Thursday 9th March
medwireNews: Thursday’s contrasting named lectures featured insights into the beta cells at the onset of type 1 diabetes, the expanding role of the incretins, and the role of the dietician in empowering diabetes patients to successfully manage their condition.
Edging closer to understanding insulitus
In the Dorothy Hodgkin lecture, Noel Morgan (University of Exeter Medical School) recounted the research that revealed two profiles of insulitis in type 1 diabetes.
He reminded the audience that everything known about the pancreas around the onset of type 1 diabetes comes from the study of less than 200 pancreatic samples, amassed mostly by pathologist Alan Foulis in the 1980s and, more recently, by the JDRF-sponsored nPOD study.
Through collaboration with Foulis and being bequeathed the samples on his retirement, Morgan’s group has had the opportunity – “a privileged opportunity” – to explore what happens in the pancreas at the time of diabetes onset.
What they found is that the composition of the immune cells that infiltrate the diabetic pancreas varies between patients. More specifically, the numbers of CD20-positive B cells can be high or low, whereas the numbers of CD4 T cells and CD8 T cells are consistent between patients, with CD8 cells being the most numerous. These CD20-defined phenotypes relate to the age of patients at the time of onset, with the “CD20-high” profile being found in patients diagnosed when younger than 7 years, and the CD20-low profile in those diagnosed when older.
“So we began to feel that type 1 diabetes is not a single disease,” said Morgan. “Many of you may well already know that from clinical experience, but here we had pathological evidence that there’s something different in very young patients.”
Furthermore, the team found that patients diagnosed at a very young age, who had the CD20-high profile, had barely any insulin-containing islets at the time of diagnosis, whereas patients who were only slightly older but had the CD20-low profile had far more insulin-producing islets remaining. And in these patients insulin-producing islets can persist for many years, being detectable in patients who have had diabetes for more than 50 years.
Morgan noted that it is not yet known why these islets survive for so long in some patients, but he said that one factor might be the variable expression of major histocompatibility complex (MHC) class 1 molecules on diabetic islets. Hyperexpression of MHC1 on islets is a known feature of type 1 diabetes, and is thought to be part of the process leading to the destruction of the islets, but whereas some islets hyperexpress this molecule, others, which can be in very close proximity, do not.
The hyperexpression of MHC1 decreases with increasing duration of diabetes, in addition to which beta cells in type 1 diabetes patients show increased proliferation, by around 10-fold, and Morgan said that this combination of proliferating cells and protection from the immune system could account for the long-term persistence of insulin-producing islets.
“But it also offers the interesting possibility that, if there are beta cells remaining, these could be reinvigorated in some way,” he said. “Rather than thinking about putting new beta cells into patients, one might think about recovering the function of those that are there.”
The missing piece from this story, of course, is the precipitating event that triggers the immune response. One of many possibilities, studied by Morgan’s group among others, is enterovirus infection. Enterovirus is found in the islets of around 70% of type 1 diabetes patients, whereas it is very rare in people without diabetes. In diabetes patients enterovirus is restricted to the beta cells and appears to be a low-level persistent infection, contrary to the typical extensive and damaging enteroviral infection.
“And so we wonder whether the development of a persistent infection might be a key component triggering the process of autoimmunity, as the virus adapts to the beta cell and the beta cell adapts to the virus and the two then live together over a long period,” concluded Morgan.
Incretins: beyond diabetes
In the RD Lawrence lecture, Victor Gault (Ulster University) discussed the incretins, which enhance insulin secretion and action and reduce blood glucose, and which he referred to as “the intelligent hormones” because they “can do this under levels of high glucose and therefore they can avoid unwanted episodes of hypoglycemia.”
Gault’s own work has focused on gastric inhibitory polypeptide (GIP), and he detailed his team’s efforts to create stable GIP analogs. The most successful of these remain stable for up to 24 hours, and are also effective in animal models of type 2 diabetes – an important issue because GIP is known to have reduced efficacy in conditions of hyperglycemia.
“So we believe GIP analogues have a place, somewhere, in the clinic,” said Gault. He outlined three likely future courses for incretin therapy: dual incretin pharmacotherapy; combined incretin and sodium-glucose cotransporter 2 inhibitor therapy; or unimolecular therapy, with researchers already attempting to create a single molecule combining the effects of both incretins.
The possibilities of incretin therapy go beyond just diabetes; there are incretin receptors in the brain, and incretins are able to cross the blood–brain barrier. And a role for incretins in cognition is implicit in the known effects of obesity and diabetes on the brain. Experiments in mouse models back this up, with incretins shown to improve cognitive function in mice via multiple effects on the hippocampus – facilitating long-term potentiation, altering gene expression, increasing neurogenesis, and reducing oxidative stress.
Gault outlined research showing that incretins also have similar effects in mouse models of Alzheimer’s disease, in association with a reduction in amyloid plaques. This had led to pilot trials of liraglutide in Alzheimer’s disease, and of exendin-4 in Parkinson’s disease, both with promising results.
“So the incretin hormones certainly not only are intelligent, I believe, for diabetes in that they can stimulate insulin release under elevated glucose, which is very important, but they also can have important effects in the hippocampus,” Gault concluded.
Empowering patients through education: the dietician’s role
In a much more clinical vein, the final named lecture of the day – the Janet Kinson lecture – explored the role of the dietician in delivering patient-centered care for diabetes patients.
The role of the dietician has come a long way in the time that Lindsay Oliver (Northumbria Healthcare NHS Foundation Trust) has been working in the field. Dieticians were once the last resort, she told the audience, and their main role was to reprimand patients for their unhealthy eating habits. Fast forward more than 20 years and Oliver has been instrumental in developing DAFNE, DESMOND, and the Year of Care, three initiatives that empower patients to share the responsibility and decision-making for their condition.
Because as Oliver reminded the audience, the time patients spend with their clinicians is tiny compared with the time they spend managing their own condition.
In 1994, Oliver was lucky to be able to take on one of the first posts created in the UK for a dietician working specifically with diabetes patients – lucky because the team was unable to find funding from the usual sources, which felt it would be “dangerous and unethical” for a dietician to be involved with long-term diabetes care, and the position was eventually funded by Kellogg’s.
So Oliver found herself working in one of the earliest examples of integrated, patient-centered diabetes care in the country, which she valued for its organized, systematic, and flexible approach, its positive clinical outcomes, and its attitude to patients. “I learnt a new phrase,” she said. “Unconditional positive regard.”
She stressed that the role of the dietician goes beyond just advising patients on their food intake; they have to think about medicines and psychology at the same time. “The dieticians at Northumbria offer people one-to-one support in a manner that doesn’t punish or tell off,” she said.
By being a primary contact, dieticians limit the “games of pass the parcel” with patients, provide a strong link between primary and secondary care, and lead on key aspects of care, such as education.
One group education program familiar to healthcare professionals working with diabetes patients is DAFNE, based on the findings of an insulin training therapy program in Düsseldorf, which had enjoyed much success. But a major aspect of the program – carbohydrate-counting – was very out of favor at the time, and it took many years for Oliver and her colleagues to convince the dietetic profession in the UK to adopt the tactic as a means of helping type 1 diabetes patients manage their blood sugars.
Diabetes patients, by contrast, loved the concept, finding it far more flexible, easy to understand, and simple to manage than the previous prescribed diet approach. And the results speak for themselves; for example, the program achieved a 61% reduction in the risk for diabetic ketoacidosis, a 72% reduction in the risk for severe hypoglycemia, and a 64% reduction in the cost of emergency medications.
“But the thing I really like about DAFNE is that it makes a difference to the individual and how they live with their diabetes on a day-to-day basis,” said Oliver. The program is judged on its ability to reduce patients’ glycated hemoglobin levels, but she would prefer more focus on patient-centered measures, such as patients’ ability to predict their blood glucose levels, eat with their family and friends, and drive with confidence.
She also believes that the impact of DAFNE extends beyond even its benefits for patients, by legitimizing the role of dieticians in diabetes care, changing the core food messages for type 1 diabetes, and providing a model for structuring and rolling out patient education programs.
One such program is DESMOND, for newly diagnosed type 2 diabetes patients, in which Oliver was also involved. This structured group education program, based on three psychologic theories of learning, tackles patients’ beliefs about and attitudes toward diabetes, empowering them to make positive behavioral changes.
Thanks to her experience with these landmark projects, Oliver then found herself involved in the NHS Year of Care project, of which she is now National Director. The project aims to improve care for patients with long-term conditions, including diabetes, which was the subject of the initial pilot trials. Rather than adopting a “box ticking” approach to patients’ health goals, it aims to maximize the effectiveness of the patients’ consultations with their clinicians, using a structured approach of information gathering and sharing in the run-up to review appointments.
This facilitates patient appointments that are more focused on having a good-quality conversation, in which patients are treated “as equals and experts in their own condition” and on discussing what matters to them and what care and support they might need.
“The most important people when we design our services are the people with diabetes themselves, and it’s our job to make them feel they can be in control and are in charge of managing their own health: in the driving seat of their diabetes,” said Oliver.
“And so I believe all of our systems should be geared towards supporting people in this way.”
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