BDNF Action in the Brain Attenuates Diabetic Hyperglycemia via Insulin-Independent Inhibition of Hepatic Glucose Production
Open accessAbstract
Recent evidence suggests that central leptin administration fully normalizes hyperglycemia in a rodent model of uncontrolled insulin-deficient diabetes by reducing hepatic glucose production (HGP) and by increasing glucose uptake. The current studies were undertaken to determine whether brain-derived neurotrophic factor (BDNF) action in the brain lowers blood glucose in uncontrolled insulin-deficient diabetes and to investigate the mechanisms mediating this effect. Adult male rats implanted with cannulas to either the lateral cerebral ventricle or the ventromedial hypothalamic nucleus (VMN) received either vehicle or streptozotocin to induce uncontrolled insulin-deficient diabetes. Three days later, animals received daily intracerebroventricular or intra-VMN injections of either BDNF or its vehicle. We found that repeated daily intracerebroventricular administration of BDNF attenuated diabetic hyperglycemia independent of changes in food intake. Instead, using tracer dilution techniques during a basal clamp, we found that BDNF lowered blood glucose levels by potently suppressing HGP, without affecting tissue glucose uptake, an effect associated with normalization of both plasma glucagon levels and hepatic expression of gluconeogenic genes. Moreover, BDNF microinjection directly into the VMN also lowered fasting blood glucose levels in uncontrolled insulin-deficient diabetes, but this effect was modest compared with intracerebroventricular administration. We conclude that central nervous system BDNF attenuates diabetic hyperglycemia via an insulin-independent mechanism. This action of BDNF likely involves the VMN and is associated with inhibition of glucagon secretion and a decrease in the rate of HGP.
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BDNF may be involved in cancer, angiogenesis, reduction of glucose production from the liver, and uptake of glucose in peripheral tissues.
“Therefore, it may also be involved in cancer, angiogenesis, reduction of glucose production from the liver [23], and in the uptake of glucose in peripheral tissues (see [24] for review).”
From Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer (2020) · cites this paper as [23]
The Results section (page unavailable) reports that central BDNF treatment reduced hepatic glucose production in rats with insulin-deficient diabetes. The copy does not address cancer or angiogenesis, the other topics preceding citation [23]. Peripheral glucose uptake is separately assigned to [24] in the citing sentence; this paper reports no increase in uptake under the conditions it studied. (LLM, conf=0.84)
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Cites
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German, J. P., Thaler, J. P., Wisse, B. E., Oh-I, S., Sarruf, D. A., Matsen, M. E., Fischer, J. D., Taborsky, G. J., Schwartz, M. W., & Morton, G. J. (2011) · Endocrinology · doi:10.1210/en.2010-0890 · Cited by 169 · cited 8× · see citing works
“Uncontrolled insulindeficient diabetes is characterized by hyperglucagonemia and hypercorticosteronemia, responses that increase HGP and that are normalized when intracerebroventricular leptin is administered at doses that normalize hyperglycemia (1).”
BackgroundMethodInfluentialSelf-citationCentral leptin increases insulin sensitivity in streptozotocin-induced diabetic rats
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Low plasma leptin levels contribute to diabetic hyperphagia in rats.
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Colucci-D’Amato, L., Speranza, L., & Volpicelli, F. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207777 · Cited by 991 · see citing works
- Authors
- Meek, T. H., Wisse, B. E., Thaler, J. P., Guyenet, S. J., Matsen, M. E., Fischer, J. D., Taborsky, G. J., Schwartz, M. W., & Morton, G. J.
- Affiliations
- University of Washington (US)
- Veterans Health Administration (US)
- Corresponding author
- Morton, Gregory J.
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2013-04-16
- Volume
- 62
- Issue
- 5
- Pages
- 1512-1518
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC3636618
- OpenAlex
- W2110539459
- Cited by
- 80
- References
- 4
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 6 · 2022: 5 · 2021: 11 · 2020: 9 · 2019: 7 · 2018: 6 · 2017: 4 · 2016: 8 · 2015: 6 · 2014: 6 · 2013: 6
- FWCI
- 2.57
- 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
- National Heart, Lung, and Blood Institute (T32HL007028)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-083042, R01DK089056, DK 035816, DK-050154-13, K08DK088872, T32 DK0007247, DK089053, F32DK097859, R56DK050154, R01DK050154, R01DK090320, P30DK035816, R01DK083042, T32DK007247)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- brain-derived neurotrophic factor, diabetic hyperglycemia, hepatic glucose production, ventromedial hypothalamus, glucagon secretion, gluconeogenic gene expression, insulin-independent glucose regulation, streptozotocin-induced diabetes, intracerebroventricular administration
- MeSH terms
- Animals, Behavior, Animal, Biological Transport, Diabetes Mellitus, Type 1, Feeding Behavior, Glucagon, Gluconeogenesis, Glucose, Hyperglycemia, Hypoglycemic Agents, Injections, Intraventricular, Insulin, Liver, Male, Neurons, Ventromedial Hypothalamic Nucleus, Rats, Wistar, Brain-Derived Neurotrophic Factor, Lateral Ventricles, Rats
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