Both type 1 and 2 diabetes are caused by inadequate insulin secretion, and in both diseases this can be ascribed in large part to loss of pancreatic beta cells that produce insulin. Both diseases can be cured by replacement of pancreatic beta cells by pancreas transplantation but this requires life long immunosuppression and there are far fewer organ donors than people with diabetes. An alternative approach to restoring pancreatic beta cells is to foster regeneration of beta cells in the patient. Is this plausible? In rodents yes, but human beta cell biology is clearly different to that in rodents. The studies proposed in this application would address the question, to what extent is beta cell regeneration feasible in humans? This goal will be approached by addressing four Specific Aims. First, we will establish the extent (and by what mechanisms) beta cell mass increases in human childhood. Second, we will establish the extent (and by what mechanisms) beta cell mass increases in response to obesity in humans. Third, we will establish if beta cell mass is maintained in non diabetic aging humans, and if so by what mechanisms. Fourth, we examine the ability of cord blood stem cells to transdifferentiate into beta cells in humans (since this approach is already in clinical trials). To accomplish these goals we will obtain well preserved human pancreas at autopsy in patients in who a recent ambulatory general medical examination (and labs) is available. We will apply a recently developed model to compute beta cell turnover permitting us to quantify beta cell turnover, and distinguish between new beta cell formation from beta cell replication and replication independent sources. These studies would be undertaken by a consortium with a long established track record of productive research with these resources.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK077967-05
Application #
8225339
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Appel, Michael C
Project Start
2008-01-15
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
5
Fiscal Year
2012
Total Cost
$301,784
Indirect Cost
$86,162
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Butler, Peter C (2016) Glucagon-like Peptide 1 Drugs as Second-line Therapy for Type 2 Diabetes. JAMA Intern Med 176:1-3
Md Moin, Abu Saleh; Butler, Peter C; Butler, Alexandra E (2016) Increased Proliferation of the Pancreatic Duct Gland Compartment in Type 1 Diabetes. J Clin Endocrinol Metab :jc20163001
Butler, Alexandra E; Matveyenko, Aleksey V; Kirakossian, David et al. (2016) Recovery of high-quality RNA from laser capture microdissected human and rodent pancreas. J Histotechnol 39:59-65
Md Moin, Abu Saleh; Dhawan, Sangeeta; Shieh, Christine et al. (2016) Increased Hormone-Negative Endocrine Cells in the Pancreas in Type 1 Diabetes. J Clin Endocrinol Metab 101:3487-96
Md Moin, Abu Saleh; Dhawan, Sangeeta; Cory, Megan et al. (2016) Increased Frequency of Hormone Negative and Polyhormonal Endocrine Cells in Lean Individuals With Type 2 Diabetes. J Clin Endocrinol Metab 101:3628-3636
Butler, Alexandra E; Dhawan, Sangeeta; Hoang, Jonathan et al. (2016) β-Cell Deficit in Obese Type 2 Diabetes, a Minor Role of β-Cell Dedifferentiation and Degranulation. J Clin Endocrinol Metab 101:523-32
Gurlo, Tatyana; Butler, Peter C; Butler, Alexandra E (2016) Evaluation of immunohistochemical staining for glucagon in human pancreatic tissue. J Histotechnol 39:8-16
Saisho, Yoshifumi; Butler, Alexandra E; Manesso, Erica et al. (2013) Response to Comment on: Saisho et al. β-cell mass and turnover in humans: effects of obesity and aging. Diabetes Care 2013;36:111-117. Diabetes Care 36:e112
Costes, Safia; Langen, Ralf; Gurlo, Tatyana et al. (2013) β-Cell failure in type 2 diabetes: a case of asking too much of too few? Diabetes 62:327-35
Butler, Peter C; Elashoff, Michael; Elashoff, Robert et al. (2013) A critical analysis of the clinical use of incretin-based therapies: Are the GLP-1 therapies safe? Diabetes Care 36:2118-25

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