BRAIN REGULATION OF BLOOD GLUCOSE LEVELS: ITS SIGNIFICANCE IN THE PATHOGENESIS OF TYPE 2 DIABETES
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Abstract
Although the number of studies is rapidly increasing, the role of the brain in regulating normal glucose homeostasis and the pathogenesis of type 2 diabetes remains incompletely understood. In this review, we propose a conceptual framework to better understand the brain’s critical role in these processes. This framework is based on evidence showing that the brain, like the pancreas, is capable of sensing changes in circulating glucose levels and responding accordingly. We also examine data suggesting that neuronal glucose sensing plays a fundamental role in determining the defended (physiologically maintained) level of blood glucose and that defects in this regulatory system contribute to the pathogenesis of type 2 diabetes. Furthermore, we discuss the close link between obesity and type 2 diabetes, which may arise from shared dysfunction in highly integrated neurocircuits that regulate both energy and glucose homeostasis. Thus, while obesity is characterized by an elevated defended level of the body’s fuel stores (e.g., adipose tissue mass), type 2 diabetes is characterized by an elevated defended level of circulating fuel (e.g., glucose). In both conditions, the underlying pathogenesis is associated with impaired sensing of, or response to, relevant humoral negative feedback signals. This perspective is increasingly supported by preclinical evidence: in type 2 diabetes, restoration of the defended blood glucose level to normal can be achieved through interventions that restore the brain’s ability to accurately sense circulating glucose.
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References
1. D Alessio DA, Kieffer TJ, Taborsky GJ Jr, Havel PJ (2001)
Activation of the parasympathetic nervous system is necessary for
normal meal-induced insulin secretion in rhesus macaques. J Clin
Endocrinol Metab 86(3):1253–1259. https://doi.org/10.1210/jcem.
86.3.7367
2. Carey M, Lontchi-Yimagou E, Mitchell W et al (2020) Central
KATP channels modulate glucose effectiveness in humans and
rodents. Diabetes 69(6):1140–1148. https://doi.org/10.2337/db19-
1256
3. Bernard C (1849) Chiens rendus diabetiques. C R Soc Bio 1:60
4. Oh Y, Lai JS, Mills HJ et al (2019) A glucose-sensing neuron pair
regulates insulin and glucagon in Drosophila. Nature 574(7779):
559–564. https://doi.org/10.1038/s41586-019-1675-4
5. Schwartz MW, Seeley RJ, Tschöp MH et al (2013) Cooperation
between brain and islet in glucose homeostasis and diabetes. Nature
503(7474):59–66. https://doi.org/10.1038/nature12709
6. Pardridge WM, Triguero D, Farrell CR (1990) Downregulation of
blood-brain barrier glucose transporter in experimental diabetes.
Diabetes 39(9):1040–1044. https://doi.org/10.2337/diab.39.9.1040
12 Diabetologia (2021) 64:5–14
7. Cornford EM, Hyman S, Cornford ME, Clare-Salzler M (1995)
Down-regulation of blood-brain glucose transport in the hyperglycemic nonobese diabetic mouse. Neurochem Res 20(7):869–873.
https://doi.org/10.1007/bf00969700
8. Hwang JJ, Jiang L, Hamza M et al (2017) Blunted rise in brain
glucose levels during hyperglycemia in adults with obesity and
T2DM. JCI Insight 2(20):e95913. https://doi.org/10.1172/jci.
insight.95913
9. Eskian M, Alavi A, Khorasanizadeh M et al (2019) Effect of blood
glucose level on standardized uptake value (SUV) in 18F-FDG
PET-scan: a systematic review and meta-analysis of 20,807 individual SUV measurements. Eur J Nucl Med Mol Imaging 46(1):
224–237. https://doi.org/10.1007/s00259-018-4194-x
10. Sprinz C, Altmayer S, Zanon M et al (2018) Effects of blood
glucose level on 18F-FDG uptake for PET/CT in normal organs:
a systematic review. PLoS One 13(2):e0193140. https://doi.org/10.
1371/journal.pone.0193140
11. Li W, Risacher SL, Huang E, Saykin AJ (2016) Type 2 diabetes
mellitus is associated with brain atrophy and hypometabolism in the
ADNI cohort. Neurology 87(6):595–600. https://doi.org/10.1212/
wnl.0000000000002950
12. Thorens B (2015) GLUT2, glucose sensing and glucose homeostasis. Diabetologia 58(2):221–232. https://doi.org/10.1007/s00125-
014-3451-1
13. Ma Y, Ratnasabapathy R, De Backer I et al (2020) Glucose in the
hypothalamic paraventricular nucleus regulates GLP-1 release. JCI
Insight 5(8):e132760. https://doi.org/10.1172/jci.insight.132760
14. Nishio T, Toyoda Y, Hiramatsu M, Chiba T, Miwa I (2006) Decline
in glucokinase activity in the arcuate nucleus of streptozotocininduced diabetic rats. Biol Pharm Bull 29(2):216–219. https://doi.
org/10.1248/bpb.29.216
15. Ma Y, Ratnasabapathy R, Izzi-Engbeaya C et al (2018)
Hypothalamic arcuate nucleus glucokinase regulates insulin secretion and glucose homeostasis. Diabetes Obes Metab 20(9):2246–
2254. https://doi.org/10.1111/dom.13359
16. Kang L, Dunn-Meynell AA, Routh VH et al (2006) Glucokinase is
a critical regulator of ventromedial hypothalamic neuronal
glucosensing. Diabetes 55(2):412–420. https://doi.org/10.2337/
diabetes.55.02.06.db05-1229
17. Cryer PE (1993) Glucose counterregulation: prevention and correction of hypoglycemia in humans. Am J Phys 264(2 Pt 1):E149–
E155. https://doi.org/10.1152/ajpendo.1993.264.2.E149
18. Asplin CM, Raghu PK, Koerker DJ, Palmer JP (1985) Glucose
counterregulation during recovery from neuroglucopenia: which
mechanism is important? Metabolism 34(1):15–18. https://doi.
org/10.1016/0026-0495(85)90053-8
19. Meek TH, Nelson JT, Matsen ME et al (2016) Functional identification of a neurocircuit regulating blood glucose. Proc Natl Acad
Sci U S A 113(14):E2073–E2082. https://doi.org/10.1073/pnas.
1521160113
20. Faber CL, Matsen ME, Velasco KR et al (2018) Distinct neuronal
projections from the hypothalamic ventromedial nucleus mediate
glycemic and behavioral effects. Diabetes 67(12):2518–2529.
https://doi.org/10.2337/db18-0380
21. Flak JN, Goforth PB, Dell Orco J et al (2020) Ventromedial hypothalamic nucleus neuronal subset regulates blood glucose independently of insulin. J Clin Invest 130(6):2943–2952. https://doi.org/
10.1172/jci134135
22. Chakera AJ, Hurst PS, Spyer G et al (2018) Molecular reductions in
glucokinase activity increase counter-regulatory responses to hypoglycemia in mice and humans with diabetes. Mol Metab 17:17–27.
https://doi.org/10.1016/j.molmet.2018.08.001
23. Spyer G, Hattersley AT, MacDonald IA, Amiel S, MacLeod KM
(2000) Hypoglycaemic counter-regulation at normal blood glucose
concentrations in patients with well controlled type-2 diabetes.
Lancet 356(9246):1970–1974. https://doi.org/10.1016/s0140-
6736(00)03322-5
24. Chowdhury GMI, Wang P, Ciardi A et al (2017) Impaired glutamatergic neurotransmission in the ventromedial hypothalamus may
contribute to defective counterregulation in recurrently hypoglycemic rats. Diabetes 66(7):1979–1989. https://doi.org/10.2337/db16-
1589
25. Tong Q, Ye C, McCrimmon RJ et al (2007) Synaptic glutamate
release by ventromedial hypothalamic neurons is part of the
neurocircuitry that prevents hypoglycemia. Cell Metab 5(5):383–
393. https://doi.org/10.1016/j.cmet.2007.04.001
26. Roncero I, Alvarez E, Chowen JA et al (2004) Expression of
glucose transporter isoform GLUT-2 and glucokinase genes in
human brain. J Neurochem 88(5):1203–1210. https://doi.org/10.
1046/j.1471-4159.2003.02269.x
27. Woods SC, Porte D Jr (1974) Neural control of the endocrine
pancreas. Physiol Rev 54(3):596–619. https://doi.org/10.1152/
physrev.1974.54.3.596
28. Osundiji MA, Evans ML (2013) Brain control of insulin and glucagon secretion. Endocrinol Metab Clin N Am 42(1):1–14. https://
doi.org/10.1016/j.ecl.2012.11.006
29. Tang SC, Baeyens L, Shen CN et al (2018) Human pancreatic
neuro-insular network in health and fatty infiltration. Diabetologia
61(1):168–181. https://doi.org/10.1007/s00125-017-4409-x
30. Havel PJ, Veith RC, Dunning BE, Taborsky GJ Jr (1988)
Pancreatic noradrenergic nerves are activated by neuroglucopenia
but not by hypotension or hypoxia in the dog. Evidence for stressspecific and regionally selective activation of the sympathetic
nervous system. J Clin Invest 82(5):1538–1545. https://doi.org/
10.1172/JCI113763