Nutritional Factors in Type 1 Diabetes Development — An Evaluation of the Research

July 2019 Issue

Diabetes Management & Nutrition Guide: Nutritional Factors in Type 1 Diabetes Development — An Evaluation of the Research
By Jamie Santa Cruz
Today’s Dietitian
Vol. 21, No. 7, P. 44

Incidence of type 1 diabetes is increasing globally by approximately 3% every year.1 About 425 million people around the world currently are living with diabetes, and while the majority have type 2 diabetes, about 7% to 12% of all diabetes cases in high-income countries are type 1.2 The causes aren’t well understood, but researchers in recent decades increasingly have turned to the study of environmental factors—including dietary factors—to determine whether they may be triggering type 1 diabetes.

What Is Type 1 Diabetes?
Type 1 diabetes occurs when the body’s immune system mistakenly attacks insulin-producing cells (called islet cells, or beta cells) in the pancreas. Insulin is a hormone that enables glucose to enter cells. However, once a sufficient number of islet cells are destroyed, the body can no longer produce insulin. Without insulin, glucose can’t enter the body’s cells and therefore builds up in the blood, causing the cells to starve.

The antibodies that attack islet cells are called islet antibodies, and their autoimmune activity can be detected even before the development of symptomatic type 1 diabetes. Individuals who have islet antibodies are said to have islet autoimmunity (IA). As long as the number of islet antibodies remains low, it’s possible to live with IA for months to years. However, 70% of individuals with multiple islet cell antibodies develop clinical diabetes within 10 years.3

The primary risk factors for development of IA and thus type 1 diabetes are genetic. Variations in the human leukocyte antigen region of the genome account for more than one-half of the genetic risk, but dozens of other genes factor in as well.4 However, genes don’t account for all of the risk; environmental factors also play a role. This is clear from the fact that only a small percentage of genetically susceptible individuals develop the disease.5 It’s also clear from the fact that type 1 diabetes prevalence varies significantly between countries such as Iceland and Norway that have populations with similar racial/ethnic backgrounds and similar frequencies of high-risk genotypes.6

There’s significant seasonal variation in when type 1 diabetes occurs, which has long led researchers to theorize that viruses may play a role in the development of the disease. Several studies in both humans and animals suggest that viral infections—especially those caused by enteroviruses—may promote type 1 diabetes development.7-14

Aside from viruses, it appears that dietary factors also may play a role in the onset of type 1 diabetes. In this article, Today’s Dietitian surveys the nutritional factors that have received the most study.

Breast-Feeding
There has been much speculation that breast-feeding could reduce risk of IA and type 1 diabetes, perhaps by enhancing the infant’s immune system or delaying exposure to other dietary factors (eg, cow’s milk or solid foods) that could trigger an immune response. Supporting these theories, a prospective study of Swedish children found that breast-fed infants had a lower risk of IA at age 5.15 Likewise, a 2012 study of high-risk Norwegian children found that breast-feeding for 12 months or longer lowered the likelihood of progressing from IA to type 1 diabetes.16 Other research has shown that children who were still breast-fed at the time cereals were introduced into their diet have a lower risk of both IA and type 1 diabetes.17,18

But the research is far from conclusive. Several prospective birth cohort studies have failed to find any protective effect of breast-feeding,17,19-21 and a 2012 pooled analysis of 43 observational studies found very weak support for any protective effect of breast-feeding.22

According to Jill Norris, PhD, MPH, chair of the department of epidemiology at the Colorado School of Public Health, various studies have used different measures of breast-feeding. Some women breast-feed exclusively throughout their child’s infancy, whereas others breast-feed but also supplement with formula beginning early on, and many studies haven’t distinguished between these groups. Norris says it may be that the impact of breast-feeding on type 1 diabetes risk is related to the proportion of breast milk to other milks (eg, formula), but it’s hard to know from current research.

Cow’s Milk
Exposure to cow’s milk in infancy has been suggested as a trigger of type 1 diabetes, but here, too, the findings are contradictory. Some studies suggest that early introduction of cow’s milk into infants’ diets increases risk of developing type 1 diabetes later on.23-25 However, most prospective birth cohort studies haven’t found a link between exposure to cow’s milk in infancy and either islet autoimmunity15,17,19,20 or type 1 diabetes.18

Perhaps the most important study on this topic is the large, international TRIGR trial. Before this trial, the theory was that cow’s milk might be a type 1 diabetes trigger because of the complex proteins it contains. Thus, TRIGR examined whether an extensively hydrolyzed formula (ie, a formula in which all complex proteins have been broken down) might reduce the risk of type 1 diabetes compared with cow’s milk formulas. However, the trial concluded that the hydrolyzed formula didn’t lower the risk of either IA or type 1 diabetes.26,27 In combination with the similar findings of other large studies, the results are “pretty convincing,” according to Norris. “Removing cow’s milk exposure in infancy did not impact risk of diabetes in the child.”

The previously mentioned studies looked at exposure to cow’s milk in infancy and how that early exposure might impact type 1 diabetes risk. But a second angle on the question is whether quantity of cow’s milk intake later in childhood could impact risk.

One case-control study found that increased intake of cow’s milk in childhood was associated with a lower risk of type 1 diabetes.28 However, multiple other studies suggest the opposite—that cow’s milk intake in childhood increases risk of both IA and type 1 diabetes.29-32 A 2015 prospective study found that cow’s milk protein may influence the entire type 1 disease process; the study suggested that not only did greater childhood intake of cow’s milk increase the risk of IA, but, in children who already had IA, cow’s milk consumption appeared to promote progression to clinical type 1 diabetes.33

One possibility for this association, according to Norris, is that the issue isn’t cow’s milk itself but rather the sugar (lactose) contained in it and how that sugar contributes to overall sugar intake. After all, in the DAISY cohort, progression from IA to diabetes was associated with cow’s milk, but it also was associated with sugar intake.34 “When we look at diet, it is very difficult to isolate one [dietary] exposure,” Norris says. “It’s possible that our observations with regard to milk are related to the sugars that are coming along with milk.”

In summary, the relationship between cow’s milk intake, either in infancy or later in childhood, and type 1 diabetes is unclear at present, and cow’s milk as a trigger for type 1 diabetes remains an active area of research.35

Cereals and Gluten
As with breast-feeding and cow’s milk, the evidence regarding the timing of cereal introduction in infants’ diets is mixed. “This is a highly controversial issue, with some studies reporting that early exposure to cereals increases the risk of islet autoimmunity and clinical type 1 diabetes, while other studies find no risk effect from cereals,” says Mikael Knip, MD, PhD, a professor of pediatrics at the University of Helsinki in Finland.

In one study, introducing cereals too early or too late (before 4 months or after 6 months of age) was associated with increased IA risk.17 This finding is consistent with another study from the same research group showing that late exposure to both rice and oats predicted type 1 diabetes.18 Together, these findings suggest that there’s an optimal window of time in which cereals should be introduced—neither too early nor too late.

This conclusion is complicated, however, by multiple other studies that have examined gluten in particular. Two studies found that early introduction of gluten was associated with an increased risk of IA and/or type 1 diabetes.19,36 However, in 2018, the large, multinational TEDDY study found that later introduction of gluten (after 9 months of age) was associated with increased risk of IA, and that introduction before 4 months of age was associated with the lowest risk of IA.37 The finding from the TEDDY study is consistent with at least one previous study that also found an association of IA with late (but not early) introduction of gluten.30 Meanwhile, other research has found no clear association between IA and gluten introduction.21

Animal models suggest that diets based on cereals (perhaps especially gluten) promote the development of type 1 diabetes.38-40 In turn, a gluten-free diet has been found to dramatically reduce the incidence of type 1 diabetes in mouse models.41 However, in a study of human infants, a gluten-free diet between 6 and 12 months of age didn’t reduce the incidence of IA in high-risk infants,42 and it also didn’t decrease the levels of multiple islet cell antibodies in children who already had established IA.43

According to Norris, “We have some evidence that age of exposure to certain foods in infancy—like gluten or cereals—is associated with the development of autoimmunity and diabetes later on.” But since the association hasn’t been seen in all studies, she adds, the question of how cereal introduction relates to type 1 diabetes is still open.

Vitamin D Status
Conversely, there’s a clear association between vitamin D status and type 1 diabetes. Multiple studies in various countries have found that individuals with type 1 diabetes have lower blood levels of vitamin D than healthy controls,44-48 and those who are newly diagnosed have lower levels than those with established diabetes.49

But the relationship between vitamin D status and type 1 diabetes is complicated, and it’s difficult to sort out cause and effect. Current research suggests the relationship is bidirectional: Low vitamin D is a trigger of the disease, but it’s also a consequence of the physiological and behavioral changes that result from the disease.1

Adding to the confusion is that the risk related to vitamin D levels appears to be dependent on genes. In the TEDDY study, children with higher vitamin D levels had a lower risk of developing IA than those with low vitamin D levels, but the effect was only evident in children with certain genetic variations at specific loci in the vitamin D metabolic pathway. According to Norris, “This suggests that kids with certain vitamin D genes may be more responsive to vitamin D than others, such that they may have to have certain variants to see the risk reduction in IA associated with higher vitamin D levels.”

The fact that low vitamin D plays a role in IA and type 1 diabetes raises the question of whether supplementation could decrease incidence of the disease. A large prospective study in Finland suggests that it can. Among Finnish children, vitamin D supplementation significantly reduced risk of type 1 diabetes during the 30-year follow-up period.50

That said, vitamin D supplementation may be more effective at certain ages than at others. In the prenatal period, the benefits of supplements haven’t been proven conclusively; some research on maternal intake of vitamin D has found an association with type 1 diabetes risk,51 but other research hasn’t.52 Supplementation in infancy, meanwhile, appears to have a clearer impact on type 1 diabetes risk. Two separate meta-analyses both concluded that supplementation in infancy decreases later risk of type 1 diabetes by close to 1.5-fold.52,53 Furthermore, it appears that the benefits of supplementation may be more pronounced later in infancy rather than earlier in infancy. According to one study, those supplemented between the ages of 7 and 12 months had a 1.8-fold lower risk of type 1 diabetes later in life than those supplemented from birth to 6 months of age.54

Role of the Gut Microbiome
Imbalances in the gut microbiome have been associated with a wide variety of diseases, including autoimmune conditions such as celiac disease. Therefore, researchers are giving increasing attention to the role of the intestinal microbiome in type 1 diabetes.55

According to Hariom Yadav, PhD, an assistant professor of molecular medicine at Wake Forest School of Medicine in Winston-Salem, North Carolina, there’s a close relationship between the gut microbiome and the immune system. Microbes in the gut are in contact with the intestinal immune system, and, in early life, intestinal microbiota help to shape the development of the human immune system.56,57 Thus, if a microbial imbalance develops in the intestine, it can trigger inappropriate immune reactions or vice versa.

Multiple studies have shown that individuals with type 1 diabetes have lower levels of Firmicutes and higher levels of Bacteroidetes in their guts.58-61 Both of these phyla are common in a healthy gut microbiome, but maintaining a proper balance between the two appears to be important, as altered ratios of Firmicutes to Bacteroidetes are associated with a predisposition to disease states.62 Type 1 diabetes also has been associated with a reduction in the overall diversity of intestinal bacteria.63 According to Yadav, untangling the cause-and-effect relationship between microbial imbalances and type 1 diabetes is difficult, because type 1 diabetes itself alters microbiota composition in the gut. However, there’s some evidence that changes in the microbiota precede development of the disease and therefore may contribute to disease development.59,61,63

Probiotics for Type 1 Prevention
If imbalances in the gut microbiome are associated with type 1 diabetes development, this raises the question of whether probiotics could have a role in preventing the disease. “Prevention studies are very underdeveloped,” Yadav says. However, several mouse studies have found that supplementation with various specific probiotics—including particular strains of Lactobacillus, Bifidobacterium, Streptococcus salivarius, and Thermophilus—protects against the development of IA and type 1 diabetes.64-69

Research in humans is limited, but several studies have found that administration of specific probiotics—including strains of Lactobacillus and Bifidobacterium—modulates the immune system in positive ways and helps to preserve the function of pancreatic beta cells, potentially decreasing the incidence of type 1 diabetes.70,71

According to Yadav, the most significant findings so far related to probiotics for prevention of type 1 diabetes come from the multinational TEDDY study.72 In this study of more than 7,000 children, probiotic supplementation within the first 27 days of life was associated with a substantial reduction in IA risk compared with no supplementation or supplementation after 27 days. The benefits were seen only in children at high genetic risk, but, among that group, early probiotic intake was associated with a 60% lower risk of IA. Unfortunately, the study looked at probiotic supplementation in general and didn’t examine the impact of specific species or quantities. Most of the supplements the TEDDY children took contained a mixture of various Lactobacillus and Bifidobacterium species, but it’s currently unknown which specific species or doses would have the largest benefit.

Take-Aways for RDs
Many unknowns remain about the role of diet in type 1 diabetes development. “I think it is safe to say that we know now that the etiology of [type 1 diabetes] is very complex, more complex than what was ever anticipated,” says Ulla Uusitalo, PhD, an associate professor in the Health Informatics Institute at the University of South Florida.

The key take-aways based on current research include the following:

• The jury is still out on breast-feeding, cow’s milk, and cereals. Despite a wealth of research on each of these factors, it’s still uncertain how any of them impact risk of IA and type 1 diabetes—or whether they impact risk at all.

• Intervention trials are needed. A key weakness of the current research is that most of the studies examining dietary factors and type 1 diabetes risk have been observational in nature, so little is known about how specific interventions might impact risk. “There is a definite need of intervention studies to assess or refute disease protection conferred by nutritional factors,” Knip says.

• Vitamin D supplements and probiotic supplements seem to reduce type 1 diabetes risk. With vitamin D, supplementation in infancy (as opposed to maternal supplementation during pregnancy) seems to have a clearer positive effect. Regarding probiotics, parents who offer infant formula should search for a brand that contains probiotics in the formulation, Yadav says. If supplementing an infant apart from formula, Yadav advises choosing a probiotic that’s marketed specifically for infants to make sure the product is safe for infants.

— Jamie Santa Cruz is a freelance writer of health and medical topics in the greater Denver area.

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