Loss of arginine vasopressin- and vasoactive intestinal polypeptide-containing neurons and glial cells in the suprachiasmatic nucleus of individuals with type 2 diabetes

Rick Hogenboom, Martin J Kalsbeek, Nikita L Korpel, Paul de Goede, Marit Koenen, Ruud M Buijs, Johannes A Romijn, Dick F Swaab, Andries Kalsbeek, Chun-Xia Yi, Rick Hogenboom, Martin J Kalsbeek, Nikita L Korpel, Paul de Goede, Marit Koenen, Ruud M Buijs, Johannes A Romijn, Dick F Swaab, Andries Kalsbeek, Chun-Xia Yi

Abstract

Aims/hypothesis: The central pacemaker of the mammalian biological timing system is located within the suprachiasmatic nucleus (SCN) in the anterior hypothalamus. Together with the peripheral clocks, this central brain clock ensures a timely, up-to-date and proper behaviour for an individual throughout the day-night cycle. A mismatch between the central and peripheral clocks results in a disturbance of daily rhythms in physiology and behaviour. It is known that the number of rhythmically expressed genes is reduced in peripheral tissue of individuals with type 2 diabetes mellitus. However, it is not known whether the central SCN clock is also affected in the pathogenesis of type 2 diabetes. In the current study, we compared the profiles of the SCN neurons and glial cells between type 2 diabetic and control individuals.

Methods: We collected post-mortem hypothalamic tissues from 28 type 2 diabetic individuals and 12 non-diabetic control individuals. We performed immunohistochemical analysis for three SCN neuropeptides, arginine vasopressin (AVP), vasoactive intestinal polypeptide (VIP) and neurotensin (NT), and for two proteins expressed in glial cells, ionised calcium-binding adapter molecule 1 (IBA1, a marker of microglia) and glial fibrillary acidic protein (GFAP, a marker of astroglial cells).

Results: The numbers of AVP immunoreactive (AVP-ir) and VIP-ir neurons and GFAP-ir astroglial cells in the SCN of type 2 diabetic individuals were significantly decreased compared with the numbers in the SCN of the control individuals. In addition, the relative intensity of AVP immunoreactivity was reduced in the individuals with type 2 diabetes. The number of NT-ir neurons and IBA1-ir microglial cells in the SCN was similar in the two groups.

Conclusions/interpretation: Our data show that type 2 diabetes differentially affects the numbers of AVP- and VIP-expressing neurons and GFAP-ir astroglial cells in the SCN, each of which could affect the daily rhythmicity of the SCN biological clock machinery. Therefore, for effectively treating type 2 diabetes, lifestyle changes and/or medication to normalise central biological clock functioning might be helpful.

Keywords: Astroglial cells; Biological clock; Insulin resistance; Microglia; Neurotensin; Rhythmicity; Type 2 diabetes mellitus.

Figures

Fig. 1
Fig. 1
AVP-ir neurons, VIP-ir neurons and NT-ir neurons in the SCN of non-diabetic and type 2 diabetic individuals. Representative images of AVP-ir (a, b), VIP-ir (e, f) and NT-ir (i, j) neurons in the SCN of non-diabetic (Ctrl) and type 2 diabetic (T2DM) individuals. Comparison of the number of soma of the AVP-ir (c), VIP-ir (g) and NT-ir (k) neurons, the relative intensity of immunoreactivity of the AVP-ir (d), VIP-ir (h) and NT-ir (l) neurons (shown as fold of Ctrl) in the SCN of non-diabetic and type 2 diabetic individuals. Data are presented as mean ± SEM. *p<0.05, ***p<0.001. III, third cerebral ventricle. Scale bar, 300 μm
Fig. 2
Fig. 2
GFAP-ir astroglial cells and IBA1-ir microglial cells in the SCN of non-diabetic and type 2 diabetic individuals. Representative images of GFAP-ir (a, b) and IBA1-ir (e, f) in the SCN of non-diabetic control (Ctrl) and type 2 diabetic (T2DM) individuals. (c) Higher magnification image of the area framed in (a) (arrows point to GFAP-ir cells). Comparison of number of soma of GFAP-ir cells (d) and number of soma (g) and soma size (h) of the IBA1-ir cells in the SCN of Ctrl and type 2 diabetic individuals. Data are presented as mean ± SEM. **p<0.01. III, third cerebral ventricle. Scale bar, 300 μm in (a, b, e, f); 100 μm in (c)

References

    1. Antle MC, Silver R. Orchestrating time: arrangements of the brain circadian clock. Trends Neurosci. 2005;28(3):145–151. doi: 10.1016/j.tins.2005.01.003.
    1. Mai JK, Kedziora O, Teckhaus L, Sofroniew MV. Evidence for subdivisions in the human suprachiasmatic nucleus. J Comp Neurol. 1991;305(3):508–525. doi: 10.1002/cne.903050312.
    1. Kalsbeek A, Yi CX, La Fleur SE, Fliers E. The hypothalamic clock and its control of glucose homeostasis. Trends Endocrinol Metab. 2010;21(7):402–410. doi: 10.1016/j.tem.2010.02.005.
    1. Schwartz MW, Woods SC, Porte D, Jr, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature. 2000;404(6778):661–671. doi: 10.1038/35007534.
    1. Buijs FN, Guzman-Ruiz M, Leon-Mercado L, et al. Suprachiasmatic nucleus interaction with the arcuate nucleus; essential for organizing physiological rhythms. eNeuro. 2017;4(2):ENEURO.0028-17.2017. doi: 10.1523/ENEURO.0028-17.2017.
    1. Arble DM, Bass J, Behn CD, et al. Impact of sleep and circadian disruption on energy balance and diabetes: a summary of workshop discussions. Sleep. 2015;38(12):1849–1860. doi: 10.5665/sleep.5226.
    1. Stenvers DJ, Scheer F, Schrauwen P, la Fleur SE, Kalsbeek A. Circadian clocks and insulin resistance. Nat Rev Endocrinol. 2019;15(2):75–89. doi: 10.1038/s41574-018-0122-1.
    1. Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol. 2006;112(4):389–404. doi: 10.1007/s00401-006-0127-z.
    1. Goncharuk VD, van Heerikhuize J, Dai JP, Swaab DF, Buijs RM. Neuropeptide changes in the suprachiasmatic nucleus in primary hypertension indicate functional impairment of the biological clock. J Comp Neurol. 2001;431(3):320–330. doi: 10.1002/1096-9861(20010312)431:3<320::AID-CNE1073>;2-2.
    1. Liu RY, Unmehopa UA, Zhou JN, Swaab DF. Glucocorticoids suppress vasopressin gene expression in human suprachiasmatic nucleus. J Steroid Biochem Mol Biol. 2006;98(4–5):248–253. doi: 10.1016/j.jsbmb.2005.10.002.
    1. Streit WJ, Mrak RE, Griffin WS. Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation. 2004;1(1):14. doi: 10.1186/1742-2094-1-14.
    1. Gomez F, Chapleur M, Fernette B, Burlet C, Nicolas JP, Burlet A. Arginine vasopressin (AVP) depletion in neurons of the suprachiasmatic nuclei affects the AVP content of the paraventricular neurons and stimulates adrenocorticotrophic hormone release. J Neurosci Res. 1997;50(4):565–574. doi: 10.1002/(SICI)1097-4547(19971115)50:4<565::AID-JNR7>;2-C.
    1. Teclemariam-Mesbah R, Kalsbeek A, Pevet P, Buijs RM. Direct vasoactive intestinal polypeptide-containing projection from the suprachiasmatic nucleus to spinal projecting hypothalamic paraventricular neurons. Brain Res. 1997;748(1–2):71–76. doi: 10.1016/S0006-8993(96)01246-2.
    1. Vinik AI, Erbas T. Diabetic autonomic neuropathy. Handb Clin Neurol. 2013;117:279–294. doi: 10.1016/B978-0-444-53491-0.00022-5.
    1. Brancaccio M, Edwards MD, Patton AP, et al. Cell-autonomous clock of astrocytes drives circadian behavior in mammals. Science. 2019;363(6423):187–192. doi: 10.1126/science.aat4104.
    1. Nakanishi-Minami T, Kishida K, Funahashi T, Shimomura I. Sleep-wake cycle irregularities in type 2 diabetics. Diabetol Metab Syndr. 2012;4(1):18. doi: 10.1186/1758-5996-4-18.
    1. Lucassen PJ, Hofman MA, Swaab DF. Increased light intensity prevents the age related loss of vasopressin-expressing neurons in the rat suprachiasmatic nucleus. Brain Res. 1995;693(1–2):261–266. doi: 10.1016/0006-8993(95)00933-H.

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