Are the available experimental models of type 2 diabetes appropriate for a gender perspective?

Abstract

Several experimental models have so far been developed to improve our knowledge of the pathogenetic mechanisms of type 2 diabetes mellitus (T2D), to determine the possible pharmacological targets of this disease and to better evaluate diabetes-associated complications, e.g. the cardiovascular disease. In particular, the study of T2D gained the attention of several groups working with different animal species: rodents, cats or pigs, as well as other non-human primate species. Each of these species provided useful and different clues. However, T2D has to be considered as a gender-associated disease: sex differences play in fact a key role in the onset as well as in the progression of the disease and a higher mortality for cardiovascular diseases is detected in diabetic women with respect to men. The results obtained from all the available animal models appear to only partially address this issue so that the search for more precise information in this respect appears to be mandatory. In this review we summarize these concepts and literature in the field and propose a reappraisal of the various animal models for a study of T2D that would take into consideration a gender perspective.

Introduction

Type 1 and type 2 diabetes mellitus (T1D and T2D) are the more common forms of diabetes but further rare forms including maturity-onset diabetes of the young (MODY1) [1], gestational diabetes [2], and latent autoimmune diabetes in adults (LADA1) [3] have also been characterized. In particular, among these different forms of diabetes, T2D is the most common endocrine disease with steadily increasing incidence [2]. Importantly, many gender differences have been described in this disease, including risk factors and clinical management [4], [5]. For instance, it has been suggested that diabetic women have a higher morbility and mortality for cardiovascular diseases [6], [7], [8] with respect to men.

In order to improve our knowledge of the pathogenetic mechanisms of T2D, many experimental models have so far been developed to determine the possible pharmacological targets of the disease and to better evaluate diabetes-associated complications, e.g. the cardiovascular disease. Many spontaneous, but highly heterogeneous, animal models of T2D are in fact available (Table 1). The rodent model seems to be the more suitable and includes different species such as rats [9], [10], [11], [12], [13], including Psammomys obesus [14], and mice [13], [15]; however, cats [16], [17], pigs [18], and non-human primates [19] have also been taken into consideration. Besides, T2D can also experimentally be induced. For example, chemical destruction or removal of beta cells, lesioning the ventromedial hypothalamus (VMH) [13], [20], feeding animals with high-fat and high-sugar diet [21], malnutrition in utero [22], [23], glucocorticoids administration or other chemicals such as glutamate [24], [25] have been employed. Furthermore, animal models of diabetes have also been constructed through genetic manipulation [26]. Together, genetic animal models have provided major insights into the roles of proteins that modulate glucose homeostasis, but it is not yet known how and to what extent these genes could contribute to the disease. It is worth recalling that T2D is a polygenic disease and it is heavily influenced by environmental factors. However, T2D has to be considered as a gender-associated disease [4], [5]. Hence the main topic of this review will be to evaluate whether the available experimental models of T2D could provide useful information that can be transferred to humans, i.e. to men and women.