Tag Archives: Pancreas

Microbiology

First clinical trial of GABA/GAD focused exclusively on children with recent onset Type 1 diabetes

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Reviewed by Emily Henderson, B.Sc.Feb 22 2023

For the first time, humans with newly diagnosed Type 1 diabetes, or T1D, have received two treatments called GABA and GAD that have shown promise in animal studies and in isolated human pancreas islets. This investigator-initiated clinical trial, published in Nature Communications, focused exclusively on children with recent onset T1D.

Diabetes is a disease affecting two pancreatic hormones -; insulin and glucagon. In healthy people, insulin helps cells take up glucose from the blood when glucose levels are high. In contrast, glucagon helps the liver release glucose into the bloodstream when glucose levels are low. Thus, levels of blood glucose remain steady.

In T1D, autoantibodies destroy the pancreatic beta cells, insulin release is diminished, and glucagon release is excessive relative to the insulin deficiency. This can cause a vicious cycle of escalating blood glucose levels. Strategies to ameliorate or cure T1D, therefore, target the preservation of insulin-secreting beta cells and/or attenuation of the relative excess of alpha cell glucagon. Most importantly, concerning the inhibition of alpha cell glucagon in this trial by GABA/GAD, recent studies in animals made diabetic have shown that inhibition of glucagon leads to expansion of insulin-secreting beta cells and improvements in hyperglycemia.

Researchers in the study, led by University of Alabama at Birmingham physicians, were able to enroll children within the first five weeks of diagnosis, before the near total eradication of beta cells. Forty percent of the study participants were younger than 10 years old. The study -; which was constrained to lower-dose GABA therapy by the United States Food and Drug Administration because it was the first human trial with GABA -; did not achieve its primary outcome, the preservation of insulin production by beta cells. However, it did meet the clinically relevant secondary outcome of reduced serum glucagon. Significantly, the trial confirmed the safety and tolerability of oral GABA. Additionally, in collaboration with the immunology team of Hubert Tse, Ph.D., at the UAB Comprehensive Diabetes Center, a separate manuscript under review will describe a salutary effect of GABA alone and in combination with GAD on cytokine responses in peripheral blood mononuclear cells from trial participants.

GABA is gamma aminobutyric acid, a major inhibitory neurotransmitter. In the endocrine pancreas, GABA participates in paracrine regulation -; meaning a hormone that acts on nearby cells -; on the beta cells that produce insulin and the alpha cells that produce glucagon. In various mouse model studies, GABA was able to delay diabetes onset, and restore normal blood glucose levels after diabetes had already commenced. GABA treatment also led to significant decreases in the inflammatory cytokine expression that participates in the pathogenesis of T1D.

GAD is glutamic acid decarboxylase, the enzyme that acts on glutamate to form GABA. Animal and pancreatic islet cell studies show that immunization with GAD alone may help preserve beta cells. Both GABA and GAD are highly concentrated in the pancreatic islet, which is the autoimmune target of T1D.

The study, which was conducted between March 2015 and June 2019, screened 350 patients and enrolled 97, whose ages averaged 11 years. Forty-one took oral GABA twice a day; 25 took the oral GABA in combination with two injections of GAD, one at the baseline visit and one at the one-month visit. The remaining 31 children received a placebo treatment. Analysis after one year of treatment included 39 in the GABA group, 22 in the GABA/GAD group and 30 in the placebo group.

Given that GABA reduces immune inflammation at higher doses in several diabetic rodent models, it is plausible that increased GABA doses, or longer-acting preparations, could offer sufficiently prolonged, above-threshold GABA concentrations to preserve islet cells, particularly during stage 1 diabetes.”

Gail Mick, M.D., UAB Professor in the Department of Pediatrics’ Division of Pediatric Endocrinology and Diabetes

Mick and Kenneth McCormick, M.D., who recently retired from UAB Pediatrics, co-led the trial.

Alexandra Martin and Mick, UAB Department of Pediatrics, are co-first authors of the study, “A randomized trial of oral gamma aminobutyric acid (GABA) or the combination of GABA with glutamic acid decarboxylase (GAD) on pancreatic islet endocrine function in children with newly diagnosed type 1 diabetes.”

Other authors are Heather M. Choat, Alison A. Lunsford and Kenneth L. McCormick, UAB Department of Pediatrics; Hubert M. Tse, UAB Department of Microbiology; and Gerald G. McGwin Jr., Department of Epidemiology, UAB School of Public Health.

Source:

University of Alabama at Birmingham

Journal reference:

Martin, A., et al. (2022) A randomized trial of oral gamma aminobutyric acid (GABA) or the combination of GABA with glutamic acid decarboxylase (GAD) on pancreatic islet endocrine function in children with newly diagnosed type 1 diabetes. Nature Communications. doi.org/10.1038/s41467-022-35544-3.

Microbiology

Novel immunotherapy offers a promising new strategy to fight hard-to-treat cancers

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Reviewed by Emily Henderson, B.Sc.Dec 16 2022

Scientists at UC San Francisco (UCSF) have engineered T cells to produce a potent anti-cancer cytokine, but only when they encounter tumor cells. The immunotherapy eliminated melanoma and pancreatic cancer in mice without major side effects, and it offers a promising new strategy for fighting these and other hard-to-treat cancers.

The cells deliver IL-2, a powerful inflammatory molecule that is naturally produced by the immune system. IL-2 supercharges T cells, immune cells that can kill cancer cells and also protect against infection. While oncologists have known for decades that IL-2 has potent anti-cancer activity, its use has been limited by the toxic response it produces when given systemically.

In the study, published Dec. 15, 2022, in Science, the researchers were able to keep the cytokine contained within the cancer by programming the tumor-infiltrating T cells to make their own IL-2 when they recognized a cancer cell.

We’ve taken advantage of the ability of these cells to be local delivery agents and to crank out their T-cell amplifiers only when they recognize they’re in the right place. I think this is a model for how we can use cell therapies to deliver many types of potent but toxic therapeutic agents in a much more targeted manner.”

Wendell Lim, PhD, the Byers Distinguished Professor in cellular and molecular biology, director of the UCSF Cell Design Institute and senior author on the study

Slipping past the barriers

Cellular therapies have been highly effective against many blood cancers, where the cells are easily accessible because they are floating freely. Solid tumors, however, build multiple defensive walls that prevent therapeutic T cells from entering. And even if the cells do get into the tumor, they often tire out before they’re able to finish off the cancerous cells.

Since the 1980’s, oncologists have known that high doses of IL-2 enable T cells to overcome these barriers, and the cytokine has been used as cancer therapy in challenging cancer cases. But simply infusing patients systemically with IL-2 can cause high fever, leaky blood vessels, and organ failure.

Lim and lead author Greg Allen, MD, PhD, adjunct assistant professor of medicine and a fellow at the Cell Design Institute, aimed to tame IL-2’s effects by engineering cells that enhance the cancer-killing immune response only where it’s needed: in the tumor.

They chose to go after notoriously difficult-to-treat tumors, like those of the pancreas, ovary and lung, that form nearly iron-clad barriers against T cells.

To engineer cells T cells that could sense when they were in the tumor, the researchers used a synthetic Notch (or synNotch) receptor, a flexible type of molecular sensor, which Lim’s lab developed several years earlier. These receptors span the cell membrane, with ends that protrude both inside and outside the cell. The outside portion recognizes and binds to tumor cells, triggering the inside portion to set the production of IL-2 in motion.

The team tested the synNotch cells on a number of deadly tumors, including melanoma and pancreatic cancer, and found that the cells worked exactly as planned.

“We were able to design these therapeutic cells to slip past the tumor’s defensive barriers. Once in the tumor, they could establish a foothold, and begin effectively killing cancerous cells,” said Allen. “We got on top of these tumors and in some cases cured them.”

A positive-feedback circuit

The approach owes its success to engineering a circuit in the cell that amplifies the immune response in a controlled way. This induces the cell to produce IL-2 only under the specific conditions it’s programmed to recognize.

“This induction circuit is really a positive-feedback loop, an important element behind making these designer T cells that are able to operate so effectively,” Allen said.

The circuit begins when the synNotch receptor tells the T cell to make IL-2. That IL-2 feeds back on the cell, causing it to divide, in turn creating more cells that make even more IL-2. The entire process is confined within the tumor, protecting the rest of the body from harm.

Allen, who is both a researcher and an oncologist, hopes to begin testing the therapeutic approach in clinical trials with pancreatic cancer patients in 2024.

“The most advanced immunotherapies are just not working in a lot of these difficult solid tumors,” he said. “We think this type of design can overcome one of the major barriers and do it in a way that’s safe and free of side effects.”

Source:

University of California – San Francisco

Journal reference:

Allen, G.M., et al. (2022) Synthetic cytokine circuits that drive T cells into immune-excluded tumors. Science. doi.org/10.1126/science.aba1624.

Microbiology

Study can provide deeper insight into the link between common oral bacteria and other diseases

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Reviewed by Emily Henderson, B.Sc.Nov 24 2022

Researchers at Karolinska Institutet in Sweden have identified the bacteria most commonly found in severe oral infections. Few such studies have been done before, and the team now hopes that the study can provide deeper insight into the association between oral bacteria and other diseases. The study is published in Microbiology Spectrum.

Previous studies have demonstrated clear links between oral health and common diseases, such as cancer, cardiovascular disease, diabetes and Alzheimer’s disease. However, there have been few longitudinal studies identifying which bacteria occur in infected oral- and maxillofacial regions. Researchers at Karolinska Institutet have now analysed samples collected between 2010 and 2020 at the Karolinska University Hospital in Sweden from patients with severe oral infections and produced a list of the most common bacteria.

This was a collaborative study that was performed by Professor Margaret Sällberg Chen and adjunct Professor Volkan Özenci’s research groups.

We’re reporting here, for the first time, the microbial composition of bacterial infections from samples collected over a ten-year period in Stockholm County. The results show that several bacterial infections with link to systemic diseases are constantly present and some have even increased over the past decade in Stockholm.”

Professor Sällberg Chen, Department of Dental Medicine, Karolinska Institutet

A role in other diseases

The study shows that the most common bacterial phyla amongst the samples were Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria, while the most common genera were Streptococcus spp, Prevotella spp, and Staphylococcus spp.

“Our results provide new insight into the diversity and prevalence of harmful microbes in oral infections,” says Professor Sällberg Chen. “The finding isn’t only of importance to dental medicine, it also helps us understand the role of dental infection in patients with underlying diseases. If a certain bacterium infects and causes damage in the mouth, it’s very likely that it can be harmful to tissues elsewhere in the body as the infection spreads.”

The research group has previously shown that the occurrence of oral bacteria in the pancreas reflects the severity of pancreatic tumours.

Useful method in dental care

The study was conducted using 1,014 samples from as many patients, of whom 469 were women and 545 men, and a mass-spectrometric method called MALDI-TOF that rapidly identifies individual living bacteria in a sample, but that is rarely used in dental care.

“Our study was a single centre epidemiology study and to ensure the validity of the results we need to make more and larger studies,” says Volkan Özenci at the Department of Laboratory Medicine, Karolinska Institutet. “We now hope that dentists will collaborate with clinical microbiology laboratories more to gain a better understanding of the bacteria that cause dental infections, to improve diagnostics and therapeutic management of oral infections.”

The study is part of Khaled Al-Manei’s doctoral thesis, the next step of which is a similar epidemiological study of fungal infections in the mouth that aims to identify new fungi and microbes and understand what causes their possible malignancy.

The study was financed by the Swedish Research Council, the Swedish Cancer Society and CIMED (the Centre for Innovative Medicine).

Source:

Karolinska Institutet

Journal reference:

Al-Manei, K., et al. (2022) Clinical Microbial Identification of Severe Oral Infections by MALDI-TOF Mass Spectrometry in Stockholm County: An 11-Year (2010-2020) Epidemiological Investigation. Microbiology Spectrum. doi.org/10.1128/spectrum.02487-22.