Infant feeding, type-1 diabetes and a patent for a new-improved formula

I wrote yesterday about the coming strategy of marketing infant formula with an insulin supplement as 'closer to breastmilk', with the claim it could reduce the higher incidence of diabetes in formula-fed infants. See:

Infants who are not breastfed, for whatever reason, are at greater risk of short and long-term illness and we want to see those risks reduced. We have been working on this for years - as well as protecting breastfeeding - and recently launched a 'making formula safer' campaign to make it clearer that the regulations we want to see implemented and enforced are there to protect all mothers and babies.

Our main focus at the moment is on responding to a UK government consultation on proposed regulations for the marketing of formula. As they stand, these would allow companies to introduce new ingredients into formula and launch them onto the market without seeking any approval, without registering any evidence on the safety or need for the new ingredients, without any independent review of evidence and without an independent monitoring system for health workers and others to report concerns. All companies will have to do is present a model label of their new product to the Food Standards Agency. In theory they have to have studies that demonstrate the safety of the ingredients, but there is no requirement to present this or for the ingredients to be approved before being put on the market. You can help us achieve better controls by supporting our safer formula campaign and our work (why not become a member of Baby Milk Action?)

The forthcoming added-insulin formulas I wrote about yesterday have prompted me to do a little more digging for this blog.

The patent awarded to the company and Dr. Naim Shehadeh (who appeared in the media report cited yesterday) for the proposed formula is No. 6399090. You can find it here:

In presenting the possible benefits of the invention, this states: "exposure to bovine insulin present in fresh cow milk, which differs from human insulin only by three amino acids, may break the tolerance to insulin and lead to autoimmune diabetes."

Autoimmune diabetes or type-1 diabetes is also known as insulin-dependent diabetes mellitus (IDDM). This is where the pancreas is damaged and so cannot produce the insulin needed to control blood sugar levels. Damage may occur due to a virus or it can be because the immune system attacks the cells in the pancreas. This type of diabetes can affect children.

The other type of diabetes, type-2 or non insulin-dependent diabetes (NIDDM), is more common and is associated with adults and their lifestyles.

Both are on the increase. The annual conference of Diabetes UK earlier this year heard about a new study on the increase of type-1 diabetes, as reported by the BBC. See:

---Extract begins
Lead researcher Professor Polly Bingley said the rate of childhood Type 1 diabetes was increasing all over Europe, particularly in the very young.

She said the increase was too steep to be put down to genetic factors alone.

"So it must be due to changes in our environment.

"This could either mean that we are being exposed to something new, or that we now have reduced exposure to something that was previously controlling our immune responses."

She suggested that fewer mums opting to breastfeed their babies might be a factor.

Another possibility is that children are being exposed to fewer germs, affecting the development of their immune systems.
---extract ends

Dr. Shehadeh's patent suggests that exposure to bovine insulin in cow's milk, the primary ingredient of most infant formula, may provoke an immune response in the child. In other words, the suggestion is the child's body sees the bovine insulin as an infection and produces antibodies to attack it. This reaction may prompt the immune system to go on to attack insulin-producing cells in the pancreas, so causing type-1 diabetes.

While the patent talks of fresh milk, the reference cited is actually for infant formula. I find this a little curious.

It is this study: Vaarala O, Paronen J, Otonkoski T, Akerblom H K. Cow milk feeding induces antibodies to insulin in children--A link between cow milk and Insulin-Dependent Diabetes Mellitus?. Scand J Immunol 47:131-135, 1998.

You can find it here:

It states:

---Extract begins
Exposure to cow milk (CM)-based formulas in early infancy has been associated with an increased risk of insulin-dependent diabetes mellitus (IDDM), but studies on the possible pathogenic mechanism(s) linking CM and IDDM are contradicting. We hypothesized that if CM formulas contained bovine insulin (BI), exposure to them could lead to immunization against insulin, which is the only known β-cell-specific autoantigen in IDDM.
---extract ends

They did find higher incidence of antibodies in infants fed on cow's milk formula than infants fed on hydrolised formula (where the protein has been broken down) or breastmilk.

They suggest: "The high incidence of insulin-binding antibodies in young children with IDDM may be explained by oral immunization to BI present in CM. Exposure to BI, which differs from HI only by three amino acids, may break the tolerance to insulin."

So the higher incidence of type-1 diabetes in formula-fed infants, and the increase in this in recent years (now affecting 20,000 school-age children, notes the BBC report) may have something to do with this reaction to bovine insulin in formula. Though, as the study says, the evidence on the mechanism has been contradicting.

Dr. Shehadeh has published a paper in which he proposes the mechanism by which insulin in breastmilk protects against type-1 diabetes. The reference is: Shehadeh N, Shamir R, Berant M, Etzioni A. Insulin in human milk and the prevention of type 1 diabetes. Pediatr Diabetes. 2001 Dec;2(4):175-7.

You can find it here:

This is the abstract:

Although controversial, exclusive breast milk feeding was shown to exert a protective effect in preventing type 1 diabetes. In contrast, an early introduction of cow's milk-based formula in young infants may enhance the risk of disease, especially in genetically susceptible children, presumably by an increase of intestinal permeability to macromolecules such as bovine serum albumin and beta-casein, which may arouse autoimmunity.

We have shown that human milk contains insulin in substantial concentrations, while insulin is barely detectable (if at all) in infant formulas. Orally administered insulin was demonstrated to promote gut maturation and to reduce intestinal permeability to macromolecules.

Furthermore, oral insulin may induce tolerance to insulin and protect against the development of type 1 diabetes. We herewith raise a hypothesis that human milk is protective against the development of type 1 diabetes by virtue of the effects of its substantial content of insulin.

So the study suggests that the relatively high levels of insulin in breastmilk help the development of the gut, so preventing substances entering the blood stream to provoke an immune response. And at the same time, exposure to the insulin in breastmilk may induce tolerance to insulin, rather than an immune response.

The patent is a little more definite in its claimed benefits:

---quote begins
Addition of insulin to infant formula leads for the following beneficial effects. First, it renders the infant formula more similar to human milk. Second, it protects from the development of Type-1 diabetes. Third, it improve the development and maturation of infants intestine. The addition of insulin to infant formula is safe for at least two reasons. First, the concentration of insulin is selected similar to that found in human milk. Second, oral insulin administration is already used in several human trials
---quote ends

As I wrote yesterday, expect 'closer to breastmilk' claims and the suggestion the formula helps prevent diabetes.

The proposed UK law would allow this product onto the market. All the company has to do is send a label to the Food Standards Agency. That's all. The authorities don't have to check the science or evaluate the safety of the product. A product that will be the sole food for a child in its most critical phase of development outside of the womb can be launched without prior authorisation.

It may well be that adding insulin will mean that formula-fed infants are less at risk - but it may put them at greater risk. While the patent covers the possibility of adding insulin with the same amino acid sequence as human insulin, it covers other possibilities too. If it is true that bovine insulin, which has only three amino acids different, can provoke an immune response, what of the synthetic insulin this patent allows for?

Though the patent glosses over the fact by referring to fresh cow's milk, the study cited to show that bovine insulin may provoke type-1 diabetes is for infant formula. Is it certain that added insulin will protect against the bovine insulin in the formula that carries it?

A few years ago Dr. Shehadeh responded to a study on giving insulin to premature infants published in the British Medical Journal. See:

He commented:

---Extract begins
We suggest to add human insulin to infant formulas in a concentration similar to insulin concentration present in human milk. This addition may lead to the following beneficial effects: It will make infant formula similar to human milk; it may fasten gut maturation; and it may protect from the development of type 1 diabetes.
---extract ends

The lead researcher, Robert J. Shulman M.D., responded:

---Quote begins
I am familiar with the work of Dr Shehadeh et al. There may indeed be a place for insulin in infant formula. However, before such a step is taken, I believe that it is imperative that appropriate prospective studies be done, including safety monitoring. Although our human pilot study and animal studies suggest there may be a benefical effect of oral insulin, much more work needs to be done and recommending its use now is, to my mind, not appropriate.
---quote ends

There needs to be more research, something the company plans to do. However, there are a whole host of ethical issues about how to do research on new-born infants and the role that companies wishing to bring a product to market should have in them.

I hope to return to this topic with more information on current thinking on whether adding insulin will reduce the health risks of formula feeding and the ethical concerns about research.

The more pressing task is working to ensure the UK law will only allow products onto the market with new ingredients if they are safe and necessary. You can support our campaign for safer formula at:

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