30 January 2022
Type 1 diabetes is an autoimmune disease which attacks and depletes the β-cells of the pancreas responsible for secreting the hormone insulin, which mediates the uptake of glucose by cells. For many years the standard treatment has been regular administration of insulin, but this only manages the symptoms rather than preventing or reversing the progress of the disease.
Many patients cannot achieve long-term effective control of their blood glucose using insulin. They remain at risk from ketosis, the generation of ketones when fat is used as an energy source, and can also experience erratic fluctuations in blood glucose levels, including damaging episodes of low blood sugar (hypoglycemia). The long-term effects of these issues can include vascular problems causing serious damage to the eyes, kidneys, and feet.
Researchers are exploring several avenues for novel therapies that might offer a more convenient treatment, a reduction in the complications and limitations of long-term insulin administration, and the possibility of detecting the disease in its early stages and limiting its impact.
One option uses transplanted donor cells, including stem cells, to try to generate a new population of healthy β-cells. However, while it shows some promise, this approach has been hampered by considerable challenges in obtaining suitable cells for transplantation and getting them to integrate and flourish in their new environment.
Two recent clinical trials have demonstrated the potential of alternative approaches based on modulating auto-immune attack or biochemically improving blood glucose control, possibly through improved β-cell survival and function.
In one of these approaches, researchers at the University of North Carolina, USA and the company vTv Therapeutics in North Carolina conducted a Phase 1b/2 adaptive trial of a drug that activates an enzyme in the liver1. The drug, known as TTP399, binds to and activates the enzyme glucokinase, which adds phosphate groups to glucose. This enzyme has attracted the attention of researchers because mutations in the gene that encodes it are associated with changes in blood glucose and insulin balance. In a trial involving fewer than 100 subjects, the drug effectively and safely counteracted hypoglycemia in people with type 1 diabetes. The treatment was not tested as an alternative to insulin therapy but as an additional or ‘adjunct’ treatment that might improve blood glucose control and reduce the complications associated with insulin treatment alone.
The frequency of severe hypoglycemic attacks was reduced by as much as 40% in treated patients compared with those receiving only their usual insulin treatment plus placebo. Their ketone levels, detected by excretion in urine, were also significantly reduced.
The authors say their results suggest that the treatment improves the control of blood sugar levels in a way that “to our knowledge is unique.” They add that by preventing complications associated with other treatments, “it would be a substantial advance in the treatment of type 1 diabetes.”
In recognition of its promise, the US Food and Drug Administration (FDA) has granted this approach a Breakthrough Therapy designation. This opens access to greater financial support for vTv, the company developing the treatment, as well as the possibility of facilitating FDA development and expediting the review process leading towards approval for clinical use.
The second approach also recently underwent a phase 2 clinical trial. A large international research team tested a combination therapy based on an antibody designed to modulate the immune attack on β-cells together with the drug liraglutide, which is more commonly used to treat type 2 diabetes2.
The antibody, known as anti-interleukin-21 (IL-21), is designed to bind to and inhibit the action of interleukin-21, a natural signalling protein implicated in promoting the progression of type 1 diabetes in animal models. Liraglutide is a large synthetic molecule known to improve the function and survival of β-cells.
The trial concluded that the combination therapy could preserve β-cell function in young adults who have been recently diagnosed with type 1 diabetes. While its efficacy appears to be similar to existing treatments, the trial data suggest that it has a better safety profile. The researchers feel that these results are sufficiently encouraging to move into third phase of clinical trials, involving a much larger group of subjects.
“Disease-modifying therapeutic interventions in type 1 diabetes will become the new standard in newly diagnosed patients,” says Thomas Pieber of the Medical University of Graz in Austria, the corresponding author of the research paper reporting the results.
Pieber says the Phase 3 trials will expand the research to children, who are one of the groups most likely to benefit in the long term from a new intervention that can control the disease in its earliest stages.
There are also several promising developments in early stage laboratory work that has not yet reached clinical trials. Researchers in Germany, for example, have discovered a novel cell membrane receptor involved in insulin signaling which is more active in people with type 1 diabetes. Early work with mice suggests that inhibiting this receptor holds the potential to prevent the depletion of β-cells or even support their regeneration3.
In a recent review article, researchers at Sidra Medicine in Qatar discussed why they believe type 1 diabetes is a very promising candidate for a personalized medicine approach, which aims to apply “the right therapy at the right time, to the right patient”. They review a wide range of initiatives, from gene therapy to new drugs to changes in nutrition, which they say might herald a new dawn in treatments targeted to the specific needs of each individual4. A personalized approach might bring significant benefits since the onset and progress of the disease, as well as the response to therapy, can vary widely among different individuals.
The outlook for improved control, reversal or prevention of type-1 diabetes therefore seems promising on several fronts. However, all of these hopes are subject to the familiar caveats in translating laboratory research to early clinical trials, followed by confirmation in wider trials and eventually extended clinical practice.
Klein, K. R., et al. The SimpliciT1 Study: A Randomized, Double-Blind, Placebo-Controlled Phase 1b/2 Adaptive Study of TTP399, a Hepatoselective Glucokinase Activator, for Adjunctive Treatment of Type 1 Diabetes. Diabetes Care 44 960-968 (2021). | article
von Herrath, M., et al. Anti-interleukin-21 antibody and liraglutide for the preservation of β-cell function in adults with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet Diabetes & Endocrinology 9 212-224 (2021). | article
Jain, A. C., et al. Inceptor counteracts insulin signalling in β-cells to control glycaemia. 590 326-331 Nature, 590 326-331 (2021). | article
Akil, A. A-S., et al. Diagnosis and treatment of type 1 diabetes at the dawn of the personalized medicine era. Journal of Translational Medicine 19 Article No. 137 (2021) | article