Iatrogenic hypoglycemia is the most serious acute complication in intensively insulin-treated diabetes and it remains the limiting factor in maintaining proper glycemic control. The brain, and especially the ventromedial hypothalamus (VMH), plays a crucial role in sensing hypoglycemia and in initiating the physiological counterregulatory responses that correct it. However, both reoccurring exposure to hypoglycemia and longstanding diabetes can impair the mechanisms that normally correct hypoglycemia. This research proposal addresses whether diabetes and antecedent hypoglycemia alter brain fuel metabolism in a manner that prevents it from properly sensing falling blood glucose levels. The long-term objectives of this research are to understand how the brain senses changes in blood glucose levels, how it communicates these signals to peripheral organs to initiate counterregulatory responses and why these mechanisms are impaired with antecedent hypoglycemia and in diabetes. It is essential that we achieve a better understanding of how the body detects and activates defense mechanisms against hypoglycemia so that appropriate therapies can be developed to more effectively prevent hypoglycemia outcomes in diabetic patients. If proven successful, these studies could potentially reveal new therapeutic targets for the development of insulin co-therapies.

Public Health Relevance

Achieving a better understanding of how the body detects and activates defense mechanisms against low blood sugars or 'hypoglycemia' is essential for developing appropriate therapies to more effectively prevent hypoglycemia outcomes in diabetic patients. If hypoglycemia can be prevented, it will enable physicians to treat diabetes more aggressively and allow patients to achieve more optimal glucose targets, decrease the risk of diabetic complications and improve lifelong outcomes. This will undoubtedly have a significant impact on the ~24 million Americans who currently suffer from diabetes and alleviate some of the $174B in healthcare dollars that go into treating diabetes and its associated complications such as neuropathy, cardiovascular and renal complications.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Teff, Karen L
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Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
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Hammadi, Soumia; Chan, Owen; Abdellali, Mohamed et al. (2018) Hyperactivation of the hypothalamo-pituitary-adrenocortical axis in streptozotocin-diabetic gerbils (Gerbillus gerbillus). Int J Exp Pathol 99:172-179
Chowdhury, Golam M I; Wang, Peili; Ciardi, Alisha et al. (2017) Impaired Glutamatergic Neurotransmission in the Ventromedial Hypothalamus May Contribute to Defective Counterregulation in Recurrently Hypoglycemic Rats. Diabetes 66:1979-1989
Yue, Jessica T Y; Abraham, Mona A; Bauer, Paige V et al. (2016) Inhibition of glycine transporter-1 in the dorsal vagal complex improves metabolic homeostasis in diabetes and obesity. Nat Commun 7:13501
Kudrick, Necla; Chan, Owen; La Gamma, Edmund F et al. (2015) Posttranscriptional regulation of adrenal TH gene expression contributes to the maladaptive responses triggered by insulin-induced recurrent hypoglycemia. Physiol Rep 3:
Fan, Xiaoning; Chan, Owen; Ding, Yuyan et al. (2015) Reduction in SGLT1 mRNA Expression in the Ventromedial Hypothalamus Improves the Counterregulatory Responses to Hypoglycemia in Recurrently Hypoglycemic and Diabetic Rats. Diabetes 64:3564-72
Chan, Owen; Sherwin, Robert S (2014) Is there cross talk between portal and hypothalamic glucose-sensing circuits? Diabetes 63:2617-9
LaGamma, Edmund F; Kirtok, Necla; Chan, Owen et al. (2014) Partial blockade of nicotinic acetylcholine receptors improves the counterregulatory response to hypoglycemia in recurrently hypoglycemic rats. Am J Physiol Endocrinol Metab 307:E580-8
Chan, Owen; Paranjape, Sachin A; Horblitt, Adam et al. (2013) Lactate-induced release of GABA in the ventromedial hypothalamus contributes to counterregulatory failure in recurrent hypoglycemia and diabetes. Diabetes 62:4239-46
Chan, Owen; Sherwin, Robert (2013) Influence of VMH fuel sensing on hypoglycemic responses. Trends Endocrinol Metab 24:616-24