Preclinical Study Offers New Clues to the Link Between ALS and Type 2 Diabetes

Preclinical Study Offers New Clues to the Link Between ALS and Type 2 Diabetes
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The presence of autoantibodies against a calcium channel in people with amyotrophic lateral sclerosis (ALS) may explain the frequent development of type 2 diabetes in these patients, a preclinical study suggests.

The data, which pinpoint the toxic effects of these autoantibodies in mouse insulin-secreting pancreatic cells, shed light on potential therapeutic targets for treating people who have both ALS and type 2 diabetes.

The study, “IgGs from patients with amyotrophic lateral sclerosis and diabetes target CaVα2δ1 subunits impairing islet cell function and survival,” was published in the journal PNAS.

Type 2 diabetes is a disease in which blood sugar levels are too high due to insufficient production of insulin — the hormone that helps move sugar into cells for energy — by specialized pancreatic cells (beta cells), or to insulin resistance, meaning that cells do not use it appropriately.

Several neurodegenerative diseases, including ALS, Parkinson’s, Alzheimer’s, and multiple sclerosis, are known to be linked to the development of symptoms associated with type 2 diabetes, but the underlying mechanisms of this linkage are unknown.

Similarly, the exact mechanisms behind ALS development remain unclear. However, abnormal immune responses associated with the incorrect  recognition of the body’s own molecules and cells as foreign, resulting in the production of autoantibodies against them, have been suggested to contribute to developing the disease.

Previous studies have shown that autoantibodies present in the blood of ALS patients lead to the abnormal functioning of calcium channels and elevated calcium levels in rodent motor neurons, causing calcium-dependent damages, including injury to the mitochondria (the cells’ powerhouses) and calcium-dependent cell death.

“Interestingly, pancreatic beta cells and neurons are equipped with similar types of calcium channels and share a series of [calcium-dependent] physiological and pathological mechanisms for their function/dysfunction and survival/death,” Per-Olof Berggren, the study’s senior co-author, and director of the Rolf Luft Research Center, Karolinska Institutet, in Sweden, said in a press release.

These similarities suggested that autoantibodies of ALS patients could recognize calcium channels not only in nerve cells, but also in pancreatic beta cells as foreign, potentially leading to similar calcium-associated damage in beta cells and subsequently to type 2 diabetes.

To clarify this, a team of researchers at the Karolinska Institutet, along with colleagues in Korea, China, the U.S., and the U.K, evaluated the effects of exposing mouse pancreatic beta cells cultured in the lab to the blood of 12 ALS patients with type 2 diabetes.

These effects were compared with those of blood from eight ALS patients, eight people with type 2 diabetes, and 12 healthy people.

Results showed that blood from people with both ALS and type 2 diabetes led to the greatest calcium response in beta cells among the four groups, and that there were no significant differences between the other three groups.

Further analyses revealed that the blood of 60% of ALS patients with type 2 diabetes induced exaggerated calcium responses in beta cells due to the presence of autoantibodies against a subunit of the calcium channel (Cav1.2) in beta cells’ membrane.

The team also discovered that by binding to Cav1.2, these autoantibodies promoted the channel’s overactivation, resulting not only in elevated calcium levels, but also in mitochondrial damage, impaired insulin production, and beta cell death.

The data highlighted that these autoantibodies in ALS patients with type 2 diabetes serve as a causal link between the two diseases by binding to and modulating this type of calcium channel.

These findings also suggested that “altered [antibody-related] immunity can serve as a critical pathogenic [disease-causing] mechanism in the development of diabetes,” said Shao-Nian Yang, MD, the study’s other senior co-author and associate professor at the department of molecular medicine and surgery at the Karolinska Institutet.

“This may lay the foundation for a new immunotherapy strategy for patients suffering from both ALS and diabetes,” Yang added.

While the exact reason why only a fraction of ALS patients develop type 2 diabetes remains unclear, the researchers hypothesized that a given combination of genetic and environmental factors may lead to the production of these autoantibodies.

“The extent to which the pathogenic mechanism that we discovered in patients with both ALS and type 2 diabetes may be generalized to other neurodegenerative diseases associated with diabetes will be the focus for future studies,” Berggren said.

Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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Inês holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in blood vessel biology, blood stem cells, and cancer. Before that, she studied Cell and Molecular Biology at Universidade Nova de Lisboa and worked as a research fellow at Faculdade de Ciências e Tecnologias and Instituto Gulbenkian de Ciência. Inês currently works as a Managing Science Editor, striving to deliver the latest scientific advances to patient communities in a clear and accurate manner.
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Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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