Project Details
Description
Project Summary/Abstract
Endogenous glucose production (EGP) is a crucial process that maintains blood
glucose levels under fasting conditions and is normally inhibited by both glucose and
insulin. Inappropriately high EGP is the major source of hyperglycemia in individuals
with type 2 diabetes (T2D) and contributes significantly to diabetes complications. Our
groups’ ongoing work suggests that central nervous system (CNS) signals play an
important role in regulating EGP. ATP-sensitive potassium (KATP) channels in the
ventromedial hypothalamus (VMH) appear to mediate some of the suppressive effects
of circulating insulin and glucose on EGP, but this regulation is impaired in T2D and
diabetic rodents. We have observed that lowering free fatty acid (FFA) levels completely
restored the regulation of EGP by central KATP channel activation. Therefore, we
hypothesize that chronic lipid overload may contribute to the central signaling defects in
T2D. Thus, through complementary human and rodent studies we propose to expand
our understanding of how specific CNS signaling pathways regulate EGP through the
following specific aims: 1) To establish whether central regulation of EGP can be
restored by lowering FFA levels in patients with T2D, 2) To determine whether intact
hepatic innervation is required for restoration of central regulation of EGP upon lowering
FFA in individuals with T2D, and 3) To establish whether the impaired central regulation
of EGP in T2D is mediated by neuron-specific defects in KATP channel activation within
the VMH. Furthermore, we will determine whether lowering FFA levels contributes to
restoring central regulation of glucose production by reducing endoplasmic reticulum
(ER) stress in specific glucose-sensing neurons. Collectively, these studies should
provide mechanistic explanation(s) for the impaired central regulation of EGP in T2D
and help point toward novel therapeutic targets.
Status | Active |
---|---|
Effective start/end date | 6/15/06 → 4/30/24 |
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases: $563,391.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $729,169.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $510,604.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $560,206.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $323,823.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $46,419.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $705,944.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $323,823.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $330,431.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $553,838.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $340,129.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $320,584.00
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