Gruber Judith, Hanssen Ruth, Qubad Mishal, Bouzouina Aicha, Schack Vivi, Sochor Hannah, Schiweck Carmen, Aichholzer Mareike, Matura Silke, Slattery David A, Zopf Yurdaguel, Borgland Stephanie L, Reif Andreas, Thanarajah Sharmili Edwin
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Frankfurt, Germany.
University of Cologne, Faculty of Medicine and University Hospital Cologne, Policlinic for Endocrinology, Diabetology and Prevention Medicine, Germany.
Neurosci Biobehav Rev. 2023 Jun;149:105179. doi: 10.1016/j.neubiorev.2023.105179. Epub 2023 Apr 12.
Type 2 diabetes and major depressive disorder (MDD) are the leading causes of disability worldwide and have a high comorbidity rate with fatal outcomes. Despite the long-established association between these conditions, the underlying molecular mechanisms remain unknown. Since the discovery of insulin receptors in the brain and the brain's reward system, evidence has accumulated indicating that insulin modulates dopaminergic (DA) signalling and reward behaviour. Here, we review the evidence from rodent and human studies, that insulin resistance directly alters central DA pathways, which may result in motivational deficits and depressive symptoms. Specifically, we first elaborate on the differential effects of insulin on DA signalling in the ventral tegmental area (VTA) - the primary DA source region in the midbrain - and the striatum as well as its effects on behaviour. We then focus on the alterations induced by insulin deficiency and resistance. Finally, we review the impact of insulin resistance in DA pathways in promoting depressive symptoms and anhedonia on a molecular and epidemiological level and discuss its relevance for stratified treatment strategies.
2型糖尿病和重度抑郁症（MDD）是全球致残的主要原因，且合并症发生率高，会导致致命后果。尽管这两种病症之间的关联早已确立，但其潜在的分子机制仍然不明。自大脑中发现胰岛素受体以及大脑奖赏系统以来，越来越多的证据表明，胰岛素可调节多巴胺能（DA）信号传导和奖赏行为。在此，我们综述来自啮齿动物和人类研究的证据，即胰岛素抵抗会直接改变中枢DA通路，这可能导致动机缺陷和抑郁症状。具体而言，我们首先阐述胰岛素对腹侧被盖区（VTA，中脑主要的DA源区域）和纹状体中DA信号传导的不同影响及其对行为的影响。然后，我们聚焦于胰岛素缺乏和抵抗所引发的改变。最后，我们从分子和流行病学层面综述DA通路中胰岛素抵抗在促进抑郁症状和快感缺失方面的影响，并讨论其与分层治疗策略的相关性。
