Objectives of the current RFA include elucidating the """"""""identity, locus and functional characteristics of glucose sensing neurons"""""""", understanding """"""""the relative roles and interactions of peripheral and central glucose sensing"""""""", and determining """"""""how these are altered with recurrent hypoglycemia"""""""". While two important loci for hypoglycemic detection have been identified, the brain and portal vein, the specific neurons involved, the mechanism(s) by which they detect ambient glycemia, and how afferent input from these two critical loci is integrated remain to be fully elucidated. Our long-term goal is to elucidate the mechanisms of peripheral hypoglycemic detection, providing insight towards more effective treatment of diabetes. In the current proposal we focus on the portal vein glucosensors. We provided the first physiological evidence that glucosensors in the portohepatis were important for the sympathoadrenal response to hypoglycemia. Subsequently we constrained the glucosensing locus to the portal vein and demonstrated the essential role of portal vein innervation. In the Preliminary Results we provide new evidence that the neurons involved in portal glucose sensing are spinal in origin (not vagal), capsaicin sensitive, and respond to alternative fuels, e.g. lactate. ? ? In the current proposal we will employ selective denervation procedures and the """"""""local irrigation technique""""""""(developed in our lab) to address the following specific aims: 1) to identify the origin, axis and type of neurons involved in for portal vein glucose sensing, 2) ascertain the relative contribution of portal vein vs. CNS glucosensors towards hypoglycemic detection under conditions of varying rates of glycemic decline, and 3) to quantify the impact of recurrent hypoglycemia upon portal glucosensing and elucidate the mechanism(s) underlying this impairment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK062471-04
Application #
6909867
Study Section
Special Emphasis Panel (ZRG1-END (03))
Program Officer
Arreaza-Rubin, Guillermo
Project Start
2002-07-16
Project End
2008-06-30
Budget Start
2005-07-01
Budget End
2008-06-30
Support Year
4
Fiscal Year
2005
Total Cost
$325,000
Indirect Cost
Name
University of Southern California
Department
Miscellaneous
Type
Schools of Arts and Sciences
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Donovan, Casey M; Watts, Alan G (2014) Peripheral and central glucose sensing in hypoglycemic detection. Physiology (Bethesda) 29:314-24
Routh, Vanessa H; Donovan, Casey M; Ritter, Sue (2012) 2. Hypoglycemia Detection. Transl Endocrinol Metab 3:47-87
Watts, Alan G; Donovan, Casey M (2010) Sweet talk in the brain: glucosensing, neural networks, and hypoglycemic counterregulation. Front Neuroendocrinol 31:32-43
Saberi, Maziyar; Bohland, MaryAnn; Donovan, Casey M (2008) The locus for hypoglycemic detection shifts with the rate of fall in glycemia: the role of portal-superior mesenteric vein glucose sensing. Diabetes 57:1380-6
Gorton, Lori M; Khan, Arshad M; Bohland, Maryann et al. (2007) A role for the forebrain in mediating time-of-day differences in glucocorticoid counterregulatory responses to hypoglycemia in rats. Endocrinology 148:6026-39
Fujita, Satoshi; Bohland, Maryann; Sanchez-Watts, Graciela et al. (2007) Hypoglycemic detection at the portal vein is mediated by capsaicin-sensitive primary sensory neurons. Am J Physiol Endocrinol Metab 293:E96-E101
Matveyenko, Aleksey V; Bohland, Maryann; Saberi, Maziyar et al. (2007) Portal vein hypoglycemia is essential for full induction of hypoglycemia-associated autonomic failure with slow-onset hypoglycemia. Am J Physiol Endocrinol Metab 293:E857-64