Vitamin D and risk of Type 1 diabetes Dr Elina Hyppönen MSc, MSc, MPH, PhD Centre for Pediatric Epidemiology and Biostatistics Institute of Child Health London, UK email: e.hypponen@ich.ucl.ac.uk Links: MSc http://www.uku.fi/laitokset/klravi/introduction.shtml http://www.lshtm.ac.uk/prospectus/masters_deg/md14.htm MPH http://www.uku.fi/~marjauhi/mph/mph.html PhD http://acta.uta.fi/english/teos.phtml?5436 Institute of child health: http://www.ich.ucl.ac.uk/

Overview Health effects of Vitamin D Type 1 diabetes Vitamin D and type 1 diabetes Public health importance I will start this lecture by describing briefly the conventional and non-conventional health effects of vitamin D. Next I go though the etiology of type 1 diabetes, aiming to help you to understand in very simple terms why we could expect vitamin D to affect diabetes risk and what kind of factors make it difficult to investigate the risk factors. The next section goes through the limited number of studies investigating these associations and in the final part of this lecture I suggest two frameworks for the putative public health importance. Throughout the lecture, I will use ‘vitamin D’ as a general term, without attempting to differentiate specific dietary or metabolic forms. As the etiology of type 1 diabetes as well as the range of vitamin D action are only partly understood, I decided to keep this review at a relatively general level, without including detailed hypotheses on mechanisms. On the whole, my aim is to rise questions rather than to attempt to answer them. At the end of this lecture, I feel you will have understood the most important things, if you find yourself (as happened to me) being surprised about how little we actually know, but at the same time also understanding the reasons for this. Link: Vitamin D and type 1 diabetes http://acta.uta.fi/english/teos.phtml?5436

Health effects of vitamin D Traditionally: regulation of calcium homeostasis and bone metabolism More recently suggested to affect a wide-range of diseases, including autoimmune disorders, cancer, metabolic syndrome Vitamin D is known to modulate immune function in humans suppresses (overaggressive) reactions Although called “a vitamin”, vitamin D is in fact a hormone, which is synthesized in the skin after exposure to UV-B radiation from the sun. It can also be obtained thorough diet, although most foods contain only small amounts or no vitamin D. The main natural dietary source is fish, but the concentration varies between fish species and even between individual fish. Because the intake is often very low, some foods are fortified with small amounts of of vitamin D (e.g. margarine, milk). In many countries vitamin D supplementation is recommended for infants and other special groups which often have restricted intake (e.g. elderly individuals). It has been known for long time that vitamin D is essential for bone health, severe deficiency leading to rickets in children or osteomalasia in adults. During recent years scientific literature has suggested a wide-range of health effects for vitamin D, although only a few associations have been well demonstrated to date. Vitamin D receptors have been discovered from all over the body (e.g. immune-cells, brain, heart, pancreas, intestine) suggesting that vitamin D is likely to have some kind of function in these tissues. It is already known that vitamin D affects the immune system in humans. How would you measure vitamin D intake in an epidemiological study? What aspects would you need to consider? Links: Vitamin D http://cancerweb.ncl.ac.uk/cgi-bin/omd?Vitamin+D Rickets http://cancerweb.ncl.ac.uk/cgi-bin/omd?rickets

Etiology of type 1 diabetes Destruction of beta cells by autoimmune process Length of latency period varies, often very long Disease develops in a genetically susceptible individual after (series of) environmental insults Viral infections and several dietary factors suggested to be involved in the pathogenic process Type 1 diabetes is an autoimmune disease, where the insulin secreting beta cells in the pancreas are destroyed by the body’s own overaggressive immune defence system. Clinical disease emerges at a relatively late stage of the beta cell destruction process, and typically diabetes is diagnosed when approximately 80% of the beta cells have already been destroyed. It is not well-known, what causes the disease, but it is generally accepted that the process occurs in a genetically susceptible individual after some kind of environmental insults that may affect several stages of the pathogenic process. The length of the latency period from the initiation of the beta cell destruction to the development of disease is thought to vary, and in some cases it may last for decades whereas in others the process may be relatively rapid. Among the environmental factors that have been suggested to affect the development of type 1 diabetes are virus infections and several dietary factors. Vitamin D is one of the rare ’positive’ dietary factors for which there is some evidence that it may reduce disease risk. Why may it be difficcult to investigate the risk factors for type 1 diabetes?

Vitamin D & Type 1 diabetes - Seasonal and geographical variation Some evidence for north-south gradient exceptions (e.g. Sardinia) association diluted by variations in genetic susceptibility? Little evidence for seasonal variation by time of birth in diabetic cases or according to season of the onset of the disease multifactorial disease, latency may be long confounded by use of vitamin D supplements, recommended during the dark seasons of the year As most vitamin D is derived through production in the skin after exposure to sunlight, it is logical to look at seasonal and geographic variations in the occurrence of the disease. There is some evidence for higher incidence rates for Norther regions vs. more Southern areas, but this North-South gradient is broken by exceptions such as Sardinia. Differences in genetic susceptibility are likely to explain some of the geographical variation, and may distort any clear North-South gradients that could be due to sunlight availability. Seasonal trends in the time of birth or time of onset of the disease can be used to indicate a link between vitamin D exposure and a disease. Studies investigating these associations have failed to show any generally persistent trends. I believe this may be due to the multifactorial nature of type 1 diabetes, seasonal differences in the supplementation recommendations and the often long latency period from the actual initiation of the process until manifestation of identifiable symptoms.

Vitamin D & Type 1 diabetes -Studies in animals and humans Type 1 diabetes prevented by 1,25-(OH)2D in animal models Some evidence for protective effect in humans only a few studies published to date In man, there is evidence for an association between vitamin D and type 1 diabetes, although there are only a few studies published to date.

Vitamin D & Type 1 diabetes - Relevant time window? Pregnancy mothers cod liver oil consumption  diabetes risk  Infancy any vitamin D supplementation  diabetes risk  dose of supplementation   diabetes risk  vitamin D deficiency  diabetes risk  Childhood ? Adolescence? Adulthood? Most studies have concentrated on investigating the effect of vitamin D exposure in infancy. Although infancy is thought to be potentially a crucial period for the development of type 1 diabetes, studies have focused on this stage of life mostly because vitamin D intake of the infant is (relatively) easily measurable. Results have been relatively consistent. In a Norwegian study, mother’s cod liver oil consumption during pregnancy was observed to be associated with a reduced risk of type 1 diabetes in the offspring. In another case-control study, carried out in 7 European countries, diabetes risk was found to be reduced by 30% if the child had received vitamin D supplementation. In the Northern Finland 1966 Cohort study, we found also an association between vitamin D and reduced diabetes risk , and I will talk about this study in more detail next. To my knowledge, there is practically no published data on the effect of vitamin D intake or status after infancy, before the onset of the disease.

Intake of vitamin D and risk of type 1 diabetes: a birth cohort study Elina Hyppönen, Esa Läärä, Antti Reunanen, Marjo-Riitta Järvelin, Suvi Virtanen Link: Lancet http://www.thelancet.com/ Lancet 2001;358:1500-1503

Northern Finland 1966 Cohort Study All pregnant mothers in the two northernmost provinces of Finland (Oulu and Lapland) with expected date of delivery in 1966 invited to participate -> 12,058 live births Information on vitamin D intake/status collected at 1 year of age (n=10, 366) Follow-up for type 1 diabetes up to December 1997 This slide describes briefly basic information for the Northern Finland 1966 Cohort Study. Hyppönen et al. Lancet 2001;358:1500-1503

Incidence of type 1 diabetes by use of vitamin D supplements in infancy Despite the fact that this cohort of Finnish mothers were very prudent in giving their children vitamin D suppelementation as recommended (leading to relatively small numbers of exposed subjects), we observed a strikingly consistent association between all the indicators of vitamin D intake intake and status. At first we looked at the association between type 1 diabetes and frequency of giving vitamin D supplementation to the infants and observed on average a 80% reduction in the risk if the child had received at least some vitamin D. * Adjusted for neonatal, social and anthropometric factors. Hyppönen et al. Lancet 2001;358:1500-1503

Incidence of type 1 diabetes by dose of vitamin D supplementation Next we looked at the the dose of supplementation and found that diabetes risk was reduced a further 80% among participants who had received supplementation regularly if the dose had been at least the 2000 IU recommended at the time. * Adjusted for neonatal, social and anthropometric factors. † Dose has been presented for infants receiving vitamin D regularly Hyppönen et al. Lancet 2001;358:1500-1503

Incidence of type 1 diabetes by suspected rickets in infancy Finally we looked at the effect of vitamin D deficiency, and as was expected diabetes risk was increased among children who were suspected of having had rickets during the first year of life. However, due to the small numbers of exposed subjects, confidence intervals for all the effect estimates were wide. Roughly, our results support anything from a 30% reduction up to 95% reduction in the diabetes risk for receiving at least some vitamin D supplementation. On the basis of these findings and previous studies would you trust that there is an association between vitamin D and type 1 diabetes? What would you like to know more? What kind of studies do you think are needed? * Adjusted for neonatal, social and anthropometric factors. Hyppönen et al. Lancet 2001;358:1500-1503

Associated temporal changes ? (in Finland) Increasing incidence of type 1 diabetes Dose reduction in infant vitamin D recommendations 1956: 4000-5000 IU 1964: -> 2000 IU 1975: -> 1000 IU 1992: -> 400 IU Changes in the compliance of giving vitamin D ? Increase in the incidence of rickets during 1980s AND It could be suggested that the constant increase in the incidence of type 1 diabetes could be linked to the combination of changes in the recommendations of vitamin D supplementation, and compliance in giving the supplementation to the infants. During the decades that incidence of type 1 diabetes has been increasing, the dose recommendation has been reduced (in steps) to a tenth of the original level. At the same time, there is some evidence of reduced compliance in giving vitamin D supplementation and re-occurrence of severe vitamin D deficiency i.e. rickets. How would you study the covariation in the temporal changes of vitamin D intake and incidence of type 1 diabetes? What makes a reliable evaluation of such associations difficult?

The BIG public health question IF the association between vitamin D and type 1 diabetes is shown to be causal, is it because... ...the intake is too low only to prevent the destructive autoimmune reaction in susceptible individuals ? OR Although studies on the association between vitamin D and type 1 diabetes have given promising results, it is clear that more research, including intervention studies, is needed to establish if occurrence of type 1 diabetes may be reduced by increasing vitamin D intake. However, it is interesting that currently there is no consensus on the definition of vitamin D deficiency nor for the optimum range of serum values. As vitamin D is known to affect immune function in humans, inadequate intake could affect the development of many other diseases in addition to those of autoimmune origin. ...the intake is too low to prevent human immune system from developing/working optimally ?