Have you ever wondered why animal research studies often don’t translate to humans when it comes to diabetes advancements? It seems like we often hear about big breakthroughs and even “cures” for type 1 diabetes in mice–but why are there so many seemingly promising studies but so few actual changes when it comes to human treatment?

Let’s dig deeper on several levels, by first examining exactly how type 1 diabetes is studied in rodents.

Mouse Models of Type 1 Diabetes

Mice constitute the most widely-used animal in type 1 diabetes research. There are several ways that researchers can manipulate animals to mimic the symptoms of type 1 diabetes.

Using Chemicals that Kill Beta Cells

One way involves using specific drugs (most commonly streptozotocin or alloxan) to target and destroy the pancreatic beta cells, thereby inhibiting insulin production. In this case, the mice exhibit hyperglycemia; however, the root cause of diabetes is not autoimmune. Thus, using this type of model to study new therapies that attempt to suppress the aberrant immune response is irrelevant.

The NOD Mouse: A Gold Standard

There is a type of mouse called NOD (non-obese diabetic), which is frequently used in type 1 diabetes research. This is because the NOD mice are genetically predisposed to developing the condition, and are thought to closely mimic the pathophysiology of human type 1 diabetes. It has been noted that “most female NOD mice will have type 1 diabetes by 40 weeks of age”.

Much like what is seen in humans, the NOD mice develop autoantibodies against the pancreatic beta cells. Immune cells extracted from NOD mice can even induce type 1 diabetes when injected into other types of mice.

Other Approaches

Researchers can also generate a type 1 diabetes phenotype by infecting the animals with a specific virus that attacks the beta cells or by using genetic manipulation approaches. For example, researchers can re-program the T cells at the genetic level to be reactive against specific beta cell antigens.

More recently, scientists have also been working on “humanized” mouse models to study type 1 diabetes. Using immunodeficient mice allows researchers to transplant human cells and investigate very specific aspects of how human immune cells behave in a mouse model of type 1 diabetes.

The Takeaway

Due to the complexity of the immune system and the inherent genetic and metabolic differences between humans and rodents, none of these approaches can produce a perfectly precise model of how type 1 diabetes develops in humans. While mouse models constitute very important tools in diabetes research, the differences in the systems are one reason why seemingly promising discoveries often do not hold true for humans.

“Given the complexity of T1D, a single inbred animal model of diabetes is unlikely to unravel everything there is to know about (all forms of) autoimmune diabetes (that might exist) in the human population. These animal models can however help in the identification of many of the genetic, signalling and immune pathways involved in diabetes. Differing models have differing strengths and weaknesses, and before embarking on a clinical trial, several experimental animal models need to be consulted,” researchers summarize.

Did We Really Cure Diabetes in Mice?

Most of us have probably read sensationalized headlines about type 1 diabetes being “cured” in mice, especially in the last several years. But, is it really true?

What a Catchy Title!

I vividly recall when about six years ago, as a Ph.D. candidate, I gave a seminar presentation at my university on a new academic paper entitled “Reversal of type 1 diabetes in mice by brown adipose tissue transplant.” I chose the manuscript because it was of personal interest to me and it sounded very exciting. The premise seemed so novel and interesting–can we really transplant some brown fat and the mice would be magically “cured”?

Not so, I found, as I dug deeper. In fact, while the brown fat transplants lowered glucose levels in mice chemically-rendered diabetic, the basal blood glucose levels were still markedly above normal, and glucose tolerance tests also showed substantially elevated levels in comparison to the control group. Furthermore, insulin production was not restored, and the authors went on to describe what I found to be quite a far-fetched mechanistic explanation about how the transplants may have worked.

So, although there was a lot of hype in the title of the paper about “reversal of type 1 diabetes,” actually reading it left me rather disappointed and very surprised that such a title made it past the peer review process. At the end of the day, diabetes improvement does not equal a reversal. Nevertheless, the title was definitely catchy; as of today, the manuscript has been cited 164 times, according to Google Scholar.

Similarly, I recently read a paper published in Nature Medicine about stem cell encapsulation strategies that claimed to provide the mice with “long term glycemic control.” Surprisingly, the authors of that manuscript explained that “mice with unfasted blood glucose levels below 200 mg/dL were considered normoglycemic.” This was surprising to me, as according to various literature sources, normal fasting blood glucose levels in mice are approximately 61-129 mg/dL and a nonfasting range of approximately 109-173 mg/dL. Although the treated animals exhibited markedly lower blood glucose levels, many of the measurements were still above the normal range.

The Takeaway

If exaggeration and some degree of sensationalism are happening in academia, one can only imagine to what extent it is taking place in the media. The devil is always in the details, as they say.

Nevertheless, there are exciting developments going on in the field, such as novel stem cell and islet transplantation strategies. Also, ViaCyte’s work is very promising, in my opinion. There are many other strategies in the works, in particular, those investigating the premise of immunotherapy to attempt to reverse the autoimmune attacks on the pancreas, with substantial success already demonstrated in rodents.

Also, a recent paper discussed a promising novel approach to induce beta-cell formation in adult mice. Excitingly, the authors demonstrated that they could increase beta-cell mass in the treated mice, as well as normalize fasting blood glucose levels for a year post-treatment. “The present results provide a novel approach to the generation of beta cells using the natural physiologic cellular capacity of adult cells in the pancreas to form beta cells in vivo. The CNIP cocktail has the potential to be used as a preventative or therapeutic treatment or cure for both type 1 and type 2 diabetes,” the authors concluded.

Will any of these developments actually translate to humans? Only time will tell.

Wait… Can You Repeat That?

Reproducibility is an absolute must when it comes to science. Before theories can be generally accepted, and far before any talk of human trials can even begin, results must be verified by independent laboratories.

Recently, I came across a comprehensive report detailing the inability of scientists to reproduce important research findings. The original papers were published just a few years ago and reported on novel ways of increasing the number of pancreatic beta cells by using neurotransmitter and anti-malarial drug injections in mice. Strikingly, the claims are now being called into question, as other scientists have been unable to reproduce the results time and time again.

Why the failure? At this time, we cannot be certain. Many variables go into experiments that may affect the outcomes, including the type of mice, individual response variance, and a variety of specific treatment conditions, to name a few. Moreover, in an effort to maintain ethical standards, researchers are usually quite limited in the number of animals used in the experiments. Oftentimes, there are only three subjects in a particular treatment group, which greatly limits the statistical power.

When Will We See a Cure for Type 1 Diabetes?

While being a “Debbie Downer” isn’t the intent behind this post, I personally do not anticipate seeing a true cure for type 1 diabetes anytime soon.

There has been considerable excitement about the work of Dr. Denise Faustman, whose laboratory is attempting to use an established vaccine to treat type 1 diabetes. However, looking beyond the media hype, it was easy to see that the recent research findings were underwhelming. Like many others, I was quite disappointed to find that unlike the studies previously performed in mice, the vaccine failed to restore insulin production in humans.

“While progress has clearly been made toward understanding the initiating and sustaining events in the pathogenesis of type 1 diabetes, much more investigation and discovery are needed. We believe that future attempts to prevent and/or reverse type 1 diabetes are most likely to be successful if they incorporate the recent advances in our evolving understanding of pathogenesis of the disease,” a recent review summarized.

Undoubtedly, with continuing research efforts, more and more details will be unraveled, and it is likely that we will start to see more novel treatments enter human clinical trials. At this time, however, it is difficult to accurately gauge the pace at which this will occur.

As for now, my focus will remain on using all available tools to manage my blood glucose levels as best possible to minimize the effects of type 1 diabetes on my health. While I don’t see myself getting in line for a clinical trial any time soon, I am still incredibly optimistic about the future. It’s exciting to watch the evolution of knowledge on the subject, and I do not doubt that the next several decades will bring about exciting progress and translational benefits to patients. Stay tuned!

References

Atkinson MA, von Herrath M, Powers AC, Clare-Salzler M; “Current Concepts on the Pathogenesis of Type 1 Diabetes—Considerations for Attempts to Prevent and Reverse the Disease” (2015) Diabetes Care 38(6):979-988. http://care.diabetesjournals.org/content/38/6/979.full-text.pdf

Chen Y, Matthews CE, Driver, JP; “The Role of NOD Mice in Type 1 Diabetes Research: Lessons from the Past and Recommendations for the Future” (2018) Frontiers in Endocrinology 9:51. https://www.frontiersin.org/articles/10.3389/fendo.2018.00051/full

Doiron B, Hu W, DeFronzo RA; “Beta Cell Formation in vivo Through Cellular Networking, Integration and Processing (CNIP) in Wild Type Adult Mice” (2016) Current Pharmaceutical Biotechnology 17(4):376-388. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421132/

Gunawardana SC and Piston DW; “Reversal of type 1 diabetes in mice by brown adipose tissue transplant” (2012) Diabetes 61(3):674-82. https://www.ncbi.nlm.nih.gov/pubmed/22315305

Jensen TL, Kiersgaard MK, Sorensen DB, Mikkelsen LF; “Fasting of mice: a review” (2013) Laboratory Animals 47(4):225-240. http://journals.sagepub.com/doi/pdf/10.1177/0023677213501659

Van Belle TL, Taylor P, von Herrath MG; “Mouse Models for Type 1 Diabetes” (2009) Drug Discovery Today: Disease Models 6(2):41-45. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2855847/

Vegas AJ, Veiseh O, Gurtler M, et al.; “Long term Glycemic Control Using Polymer Encapsulated, Human Stem-Cell Derived β-cells in Immune Competent mice” (2016) Nature Medicine 22(3):306-311. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4825868/

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