Diabetes Mellitus as Dysfunction of Interactions among all Organs: “Ominous Orchestra of Organs”

Abstract

Summary:Epidemiological evidence has established a link among hyperlipidemia, visceral obesity, osteoporosis, and cardiovascular diseases. We have recently proposed a hypothesis that the associations of those disorders are based on interactions of the three organs, i.e. the bone, adipose, and vascular tissues, possibly through multiple actions of several humoral factors and/or transcription factors. We call this unifi ed hypothesis 'osteo-lipo-vascular interactions', which may be explained by the common origin of the cells in each organ, such as mesenchymal stem cells or macrophages. Several groups proposed similar hypotheses. On the other hand, there have been accumulating evidences which indicate that there exist hitherto unknown various interactions between many organs, such as hypothalamus-liver, fat-liver, liver-muscle, intestine-pancreas, kidney-heart and so on. Therefore, it seems insuffi cient to consider only the interactions among several organs, and the standpoint of considering interactions among all organs may be warranted, especially in order to understand the pathogenesis of metabolic syndrome, insulin resistance and type 2 diabetes. We here propose a hypothesis that the abnormal interactions of all organs ("Ominous Orchestra of Organs") underlies the pathogenesis of type 2 diabetes. It is to be elucidated which of the "players" or the "conductor" may be mainly responsible for disharmony of the orchestra. 'Osteo-lipo-vascular Interactions'Epidemiological evidence has established a link among hyperlipidemia, visceral obesity, osteoporosis, and cardiovascular diseases (CVD), suggesting some interactions between bone, adipose tissue and vessels. We have recently proposed the hypothesis that the associations of those disorders are based on interactions of the three organs, i.e. the bone, fat, and vascular tissues [1,2]. We have called this unifi ed hypothesis 'osteo-lipo-vascular interactions' [3,4] (Fig. 1). There are several possible mechanisms to explain those interactions.First, these interactions can be attributable to actions of several humoral factors, i.e. hormone in a broad sense. Second, it can also be explained by transcription factors, which are shared by several of the three organs. Third, from the viewpoint of developmental physiology, the fact that there exist interactions between the three organs may be fully reasonable, since the three organs share the cells of common origin, i.e. mesenchymal stem cells (MSCs); the osteoblasts in the bone, the vascular smooth muscle cells (VSMCs) in the vessel, and the adipocytes in the fat (Fig. 2). Fourth, the interactions can also be attributable to the function of macrophages, which evolve into the osteoclasts in the bone, evolve into the foam cells in the vessel, and infi ltrate into the fat, causing infl ammation of the adipocytes [4,5,6] (Fig. 3).Other researchers have proposed several hypotheses based on similar concept [7,8,9]. Burnett and Vasikaran suggested a link between lipids and bone [7]. Hamerman has suggested that osteoporosis and ath...

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