:Research Design; D011795:Surveys and Questionnaires; D014481:United States; D014688:Venoms / Q000627:therapeutic use*; D055815:Young Adult
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000077561:Daclizumab; D000077270:Exenatide; D006442:Glycated Hemoglobin; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D007004:Hypoglycemic Agents; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D007328:Insulin; D010455:Peptides; D014688:Venoms