This proposal investigates the effects of recurrent hypoglycemia on glucose sensing neurons (GSNs) in the ventromedial hypothalamic nucleus (VMN). The overall objective is to gain an in depth understanding of the cellular signaling pathways by which hypoglycemia is sensed by the brain and how hypoglycemia induced alterations in these pathways may lead to hypoglycemia- associated autonomic failure (HAAF). The two hypotheses in this proposal directly address these issues. HYPOTHESIS I is that NO is an obligatory step in central glucose sensing and initiation of the counterregulatory response to hypoglycemia. However excess NO production during recurrent insulin-hypoglycemia impairs the counterregulatory response to subsequent hypoglycemia leading to HAAF. A combination of in vitro and in vivo techniques will test this hypothesis at the cellular and whole animal level. These experiments will investigate the role of a positive feedback between NO and AMP activated protein kinase in glucose sensing by VMN GSNs and initiation of the counterregulatory response to hypoglycemia. HYPOTHESIS II is that the supraphysiological NO production in response to insulin-induced hypoglycemia desensitizes the NO signaling pathway, impairing glucose sensing and leading to the developemnt of HAAF. The proposed mechanism for desensitization is that NO causes S-nitrosylation of neuronal soluble guanylyl cyclase (the NO receptor), rendering glucose sensing neurons non-responsive to subsequent NO production. These studies will provide important information regarding the way that recurrent hypoglycemia resets the glucose threshold of the brain, leading to HAAF. This will facilitate the development of new, effective, and safe treatments for Type I diabetes mellitus and its major modern complication, hypoglycemia.
Tight glycemic control with intensive insulin or glucose lowering therapies significantly improves diabetic-related complications. However, recurrent hypoglycemia, a side effect of insulin therapy, impairs the ability of the brain to sense hypoglycemia and initiate corrective responses. This proposal investigates the mechanisms by which the glucose threshold of the brain is reset, and how this may be restored to normal.
|Santiago, Ammy M; Clegg, Deborah J; Routh, Vanessa H (2016) Ventromedial hypothalamic glucose sensing and glucose homeostasis vary throughout the estrous cycle. Physiol Behav 167:248-254|
|Santiago, Ammy M; Clegg, Deborah J; Routh, Vanessa H (2016) Estrogens modulate ventrolateral ventromedial hypothalamic glucose-inhibited neurons. Mol Metab 5:823-33|
|Fioramonti, Xavier; Deak, Adam; Deshpande, Srinidhi et al. (2013) Hypothalamic S-nitrosylation contributes to the counter-regulatory response impairment following recurrent hypoglycemia. PLoS One 8:e68709|
|Routh, Vanessa H; Donovan, Casey M; Ritter, Sue (2012) 2. Hypoglycemia Detection. Transl Endocrinol Metab 3:47-87|
|Fioramonti, Xavier; Song, Zhentao; Vazirani, Reema P et al. (2011) Hypothalamic nitric oxide in hypoglycemia detection and counterregulation: a two-edged sword. Antioxid Redox Signal 14:505-17|
|Diggs-Andrews, Kelly A; Zhang, Xuezhao; Song, Zhentao et al. (2010) Brain insulin action regulates hypothalamic glucose sensing and the counterregulatory response to hypoglycemia. Diabetes 59:2271-80|
|Fioramonti, Xavier; Marsollier, Nicolas; Song, Zhentao et al. (2010) Ventromedial hypothalamic nitric oxide production is necessary for hypoglycemia detection and counterregulation. Diabetes 59:519-28|
|Routh, Vanessa H (2010) Glucose sensing neurons in the ventromedial hypothalamus. Sensors (Basel) 10:9002-25|
|Murphy, Beth Ann; Fakira, Kurt A; Song, Zhentao et al. (2009) AMP-activated protein kinase and nitric oxide regulate the glucose sensitivity of ventromedial hypothalamic glucose-inhibited neurons. Am J Physiol Cell Physiol 297:C750-8|
|Marsollier, Nicolas; Kassis, Nadim; Mezghenna, Karima et al. (2009) Deregulation of hepatic insulin sensitivity induced by central lipid infusion in rats is mediated by nitric oxide. PLoS One 4:e6649|