Modulation of β-adrenergic receptors in the ventromedial hypothalamus influences counterregulatory responses to hypoglycemia
Open accessAbstract
OBJECTIVE: Norepinephrine is locally released into the ventromedial hypothalamus (VMH), a key brain glucose-sensing region in the response to hypoglycemia. As a result, this neurotransmitter may play a role in modulating counterregulatory responses. This study examines whether norepinephrine acts to promote glucose counterregulation via specific VMH β-adrenergic receptors (BAR). RESEARCH DESIGN AND METHODS: Awake male Sprague-Dawley rats received, via implanted guide cannulae, bilateral VMH microinjections of 1) artificial extracellular fluid, 2) B2AR agonist, or 3) B2AR antagonist. Subsequently, a hyperinsulinemic-hypoglycemic clamp study was performed. The same protocol was also used to assess the effect of VMH delivery of a selective B1AR or B3AR antagonist. RESULTS: Despite similar insulin and glucose concentrations during the clamp, activation of B2AR in the VMH significantly lowered by 32% (P < 0.01), whereas VMH B2AR blockade raised by 27% exogenous glucose requirements during hypoglycemia (P < 0.05) compared with the control study. These changes were associated with alternations in counterregulatory hormone release. Epinephrine responses throughout hypoglycemia were significantly increased by 50% when the B2AR agonist was delivered to the VMH (P < 0.01) and suppressed by 32% with the B2AR antagonist (P < 0.05). The glucagon response was also increased by B2AR activation by 63% (P < 0.01). Neither blockade of VMH B1AR nor B3AR suppressed counterregulatory responses to hypoglycemia. Indeed, the B1AR antagonist increased rather than decreased epinephrine release (P < 0.05). CONCLUSIONS: Local catecholamine release into the VMH enhances counterregulatory responses to hypoglycemia via stimulation of B2AR. These observations suggest that B2AR agonists might have therapeutic benefit in diabetic patients with defective glucose counterregulation.
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Cites
(1993) · New England Journal of Medicine · doi:10.1056/nejm199309303291401 · Cited by 24,667 · see citing works
Hypoglycemia in the Diabetes Control and Complications Trial
The Diabetes Control and Complications Trial Research Group (1997) · Diabetes · doi:10.2337/diab.46.2.271 · Cited by 746 · see citing works
Gerich, J. E., Langlois, M., Noacco, C., Karam, J. H., & Forsham, P. H. (1973) · Science · doi:10.1126/science.182.4108.171 · Cited by 688 · see citing works
Tong, Q., Ye, C., McCrimmon, R. J., Dhillon, H., Choi, B., Kramer, M. D., Yu, J., Yang, Z., Christiansen, L. M., Lee, C. E., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.04.001 · Cited by 413 · see citing works
Brain Glucose Sensing, Counterregulation, and Energy Homeostasis
Marty, N., Dallaporta, M., & Thorens, B. (2007) · Physiology · doi:10.1152/physiol.00010.2007 · Cited by 330 · see citing works
Amiel, S. A., Tamborlane, W. V., Simonson, D. C., & Sherwin, R. S. (1987) · New England Journal of Medicine · doi:10.1056/nejm198705283162205 · Cited by 309 · see citing works
Ventromedial hypothalamic lesions in rats suppress counterregulatory responses to hypoglycemia.
Borg, W. P., During, M. J., Sherwin, R. S., Borg, M. A., Brines, M. L., & Shulman, G. I. (1994) · Journal of Clinical Investigation · doi:10.1172/jci117150 · Cited by 265 · see citing works
Sweet talk in the brain: Glucosensing, neural networks, and hypoglycemic counterregulation
Watts, A. G., & Donovan, C. M. (2009) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2009.10.006 · Cited by 176 · see citing works
Novel Glucosensor for Hypoglycemic Detection Localized to the Portal Vein
Hevener, A. L., Bergman, R. N., & Donovan, C. M. (1997) · Diabetes · doi:10.2337/diab.46.9.1521 · Cited by 176 · see citing works
Relationships between brain noradrenergic activity and blood glucose
Smythe, G. A., Grunstein, H. S., Bradshaw, J. E., Nicholson, M. V., & Compton, P. (1984) · Nature · doi:10.1038/308065a0 · Cited by 155 · see citing works
Chan, O. T. M., Zhu, W., Ding, Y., McCrimmon, R. J., & Sherwin, R. S. (2006) · Diabetes · doi:10.2337/diabetes.55.04.06.db05-0958 · Cited by 114 · see citing works
Counterregulation During Hypoglycemia Is Directed by Widespread Brain Regions
Frizzell, R. T., Jones, E. M., Davis, S. N., Biggers, D. W., Myers, S. R., Connolly, C. C., Neal, D. W., Jaspan, J. B., & Cherrington, A. D. (1993) · Diabetes · doi:10.2337/diab.42.9.1253 · Cited by 109 · see citing works
Nocturnal hypoglycemia in type 1 diabetes: an assessment of preventive bedtime treatments
Raju, B., Arbelaez, A. M., Breckenridge, S. M., & Cryer, P. E. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-2798 · Cited by 93 · see citing works
Noradrenergic and GABAergic systems in the medial hypothalamus are activated during hypoglycemia
Beverly, J. L., de Vries, M. G., Bouman, S. D., & Arseneau, L. M. (2001) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.2001.280.2.r563 · Cited by 87 · see citing works
Steffens, A. B., Scheurink, A. J. W., Luiten, P. G. M., & Bohus, B. (1988) · Physiology & Behavior · doi:10.1016/0031-9384(88)90322-8 · Cited by 85 · see citing works
Chafetz, M. D., Parko, K., Diaz, S., & LEIBOWITZ, S. F. (1986) · Brain Research · doi:10.1016/0006-8993(86)91182-0 · Cited by 64 · see citing works
CNS sensing and regulation of peripheral glucose levels
Levin, B. E., Dunn-Meynell, A. A., & Routh, V. H. (2002) · International review of neurobiology · doi:10.1016/s0074-7742(02)51007-2 · Cited by 54 · see citing works
Beverly, J. L., de Vries, M. G., Beverly, M. F., & Arseneau, L. M. (2000) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.2000.279.3.r990 · Cited by 50 · see citing works
Adrenergic mediation of hypoglycemia-associated autonomic failure
Ramanathan, R., & Cryer, P. E. (2011) · Diabetes · doi:10.2337/db10-1374 · Cited by 42 · see citing works
Hypoglycemia-induced noradrenergic activation in the VMH is a result of decreased ambient glucose
de Vries, M. G., Lawson, M. A., & Beverly, J. L. (2005) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00403.2005 · Cited by 36 · see citing works
A role for central postsynapticα2-adrenoceptors in glucoregulation
Smythe, G. A., & Edwards, S. R. (1991) · Brain Research · doi:10.1016/0006-8993(91)90625-6 · Cited by 26 · see citing works
Suppression of central noradrenergic neuronal activity inhibits hyperglycemia
Smythe, G. A., & Edwards, S. R. (1992) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1992.263.5.e823 · Cited by 26 · see citing works
Lee, J.-G., Choi, I. S., Park, E.-J., Cho, J.-H., Lee, M.-G., Choi, B.-J., & Jang, I. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2006.10.049 · Cited by 15 · see citing works
Schouwenberg, B. J. J. W., Smits, P., Tack, C. J., & de Galan, B. E. (2011) · Diabetologia · doi:10.1007/s00125-011-2062-3 · Cited by 7 · see citing works
The role of beta-adrenergic sensitivity in the pathogenesis of hypoglycaemia unawareness.
Fritsche, A., Tschritter, O., Häring, H.-U., Gerich, J. E., & Stümvoll, M. (2002) · PubMed · Cited by 7 · see citing works
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Forbes, J. M., & Cooper, M. E. (2013) · Physiological Reviews · doi:10.1152/physrev.00045.2011 · Cited by 2,890 · see citing works
Hypothalamic glucose sensing: making ends meet
Routh, V. H., Hao, L., Santiago, A. M., Sheng, Z., & Zhou, C. (2014) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2014.00236 · Cited by 166 · see citing works
Severe Hypoglycemia–Induced Lethal Cardiac Arrhythmias Are Mediated by Sympathoadrenal Activation
Reno, C. M., Daphna-Iken, D., Chen, Y. S., VanderWeele, J., Jethi, K., & Fisher, S. J. (2013) · Diabetes · doi:10.2337/db13-0216 · Cited by 159 · see citing works
Early Loss of the Glucagon Response to Hypoglycemia in Adolescents With Type 1 Diabetes
Siafarikas, A., Johnston, R. J., Bulsara, M. K., O’Leary, P., Jones, T. W., & Davis, E. A. (2012) · Diabetes Care · doi:10.2337/dc11-2010 · Cited by 120 · see citing works
Central mechanisms of glucose sensing and counterregulation in defense of hypoglycemia
Stanley, S., Moheet, A., & Seaquist, E. R. (2019) · Endocrine Reviews · doi:10.1210/er.2018-00226 · Cited by 112 · see citing works
Influence of VMH fuel sensing on hypoglycemic responses
Chan, O. T. M., & Sherwin, R. (2013) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2013.08.005 · Cited by 87 · see citing works
Insights into the role of neuronal glucokinase
Backer, I. D., Hussain, S., Bloom, S. R., & Gardiner, J. (2016) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00034.2016 · Cited by 59 · see citing works
Ventromedial hypothalamus glucose‐inhibited neurones: A role in glucose and energy homeostasis?
Hirschberg, P. R., Sarkar, P., Teegala, S. B., & Routh, V. H. (2019) · Journal of Neuroendocrinology · doi:10.1111/jne.12773 · Cited by 59 · see citing works
Defective Counterregulation and Hypoglycemia Unawareness in Diabetes
Reno, C. M., Litvin, M., Clark, A. L., & Fisher, S. J. (2012) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2012.11.005 · Cited by 53 · see citing works
Hypoglycemia in Patients with Type 1 Diabetes: Epidemiology, Pathogenesis, and Prevention
Awoniyi, O., Rehman, R., & Dagogo-Jack, S. E. (2013) · Current Diabetes Reports · doi:10.1007/s11892-013-0411-y · Cited by 53 · see citing works
Ibrahim, M. M. H., Alhamami, H. N., & Briski, K. P. (2019) · Brain Research · doi:10.1016/j.brainres.2019.01.012 · Cited by 50 · see citing works
Jensen, V. F. H., Bøgh, I. B., & Lykkesfeldt, J. (2014) · Journal of Neuroendocrinology · doi:10.1111/jne.12133 · Cited by 37 · see citing works
Interleukin-6 amplifies glucagon secretion: coordinated control via the brain and pancreas
Barnes, T. M., Otero, Y. F., Elliott, A. D., Locke, A. D., Malabanan, C. M., Coldren, A., Briššová, M., Piston, D. W., & McGuinness, O. P. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00343.2014 · Cited by 33 · see citing works
Briski, K. P., Mandal, S. K., Bheemanapally, K., & Ibrahim, M. M. H. (2020) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2020.01.013 · Cited by 32 · see citing works
Jokiaho, A. J., Donovan, C. M., & Watts, A. G. (2014) · Diabetes · doi:10.2337/db13-1753 · Cited by 31 · see citing works
Routh, V. H., Donovan, C. M., & Ritter, S. (2012) · Translational endocrinology & metabolism · doi:10.1210/team.9781936704200.ch2 · Cited by 19 · see citing works
Lontchi-Yimagou, E., Aleksic, S., Hulkower, R., Gospin, R., Goyal, A., Kuo, B., Mitchell, W. G., You, J. Y., Upadhyay, L., Carey, M., et al. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa539 · Cited by 17 · see citing works
Farhat, R., Su, G., Sejling, A.-S., Knight, N., Fisher, S. J., & Chan, O. (2019) · Diabetologia · doi:10.1007/s00125-018-4802-0 · Cited by 12 · see citing works
Jafarkhani, S., Khakbiz, M., Amoabediny, G., Mohammadi, J., Tahmasebipour, M., Rabbani, H., Salimi, A., & Lee, K. (2022) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2022.106233 · Cited by 11 · see citing works
Szepietowska, B., Zhu, W., & Sherwin, R. S. (2013) · Diabetologia · doi:10.1007/s00125-013-3009-7 · Cited by 9 · see citing works
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Belfort‐DeAguiar, R., Naik, S., Hwang, J. J., Szepietowska, B., & Sherwin, R. S. (2015) · Diabetes Care · doi:10.2337/dc14-2472 · Cited by 7 · see citing works
Li, F. R., Ohtani, A., Senzaki, K., & Shiga, T. (2012) · Developmental Neurobiology · doi:10.1002/dneu.22065 · Cited by 6 · see citing works
Farhat, R., Vliet, E. D. S. V., Su, G., Neely, L., Benally, T., & Chan, O. T. M. (2021) · Endocrinology Diabetes & Metabolism · doi:10.1002/edm2.226 · Cited by 5 · see citing works
Sejling, A., Wang, P., Zhu, W., Farhat, R., Knight, N. S., Appadurai, D. A., & Chan, O. T. M. (2020) · Endocrinology · doi:10.1210/endocr/bqaa241 · Cited by 5 · see citing works
Hagiwara, S., Jha, J. C., & Cooper, M. E. (2013) · Diabetology International · doi:10.1007/s13340-013-0148-5 · Cited by 4 · see citing works
Glucose sensing and homeostasis by adipocyte GPCR
Hasan, N., & Chhabra, K. H. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1657747 · Cited by 3 · see citing works
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Reno, C. M., Litvin, M., Clark, A. L., & Fisher, S. J. (2013)
Collares, E. F., Vinagre, A. M., & Collares‐Buzato, C. B. (2017) · Brazilian Journal of Medical and Biological Research · doi:10.1590/1414-431x20175948
Need of Beta 3 Agonist in Today's World as Oral Hypoglycaemic and Antiobesity
Kumar, V., & Das, S. (2018) · International Journal of Medical and Dental Sciences · doi:10.18311/ijmds/2018/18903
Management of Acute and Recurrent Hypoglycaemia
McCrimmon, R. J. (2013) · Wiley eBooks · doi:10.1002/9781118695432.ch8
- Authors
- Szepietowska, B., Zhu, W., Chan, O., Horblitt, A., Dziura, J., & Sherwin, R. S.
- Affiliations
- Yale University (US)
- Corresponding author
- Sherwin, Robert S.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2011-11-13
- Volume
- 60
- Issue
- 12
- Pages
- 3154-3158
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC3219955
- OpenAlex
- W2160721331
- Cited by
- 30
- References
- 25
- Citations by year
- 2025: 1 · 2022: 1 · 2021: 1 · 2020: 3 · 2019: 4 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 1 · 2014: 4 · 2013: 8 · 2012: 4
- FWCI
- 4.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- Yale University
- National Institute of Diabetes and Digestive and Kidney Diseases (R37DK020495)
- Yale Liver Center
- Yale Center for Clinical Investigation, Yale School of Medicine
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- beta2-adrenergic receptor, ventromedial hypothalamus, hypoglycemia, glucose counterregulation, norepinephrine, epinephrine, glucagon, beta1-adrenergic receptor, beta3-adrenergic receptor, hyperinsulinemic hypoglycemic clamp, glucose detection
- MeSH terms
- Formoterol Fumarate, Adrenergic beta-Antagonists, Animals, Blood Glucose, Epinephrine, Ethanolamines, Glucagon, Hypoglycemia, Imidazoles, Insulin, Male, Norepinephrine, Propanolamines, Receptors, Adrenergic, beta, Ventromedial Hypothalamic Nucleus, Glucose Clamp Technique, Rats, Sprague-Dawley, Rats, Adrenergic beta-2 Receptor Agonists
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