J Mol Endocrinol August 1, 2013 51 R1-R13
Francesco Maria Egro francescoegro at gmail.com
Department of Cellular and Molecular Medicine, University of Bristol, 53 Arley Hill, Bristol BS6 5PJ, UK
A series of studies have reported a constant global rise in the incidence of type 1 diabetes. Epidemiological and immunological studies have demonstrated that environmental factors may influence the pathogenesis, leading to a cell-mediated pancreatic β-cell destruction associated with humoral immunity. The search for the triggering factor(s) has been going on for the past century, and yet they are still unknown. This review provides an overview of some of the most well-known theories found in the literature: hygiene, viral, vitamin D deficiency, breast milk and cow's milk hypotheses. Although the hygiene hypothesis appears to be the most promising, positive evidence from animal, human and epidemiological studies precludes us from completely discarding any of the other hypotheses. Moreover, due to contrasting evidence in the literature, a single factor is unlikely to cause an increase in the incidence of diabetes all over the world, which suggests that a multifactorial process might be involved. Although the immunological mechanisms are still unclear, there seems to be some overlap between the various hypotheses. It is thought that the emphasis should be shifted from a single to a multifactorial process and that perhaps the ‘balance shift’ model should be considered as a possible explanation for the rise in the incidence of type 1 diabetes.
Revision received 28 May 2013; Accepted 3 June 2013; online as an Accepted Preprint 3 June 2013
© 2013 Society for Endocrinology
In a variety of epidemiological studies, type 1 diabetes appears to be conditioned by seasonal and geographical variation in u.v. light exposure (Kimpimaki et ul. 2001, Mooney et ul. 2004, Sloka et ul. 2010).
Further support has come from Finnish studies, which have reported a decrease in incidence in children following vitamin D supplement induction (Hypponen et ul. 2001) and an increase in incidence when supplementation is lowered (Mohr et ul. 2010). However, contradictory evidence has come from more recent studies (Marjamaki et ul. 2010, Simpson et ul. 2011).
Vitamin D has come to be recognised to play a role in the modulation of the innate and adaptive immune system (Fig. 3). The activation of TLRs by pathogens causes an increased expression of vitamin D receptor (VDR) and the vitamin D-activating enzyme CP27B (25OHD-1a-hydroxylase) in macrophages (Adams & Hewison 2008). Mitochondrial CP27B (also found in the classical renal proximal tubules) catalyses the conversion of 25OHD to 1,25(OH)2D3, which either binds to VDR or is secreted, inducing a variety of paracrine responses. VDR-bound 1,25(OH)2D3 has three functions:
- It acts as a transcriptional factor, inducing the expression of an antimicrobial polypeptide, cathelicidin. This will then be integrated in the pathogen-containing phagosome, leading to antimicrobial action.
- It leads to negative autoregulation by negative feedback of the enzymes CP24A and CP24A-SV.
- It causes negative autoregulation by the down-regulation of TLRs.
Why is type 1 diabetes increasing?
Role of vitamin D in innate and adaptive immunity. TLR, toll-like receptor; DBP, vitamin D-binding protein; CP27B, 25OHD3-1a-hydroxylase; CP24A, 1,25(OH)2D3 24-hydroxylase; CP24A-SV, 1,25(OH)2D3 24-hydroxylase splice variant; VDR, vitamin D receptor; 25(OH)D3, 25-hydroxycholecalciferol; 1,25(OH)2D3, 1,25-dihydroxycholecalciferol. Adapted from Adams JS & Hewison M 2008 Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity. Nature Clinical Practice. Endocrinology & Metabolism 4 80-90. Full colour version of this figure available via http://dx.doi.org/10.1530/JME-13-0067.''
1,25(OH)2D3 secreted by macrophages (or mature dendritic cells) induces a series of paracrine responses:
- Activated B cells express high levels of VDR. 1,25(OH)2D3 causes a decrease in B-cell proliferation, antibody production, memory and plasma cells.
- Activated T cells express high levels of VDR as well, and activation by 1,25(OH)2D3 causes a decrease in proliferation and Th1 responses, but an increase in Th2 responses, Treg levels and T-cell homing.
- Monocytes, which express a higher number of VDRs than macrophages, stimulate further macrophage differentiation. Immature dendritic cells, which also contain a higher number of VDRs, cause the suppression of the differentiation of dendritic cells and an increase in the secretion of CC-chemokine ligand 22 (CCL22), which supports the synthesis of Tregs (Adams & Hewison 2008).
Therefore, vitamin D plays an important role in the regulation of Th1 and Th2 balance, via the proliferation of Tregs and the release of cytokines.
What goes wrong when vitamin D is missing? Unfortunately, the exact mechanism is still unclear.
However, there is evidence from adult NOD mice that type 1 diabetes is inhibited following vitamin D analogue administration. In these models, vitamin D prevents the maturation of dendritic cells, therefore causing a decrease in the production of IL12. This has been shown to have an effect on the level of IFNg produced by Th1 cells, demonstrating a decrease in Th1 responses. This decrease has been associated with an increase in the frequency of CD4+ CD25 + Tregs, arresting the development of type 1 diabetes. Further studies have provided similar evidence (Gregori etul. 2002). The study of Boonstra etul. (2001) has shown that vitamin D in mice not only inhibits the production of IFNg and therefore Th1 response, but also increases the Th2 response, leading to an increase in the production of IL4, IL5 and IL10. It has also demonstrated the direct effect of vitamin D on Th cells by activating naive CD4+T cells with anti-CD3 and anti-CD28. This leads to a significant rise in the levels of IL4, i.e. from 8 to 55.8%. The Th2 transcription factors GATA3 and c-MAF (MAF) were found to be up-regulated as well. This indicates that vitamin D has a direct effect on Th cells, enhancing the development of Th2 cells and therefore preventing the development of type 1 diabetes.
The last factor that might influence the development of the disease is genetic polymorphism of VDR. Vitamin D induces the formation of a VDR complex, which binds to vitamin D3 response elements. This normally has a variety of calcaemic and non-calcaemic activities, of which the inhibition of the expression of IL2, INFg,TNFa and TNFb is one (Nagpal et ul.2005). The gene encoding VDR has been identified to have four common variations: FokI, BsmI, ApaI, and TaqI. These alterations translate into functional VDR proteins, which in theory may lead to an abnormal synthesis of cytokines leading to type 1 diabetes. In fact, association has been found in Indian, Japanese, Taiwanese and German populations (Zella & DeLuca 2003).
The vitamin D deficiency hypothesis has some flaws. First of all, countries that receive sufficient sunlight such as Kuwait and Sardinia (Italy) have an incidence similar to that of those countries at extreme latitudes: Finland, 40.9/100 000 per year and Sardinia, 37.8/100 000 per year. Furthermore, countries at a similar latitude may differ significantly, e.g. Finland and Russia (6.9/100 000 per year).
When observing the immunological mechanisms underlying each hypothesis (Table 1), one can notice certain similarities. When comparing one with the other, one can notice an opposing effect: protective vs diabetogenic. One can also realise that some common ground might exist between the various hypotheses, for instance, the role of TLRs in vitamin D deficiency and hygiene hypothesis. In fact, one might go as far as to suggest that vitamin D deficiency alters antimicrobial effect by modulating the function of TLRs. This alteration might also lead to a protective effect in a bystander manner. Oral tolerance induced by the protective action of human milk might compensate for dietary antigens introduced in the last century. As breast-feeding decreased throughout the 20th century, cow's milk formulas became more popular, leading to a negative shift in oral tolerance.
Comparison of the discussed hypothesis mechanisms: (A) hygiene hypothesis, (B) viral hypothesis and (C) vitamin D vs vitamin D deficiency and breast-feeding vs cow's milk hypotheses
Summary of the 'balance shift' model. Protective factors (vitamin D, early exposure to pathogens and breast milk) are opposed by diabetogenic factors (vitamin D deficiency, viruses and cow's milk). In healthy individuals, a balance is maintained, but in patients suffering from type 1 diabetes, a shift towards diabetogenic factors occurs. Full colour version of this figure available via http://dx.doi.org/10.1530/JME-13-0067.''
Taking the concept of protective vs diabetogenic factors, one might postulate that a compensatory mechanism might also occur between different hypothesised factors. In other words, an increase in vitamin D deficiency might be compensated by an increase in breast-feeding and so on. This compensation might be associated with a 'protective environment'. However, what would happen if most of the protective factors decreased? A shift might occur from a protective equilibrium towards an increase in diabetogenic factors, leading to type 1 diabetes. This change might have occurred gradually throughout the 20th century, leading to an increase in incidence. This concept is described as the 'balance shift' model, shown in Fig. 4.
A good analogy would be the use of a balancing scale with one plate on each side (each plate representing the diabetogenic and protective factors). Each plate supports a variety of weights, representing the various factors brought forward in the hypotheses described above. In healthy individuals, the weights are balanced at all times (Fig. 5A), meaning that if one of the protective weights becomes lighter, another protective one will compensate
in order to maintain the scale in equilibrium (Fig. 5B). In diabetic patients, this compensatory mechanism does not occur, therefore tilting the scale towards the diabetogenic side (Fig. 5C).
It is likely that a multifactorial process leading to a disequilibrium between protective and diabetogenic factors is the cause of this increase. This in turn causes the acceleration of the diabetic process, causing an increase in childhood onset, therefore leading to an overall increase in the incidence of type 1 diabetes.
Further research, however, might be able to identify a common denominator, leading to a greater understanding as to why the incidence of type 1 diabetes is increasing.
Analogy of the 'balance shift' model.
(A) In healthy individuals, protective and diabetogenic factors are balanced at all times.
(B) A change in this balance is normally compensated by other factors.
For example, a decrease in breast-feeding might be compensated by an increase in vitamin D.
(C) In diabetic patients, however, this compensatory mechanism does not occur, tilting the scale towards the diabetogenic side and therefore causing type 1 diabetes. Vit D, vitamin D; Def, deficiency.
Full colour version of this figure available via http://dx.doi.org/10.1530/JME-13-0067.''
PDF is attached at the bottom of this page
- Overview Diabetes and vitamin D both T1 and T2
- Type 1 diabetes associated with faulty Vitamin D receptor genes – May 2013
- 44 percent less Type 1 diabetes if high level of vitamin D – white skinned military – March 2013
- Type 1 diabetes strongly associated with low vitamin D – March 2013
- Type 1 Diabetes probability reduced by 2X if have more than 40 ng of vitamin D – Feb 2013
- Type 1 Diabetes associated with low vitamin D, especially in dark skinned youths – Dec 2012
- T1 Diabetes 35 percent more likely if 10 degrees further from equator (less vitamin D) – June 2014
- The rise in type I diabetes: A look at the theories behind the increase Vitamin D Council, July 2013
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