The overall objective of these studies is to better understand pancreatic beta and alpha cell function in human recipients of successful pancreas and islet transplantation who are taking immunosuppressive drugs and to better ascertain metabolic consequences of hemi-pancreatectomy in human donors of pancreatic segments. The general intent of the work proposed is to continue our long term follow up of recipients and donors of pancreas transplantation and to initiate new studies of type 1 diabetic recipients of intrahepatic autoislet transplantation with a major emphasis on developing an understanding why initially successful alloislet recipients later develop islet failure; the mechanism of action by which immunosuppressive drugs are toxic to beta cells; and developing a better understanding of the failure of the intrahepatic alpha cell to secrete glucagon during hypoglycemia.
The Specific Aims for this proposal are:
Specific Aim # 1. To continue long-term, longitudinal studies of insulin secretory reserve and counterregulatory hormonal responses to hypoglycemia in successful recipients of pancreas transplants and in living donors of pancreatic segments to determine whether islet beta cell and alpha cell function are stable or undergo deterioration with time.
Specific Aim # 2. To determine whether deterioration in glycemic control after successful alloislet transplantation in type 1 diabetic patients is related to resurgence of autoimmune disease, and/or toxic effects of immunosuppressive drugs, and/or the quantity and quality of islets transplanted and/or the development of obesity and insulin resistance.
Specific Aim # 3. To determine, using human isolated islets, the immunosuppressive drug concentration-adverse biologic response relationships for islet hormonal secretion, apoptosis, and cellular replication.
Specific Aim #4. To determine whether the glucagon response to hypoglycemia is consistently absent and the epinephrine response to hypoglycemia is consistently restored in successful type 1 diabetic recipients of alloislets.
Specific Aim # 5. To determine whether the glucagon response that normally occurs during hypoglycemia is dependent on a decrease in insulin secretion from adjacent beta cells as a """"""""switch off' signal. The metabolic testing of pancreas and islet recipients as well as hemi-pancreatectomized donors will take place at the University of Washington and the University of Minnesota GCRC's. The methods will include glucose potentiation of arginine induced insulin secretion, euglycemic hyperinsulinemic clamps, and hypoglycemic hyperinsulinemic clamps. The laboratory methods will include isolated human islets and studies of insulin promoter activity, insulin mRNA levels, insulin content, and insulin secretion. Studies of the mechanism of glucagon release during hypoglycemia and its disappearance in the absence of beta cells will be conducted in Sprague Dawley rats.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK039994-14
Application #
6541707
Study Section
Endocrinology Study Section (END)
Program Officer
Appel, Michael C
Project Start
1988-12-01
Project End
2006-07-31
Budget Start
2002-09-02
Budget End
2003-07-31
Support Year
14
Fiscal Year
2002
Total Cost
$417,813
Indirect Cost
Name
Pacific Northwest Research Institute
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98122
Robertson, R Paul; Bogachus, Lindsey D; Oseid, Elizabeth et al. (2015) Assessment of ?-cell mass and ?- and ?-cell survival and function by arginine stimulation in human autologous islet recipients. Diabetes 64:565-72
Robertson, R Paul (2015) Puzzling about partial glucagon responses to hypoglycemia in intrahepatic islet recipients: missing pieces. Diabetes 64:1511-2
Robertson, R Paul (2015) Islet transplantation for type 1 diabetes, 2015: what have we learned from alloislet and autoislet successes? Diabetes Care 38:1030-5
Robertson, R Paul (2015) Total pancreatectomy and islet autotransplantation for chronic pancreatitis: breaking down barriers. J Clin Endocrinol Metab 100:1762-3
Bellin, M D; Parazzoli, S; Oseid, E et al. (2014) Defective glucagon secretion during hypoglycemia after intrahepatic but not nonhepatic islet autotransplantation. Am J Transplant 14:1880-6
Bellin, Melena D; Freeman, Martin L; Gelrud, Andres et al. (2014) Total pancreatectomy and islet autotransplantation in chronic pancreatitis: recommendations from PancreasFest. Pancreatology 14:27-35
Robertson, R Paul; Raymond, Ralph H; Lee, Douglas S et al. (2014) Arginine is preferred to glucagon for stimulation testing of ?-cell function. Am J Physiol Endocrinol Metab 307:E720-7
Robertson, R P; Zhou, H; Slucca, M (2011) A role for zinc in pancreatic islet ýý-cell cross-talk with the ýý-cell during hypoglycaemia. Diabetes Obes Metab 13 Suppl 1:106-11
Robertson, R Paul (2009) Beta-cell deterioration during diabetes: what's in the gun? Trends Endocrinol Metab 20:388-93
Zhou, Huarong; Zhang, Tao; Bogdani, Marika et al. (2008) Intrahepatic glucose flux as a mechanism for defective intrahepatic islet alpha-cell response to hypoglycemia. Diabetes 57:1567-74

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