Diabetes mellitus is one of the most common chronic metabolic disorders worldwide, and its incidence in Asian countries is alarmingly high. Type 2 diabetes (T2DM) is closely associated with obesity, and the staggering rise in obesity is one of the primary factors related to the increased frequency of T2DM. Low-grade chronic inflammation is also accepted as an integral metabolic adaption in obesity and T2DM, and is believed to be a major player in the onset of insulin resistance. However, the exact mechanism(s) that cause a persistent chronic low-grade infiltration of leukocytes into insulin-target tissues such as adipose, skeletal muscle and liver are not entirely known. Recent developments in the understanding of leukocyte metabolism have revealed that the inflammatory polarization of immune cells, and consequently their immunological function, are strongly connected to their metabolic profile. Therefore, it is hypothesized that dysfunctional immune cell metabolism is a central cellular mechanism that prevents the resolution of inflammation in chronic metabolic conditions such as that observed in obesity and T2DM. The purpose of this review is to explore the metabolic demands of different immune cell types, and identify the molecular switches that control immune cell metabolism and ultimately function. Understanding of these concepts may allow the development of interventions that can correct immune function and may possibly decrease chronic low-grade inflammation in humans suffering from obesity and T2DM. We also review the latest clinical techniques used to measure metabolic flux in primary leukocytes isolated from obese and T2DM patients.

The global variation in type 1 diabetes (T1D) incidence rates is one of the most significant observed for any non-communicable disease. Geographical patterns in incidence suggest that low sun exposure may contribute to the wide disparity, with incidence rates generally increasing with distance from the Equator. T1D development is associated with hyperactivity of the adaptive immune system leading to autoimmune destruction of insulin-secreting pancreatic β cells. Both exposure to ultraviolet radiation (UVR) and vitamin D, with their known immunosuppressive effects, have the potential to delay or inhibit the disease. Efforts to confirm the role of UVR by vitamin D dependent and independent pathways in the pathogenesis of T1D have been challenged by inconsistent results among studies. Human observational studies and animal and in vitro experiments indicate that at least some of the benefits of sun exposure come from improved vitamin D status. There is no evidence of benefit for T1D risk of vitamin D supplementation during pregnancy at current recommended levels (400 IU per day); but some evidence supports that higher sun exposure and/or vitamin D sufficiency in pregnancy, or supplementation in early life, decreases T1D risk. Further research is required to confirm an association between UVR exposure and T1D and clarify the mechanisms involved.

SummaryVitamin D is produced in the skin by ultraviolet (UV) B radiation (290-320 nm). The active metabolite 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] is made systemically by hydroxylation of vitamin D in the liver and the kidney, but also locally in the epidermis, which suggests that 1,25(OH) 2 D 3 may have important functions in the skin. 1,25(OH) 2 D 3 has opposing effects: it can mimic immunosuppressive effects caused by UV irradiation in some models, or reverse UV-induced DNA damage and immunosuppression in other models. 1,25(OH) 2 D 3 exerts effects on Langerhans cells that are characteristic of those associated with UV radiation (UVR)-induced suppression of contact hypersensitivity, and topical application of the vitamin D analogue calcipotriene suppresses contact hypersensitivity in human subjects to a similar extent as UVR. However, 1,25(OH) 2 D 3 decreases DNA damage both in vitro when added to human skin cells in culture before and after UVR, and in vivo when applied to mouse skin after UVR. Furthermore, topical 1,25(OH) 2 D 3 applied to mouse skin after UVR reversed the immunosuppressive effect of UVR in a contact hypersensitivity model. This review will discuss the role of 1,25(OH) 2 D 3 as either a mediator of UVR-induced immune suppression or as a photoprotective molecule against UVR-induced DNA damage and immune suppression.

Ultraviolet radiation (UVR) from sunlight is immunomodulatory and the main source of vitamin D for humans. Vitamin D can also regulate adaptive immunity, through mechanisms that involve the induction or activation of regulatory T cells. Similar mechanisms have also been proposed for the induction of regulatory T cells after skin exposure to UVR. Here we discuss the converging and diverging immunoregulatory pathways of UVR and vitamin D, including the molecular pathways for regulatory T cell induction, non-genomic pathways regulated by vitamin D, antimicrobial peptides, skin integrity and potential interactions between vitamin D and other UVR-induced mediators. We then discuss possible in vivo approaches that could be used to demonstrate a direct (or otherwise) role for vitamin D in mediating the immunosuppressive effects of UVR such as the use of dietary vitamin D restriction to induce vitamin D deficiency, gene knockout mice or drugs to block enzymes of vitamin D metabolism. We end with discussion of the epigenetic effects of vitamin D and UVR for immunosuppression.