The impact of antidiabetic treatment on human hypothalamic infundibular neurons and microglia.

Martin J.T Kalsbeek,Chun-Xia Yi,Johannes A Romijn,Eric Fliers,Andries Kalsbeek,Susanne E La Fleur,Elly M Hol,Inge Huitinga,Nikita L Korpel,Dick F Swaab,Samantha E.C Wolff

doi:10.1172/jci.insight.133868

Martin J.T Kalsbeek, Chun-Xia Yi + Show 9 more

Open Access

https://doi.org/10.1172/jci.insight.133868

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Journal: JCI insight	Publication Date: Aug 20, 2020
Citations: 15	License type: CC BY 4.0

Affiliation: University of Amsterdam

Abstract

Animal studies indicate that hypothalamic dysfunction plays a major role in type 2 diabetes mellitus (T2DM) development, and that insulin resistance and inflammation are important mechanisms involved in this disorder. However, it remains unclear how T2DM and antidiabetic treatments affect the human hypothalamus. Here, we characterized the proopiomelanocortin (POMC) immunoreactive (-ir) neurons, the neuropeptide-Y–ir (NPY-ir) neurons, the ionized calcium-binding adapter molecule 1–ir (iba1-ir) microglia, and the transmembrane protein 119–ir (TMEM119-ir) microglia in the infundibular nucleus (IFN) of human postmortem hypothalamus of 32 T2DM subjects with different antidiabetic treatments and 17 matched nondiabetic control subjects. Compared with matched control subjects, T2DM subjects showed a decrease in the number of POMC-ir neurons, but no changes in NPY-ir neurons or microglia. Interestingly, T2DM subjects treated with the antidiabetic drug metformin had fewer NPY-ir neurons and microglia than T2DM subjects not treated with metformin. We found that the number of microglia correlated with the number of NPY-ir neurons, but only in T2DM subjects. These results indicate that different changes in POMC and NPY neurons and microglial cells in the IFN accompany T2DM. In addition, T2DM treatment modality is associated with highly selective changes in hypothalamic neurons and microglial cells.

Highlights

Hypothalamic dysfunction plays a major role in the development of obesity and type 2 diabetes (T2DM) [1, 2]
To compare neuronal and glial parameters within the infundibular nucleus (IFN) and prevent between-group differences of subjects owing to brain size, we used the sections around the area in the IFN that showed the highest neuropeptide Y (NPY) immunoreactivity (-ir) to study the different neuron and microglial markers (Figure 1A)
There was no significant difference in area under the curve between type 2 diabetes mellitus (T2DM) subjects and the matched CTRL subjects (P = 0.96), indicating the shape, size, and orientation of the IFN were comparable between the 2 groups

Summary

Introduction

Hypothalamic dysfunction plays a major role in the development of obesity and type 2 diabetes (T2DM) [1, 2]. Diet-induced obesity and T2DM have been associated with a disturbed balance between the anorexigenic POMC [3, 4] and the orexigenic NPY/AgRP neurons [5, 6]. Recent animal studies have indicated hypothalamic inflammation as an important player in the changes in hypothalamic neuronal function observed during the development of obesity and T2DM [7,8,9,10]. In these studies, hypothalamic inflammation was demonstrated by increased expression of proinflammatory factors mainly produced by reactive microglia, the resident innate immune cells of the brain. Interactions between hypothalamic neurons and microglia are apparent in animal models [11,12,13], the clinical relevance of these findings in the pathophysiology of human T2DM remains unknown

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