For individuals with Type 1 diabetes (T1DM) hypoglycemia remains the principal factor limiting the achievement of near-normal glucose control, which has been shown to reduce the microvascular complications of diabetes. This proposal aims to investigate the role of AMP-activated protein kinase (AMPK) in the ventromedial hypothalamus (VMH) in the mechanisms used by the brain to sense a falling glucose and to trigger glucose counterregulatory responses. It will also determine whether alterations in AMPK expression and activity may underlay the defects in hypoglycemia couterregulation that develop following recurrent hypoglycemia. In vivo hyperinsulinemic hypoglycemic clamps studies following microinjection of an AMPK activator to the VMH will be performed in (i) Sprague-Dawley (SD) rats to determine whether this results in the generation of a neural signal to the liver to stimulate hepatic glucose production, (ii) SD rats who have undergone 3 days of recurrent hypoglycemia to determine whether it is possible to reverse the defects in hormonal counterregulation that result from recurrent hypoglycemia by further stimulating AMPK. Additional, in vivo hyperinsulinemic glucose clamp studies following VMH microinjection of varying amounts of AMPK activator will be performed to investigate the dose-response nature of AMPK activation during hypoglycemia, and the effect of recurrent hypoglycemia on this signaling system. To support the in vivo studies in vitro Westem, and AMPK activity, analyses obtained from micropunches of rat VMH under varying physiological conditions will be obtained. Finally, the proposal aims to obtain data that will support the hypothesis that recurrent hypoglycemia induces mitochondrial biogenesis in the VMH, an effect that may be mediated by AMPK.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK069831-03
Application #
7074765
Study Section
Special Emphasis Panel (ZDK1-GRB-N (O1))
Program Officer
Arreaza-Rubin, Guillermo
Project Start
2004-09-30
Project End
2009-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
3
Fiscal Year
2006
Total Cost
$279,402
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Sang, Zhen; Zhou, Ligang; Fan, Xiaoning et al. (2010) Radix astragali (huangqi) as a treatment for defective hypoglycemia counterregulation in diabetes. Am J Chin Med 38:1027-38
Zhou, Ligang; Podolsky, Nina; Sang, Zhen et al. (2010) The medial amygdalar nucleus: a novel glucose-sensing region that modulates the counterregulatory response to hypoglycemia. Diabetes 59:2646-52
Page, Kathleen A; Williamson, Anne; Yu, Namyi et al. (2009) Medium-chain fatty acids improve cognitive function in intensively treated type 1 diabetic patients and support in vitro synaptic transmission during acute hypoglycemia. Diabetes 58:1237-44
Fan, Xiaoning; Ding, Yuyan; Cheng, Haiying et al. (2008) Amplified hormonal counterregulatory responses to hypoglycemia in rats after systemic delivery of a SUR-1-selective K(+) channel opener? Diabetes 57:3327-34
Tong, Qingchun; Ye, ChianPing; McCrimmon, Rory J et al. (2007) Synaptic glutamate release by ventromedial hypothalamic neurons is part of the neurocircuitry that prevents hypoglycemia. Cell Metab 5:383-93
Cheng, Haiying; Zhou, Ligang; Zhu, Wanling et al. (2007) Type 1 corticotropin-releasing factor receptors in the ventromedial hypothalamus promote hypoglycemia-induced hormonal counterregulation. Am J Physiol Endocrinol Metab 293:E705-12
McCrimmon, Rory J; Fan, Xiaoning; Cheng, Haiying et al. (2006) Activation of AMP-activated protein kinase within the ventromedial hypothalamus amplifies counterregulatory hormone responses in rats with defective counterregulation. Diabetes 55:1755-60