Abstract
Aims/hypothesisThe 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.MethodsWe 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).ResultsThe 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/interpretationOur 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.
Highlights
In mammals, the circadian timing system plays a critical role in coordinating the daily and seasonal rhythmicity of all physiological and behavioural processes in the body
When considering all donors (n = 40), no correlations were found between the numbers of suprachiasmatic nucleus (SCN) arginine vasopressin (AVP)-ir, vasoactive intestinal polypeptide (VIP)-ir and NT-ir neurons and age, post-mortem delay, post-absorptive blood glucose level or HbA1c (ESM Fig. 2)
Rhythmicity and monthly variation in AVP immunoreactive (AVP-ir), VIP-ir and NT-ir neurons in the SCN did not reach significance, but acrophase and amplitude in daily rhythmicity were significant in the AVP-ir neurons in non-diabetic control individuals (ESM Figs. 3, 4)
Summary
The circadian timing system plays a critical role in coordinating the daily and seasonal rhythmicity of all physiological and behavioural processes in the body. Multiple types of neurons are involved in the SCN neuronal network [1]. In rodents, these mainly include the vasoactive intestinal polypeptide (VIP)-producing and the arginine vasopressin (AVP)producing neurons [1], and in addition to these, humans possess neurotensin (NT)-containing neurons [2]. Glucose homeostasis and insulin sensitivity are tightly controlled by the circadian timing system, mainly through balancing sympathetic and parasympathetic outputs from the hypothalamus [3]. The current study aimed to profile and compare SCN neurons, especially the ones producing AVP, VIP and NT, as well as the astroglial cells (using glial fibrillary acidic protein, GFAP, as a marker) and microglia (using ionised calcium-binding adapter molecule 1, IBA1, as a marker) in control and type 2 diabetic individuals
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