Insulin resistance and adipose tissue

Insulin resistance, a key pathological feature of type 2 diabetes mellitus (T2DM), contributes to the development of many conditions, including hypertension, dyslipidemia, and atherosclerosis. In addition to the classical macro- and microvascular compilations, the care for various comorbidities, including metabolic dysfunction-associated fatty liver disease (MAFLD), cognitive disorders, sarcopenia, and certain cancers, has been becoming more and more important in the treatment of T2DM; insulin resistance is recognized as an underlying condition of such diabetes-related comorbidities. It is thus crucial to understand the pathophysiology of insulin resistance for clinicians and researchers working in the field of T2DM and related metabolic disorders.

Obesity, a most common and vital contributor to insulin resistance, is characterized by alterations in the size and function of adipose tissue. The change in the function of adipose tissue attenuates not only insulin’s effects in this tissue but those in other organs. As the size of adipose tissue expands, immune cells, including neutrophils, lymphocytes, and macrophages, infiltrate the interstitial space. Inflammation and remodeling of adipose tissue induced by the immune cells are crucial for obesity-induced insulin resistance. Among these infiltrated immune cells, macrophages play a central role in the regulation of inflammation of adipose tissues.

In the Mini-review of this issue, Nawaz et al. summarized the latest findings on the function of macrophages in adipose tissue [1]. Macrophages in adipose tissue possess diverse characteristics. Classically, these cells are roughly categorized into the M1 and M2 types. The M2 subtype secretes primarily anti-inflammatory cytokines, including IL4, IL10, and Il-13. It characterizes insulin-sensitive adipose tissue in lean individuals. The M1 subtype, on the other hand, secretes pro-inflammatory cytokines, including TNFα, IL-β, and IL-6, and infiltrates insulin-resistant adipose tissue in obese individuals. However, the subpopulation of macrophages in adipose tissue is much more heterogeneous, and the classical point of view should be substantially revised. Each subpopulation of the cells influences the regulation of insulin sensitivity as well as various biological phenomena, such as adipogenesis, angiogenesis, browning/beiging, and lipid metabolism. Moreover, recent findings challenged the classical difference in the function of the M1 and M2 subtypes; not all the macrophages classified into the M2 subtype play a role in maintaining insulin-sensitive phenotype. Instead, a specific subpopulation of the M2 macrophages contributes to the development of insulin resistance, as shown by Nawaz et al. [2]

Whereas the importance of inflammation in adipose tissues in the development of insulin resistance is well recognized, the mechanism of how inflammation is initiated in the tissues remains unclear. Furthermore, it is also ambiguous how the pathological signal is transmitted from inflamed adipose tissues to the whole body, whereas hormones and cytokines secreted from adipose tissue, at least partly, appear to be involved.

Another review article in the mini-review of this issue focuses on insulin signaling in adipocytes and insulin resistance. The review article by Imi et al. illustrates how insulin signaling in adipocytes influences insulin sensitivity in the whole body [3]. Insulin is a potent stimulator of adipogenesis, and the disruption of the insulin receptor signaling in adipocytes leads to a lipodystrophic phenotype associated with severe insulin resistance in the whole body, indicating that insulin action in adipocytes influences whole-body insulin sensitivity by control of adipose tissue size. A recent study, however, revealed that the impairment of insulin action in adipocytes triggers insulin resistance in remote organs in a manner independent of the size of adipose tissue; the impairment of insulin action increases the abundance of 5-lipoxygenase via the activation of the transcription factor FoxO1, which in turn leads to the excessive production of leukotriene B4 [4]. The increase in the pro-inflammatory lipid mediator in adipose tissue and circulation likely triggers inflammation and insulin resistance.

As a whole, inflammation and insufficient insulin action in adipocytes appears to contribute to the development of insulin resistance by reciprocally influencing each other. As the editor of the Mini-review, the author hopes that this review series will help readers understand the complex relationship in the pathogenesis of the essential condition in the care and study of T2DM.

Data availability

Given that this article is an introduction to the mini-reviews, no data supports the contents of this article.