Could Type 2 Diabetes Be a Prionlike Transmissible Disease?

Liam Davenport

August 14, 2017

The aggregates of misfolded proteins in the pancreas could cause symptoms of type 2 diabetes by a mechanism similar to that seen in prion diseases such as Creutzfeldt-Jakob disease or bovine spongiform encephalopathy (BSE, "mad cow" disease), say US researchers in controversial findings that suggest that some aspects of type 2 diabetes pathology could, in some cases, be transmissible.

In a series of experiments, the scientists found that aggregates of the islet amyloid polypeptide protein (IAPP) taken from mice with type 2 diabetes could induce similar aggregates in unaffected cells and animals and that these were accompanied by type 2 diabetes–like symptoms.

The research, which was published online by Abhisek Mukherjee, PhD, of the Mitchell Center for Alzheimer's Disease, department of neurology, University of Texas Medical School at Houston, and colleagues in the Journal of Experimental Medicine on August 1, could eventually lead to novel treatments similar to those being explored for other conditions linked to deposits of protein aggregates, such as Alzheimer's and Parkinson's diseases.

"Our results showing that induction of IAPP misfolding is sufficient to produce the main symptoms of [type 2 diabetes] in the absence of any other process (such as high-fat diet or disruption of insulin signaling) suggest that IAPP misfolding and aggregation have an important role in the pathogenesis of type 2 diabetes," the team writes.

While noting that many more studies are needed to explore these associations further, they say that the idea that aspects of type 2 diabetes "might be transmissible could open an entirely new area of research, with profound implications for public health."

They add: "Because IAPP aggregates are deposited in the periphery, the possibility that prionlike transmission events may occur is higher than in the neurodegenerative diseases, where the blood–brain barrier restricts exposure to peripherally acquired protein seeds to the brain."

There is, however, a lack of epidemiological studies to support the idea of prionlike transmission, and the researchers themselves acknowledge that the study is "experimental" in nature.

Consequently, "the results should not be extrapolated to conclude that type 2 diabetes is a transmissible disease in humans without additional studies," they note, adding that — potentially of greater significance — "the prion phenomenon may have a key role in spreading the pathology from cell to cell or from islet to islet during the progression of the disease."

Experiments Involved Transgenic Mice and Human Pancreatic Cells

The researchers initially studied transgenic mice that overexpress human IAPP. At 12 months of age, the mice develop small intracellular IAPP aggregates that later become huge extracellular deposits, alongside type 2 diabetes–like symptoms such as severe hyperglycemia, amyloid deposits, and impaired insulin production.

The researchers extracted islet cells from the mice at 3 weeks of age, before they express the IAPP aggregates, and cultured them with islet cells from older transgenic mice with IAPP aggregation or with islet cells from their wild-type counterparts, which served as controls.

They found that, in a prionlike effect, the islet cells cultured with cells from older transgenic ovexpressing human IAPP developed amyloid aggregates, while those cultured with wild-type cells did not.

Similar results were obtained with islet cells obtained at postmortem from humans without type 2 diabetes, which also accumulated substantial amyloid deposits when cultured with cells from transgenic mice overexpressing human IAPP but not with those from wild-type mice.

The researchers also repeated the experiments in vivo, injecting 3-week-old transgenic mice with a solution containing 10% pancreatic homogenate from 12-month-old transgenic mice showing overt signs of type 2 diabetes or a homogenate from age-matched wild-type mice.

At 20 weeks of age, mice injected with older transgenic pancreatic homogenate had extensive amyloid deposits, while those given homogenate from wild-type mice had only a small amount of amyloid deposits, similar to that seen in untreated transgenic mice.

The team also showed that mice pretreated with anti-IAPP–specific antibodies did not show any IAPP aggregation, while injecting pancreatic homogenate from a mouse model of diabetes that is not associated with IAPP did not lead to IAPP aggregation, further supporting the prionlike mechanism of induction.

Moreover, more than 70% of the mice that received pancreatic homogenate from older transgenic mice developed hyperglycemia by 20 weeks of age, compared with none of those treated with normal pancreatic homogenate.

These mice also developed impaired glucose homeostasis, loss of beta cells, and changes in islet morphology, changes that were, again, not seen in mice injected with control homogenate.

To confirm that the effects were specific to IAPP, the team repeated the experiments with pure, synthetic IAPP aggregates, achieving similar results. It was also demonstrated that the aggregates did not accumulate or cause toxicity in nonpancreatic tissues.

If You Don't Look, You Don't Find

"Our current study aimed to provide proof of concept for this phenomenon in diabetes, and for that reason, we used the models and methodologies traditionally used in the prion field to demonstrate the transmission process," note the researchers.

"The findings obtained in our study not only extend the concept of prionlike transmission to the most prevalent disease [type 2 diabetes] of the protein-misfolding-disorders (PMD) group but also show that transmission of protein misfolding leads to bona fide disease phenotypes. This is a subject of great importance, because, in most previous studies, the transmission of the pathologic misfolded aggregates did not induce the disease phenotype," they emphasize.

Senior author Claudio Soto, PhD, from Kathrine G McGovern Medical School, University of Texas Medical School at Houston, told Medscape Medical News that the connection between IAPP aggregates and the development of type 2 diabetes is "very easy" to make.

He said: "It is surprising that the people in the field have not really paid more attention, because, to me, it's very straightforward."

Dr Soto explained that, in cases of insulin resistance, the body thinks that there is not enough insulin to induce sufficient glucose metabolism, so it makes the pancreas produce more.

"Insulin and IAPP are regulated by the same mechanism," he noted. "So every time there is an increase in insulin, there is an increase in IAPP concentration.

"We have known for many years that the ability of proteins to aggregate is directly proportional to the concentration of the protein, so even small changes in the concentration of proteins leads to a higher propensity to form aggregates."

For example, in patients with Alzheimer's disease, only a 1.5-fold increase in protein concentrations is enough to lead to aggregation.

"Here, you have a condition where, because of the obesity, because of the insulin resistance, the concentration of IAPP substantially increases and…what we think is happening is that, when the IAPP aggregates, it kills pancreatic cells and leads to the development of type 2 diabetes."

Dr Soto believes that this aspect of diabetes pathology has been overlooked because people in the field "think that the destruction of beta cells is due to a variety of other situations, other problems."

"They have not placed enough attention, in my opinion, on the role of these IAPP aggregates," he stressed. This is surprising, he added, "Because, if you think about the evidence for the role of these aggregates, it's as good as what's happening in Alzheimer's or Parkinson's, where the field revolves around these protein aggregates."

Dr Soto thinks that the results could, eventually, lead to the development of novel treatment strategies for type 2 diabetes, including some similar to those that are already under development for Alzheimer's and Parkinson's diseases.

He also believes the evidence supporting the concept of prionlike diabetes infection could be discovered if the right epidemiological studies were to be conducted "because if you don't look, you don't see."

"Nobody has thought in this direction before, so I think now is the time to do some of those epidemiological studies," he emphasized.

And in a future extension of their work, Dr Soto and colleagues plan to study in detail different routes of transmission, including oral administration and blood transfusion, two routes that have been shown to operate in prion diseases.

The Integrated Microscopy Core was provided with funding from the Dan L Duncan Cancer Center, Baylor College of Medicine, and the John S. Dunn Gulf Coast Consortium for Chemical Genomics for providing the electron microscopy micrographs. This study was supported in part by the Jeane B Kempner postdoctoral fellowship awarded to Dr Mukherjee. The authors declare they have no relevant financial relationships.

J Exp Med. Published online August 1, 2017. Article

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