Treat diabetes not only with medications, but also by trying to restore the body’s ability to regulate blood sugar. This is one of the most ambitious frontiers of diabetes research: replacing pancreatic beta cells that no longer function, regenerating pancreatic function, starting from the cells still present and, in perspective, restoring the body’s ability to produce insulin, autonomously, even in tissues other than the pancreas, such as muscle, through gene therapy.
Regenerative medicine was at the center of the SID (Italian Society of Diabetology) Congress which ended in Rimini.
“We are witnessing a potential paradigm shift in diabetes therapy: from the simple replacement of a lost function to the possibility of restoring it, intervening on the mechanisms underlying the disease”
comments Raffaella Buzzetti, president of the Italian Society of Diabetology (SID).
Advances in cell therapy, regenerative medicine and gene therapy are opening up highly relevant therapeutic prospects, both for type 1 diabetes and, in the future, for type 2 diabetes. The possibility of obtaining cells capable of producing insulin and stimulating the regeneration of beta cells represents one of the most promising frontiers of diabetes research.
What moves
It is not science fiction and it is no longer just a question of theoretical perspectives: some strategies have already entered clinical trials on humans (from phase 1 to phase 3) and the first results open up new treatment scenarios, especially for type 1 diabetes. Other strategies, such as drugs that stimulate the proliferation of beta cells, still in the initial research phase, could expand the possibilities for intervention in type 2 diabetes in the future.
“Regenerative medicine proposes two strategies: replacing the cells we have lost or stimulating those still present to regenerate a cell mass capable of carrying out its function again”
explains Lorenzo Piemonti, director of the Diabetes Research Institute and head of the Regenerative Medicine and Transplant Unit of the IRCCS San Raffaele Hospital in Milan.
Two different paths, but potentially destined to converge. For stem cells, cell replacement is already being tested in humans. In type 1 diabetes, the immune system destroys the beta cells of the pancreas, responsible for the production of insulin. Replacing them with new cells, obtained in the laboratory, means attempting to restore a fundamental function for blood sugar control. But today it is possible to obtain insulin-producing cells from pluripotent stem cells, overcoming at least in part the limit represented by the availability of pancreatic islets from donors. The most advanced clinical experiences use cells derived from pluripotent stem lines, which are implanted with procedures inspired by those already used for pancreatic islet transplantation.
“The first results, published in international journals, show that these cells can take root, function in the body and restore endogenous insulin production, in many cases sufficient to suspend insulin injections. But the price to pay is that they require continuous immunosuppressive therapy”
indicates Piedmont.
How to protect the cells that produce insulin
As new cell sources are explored, including induced pluripotent stem cells obtained by reprogramming adult cells, research advances. The possibility of using autologous cells, i.e. cells derived from the patient himself, could in the future reduce some problems related to immunological compatibility and ‘lighten’ or even avoid the use of immunosuppressants to prevent rejection. However, it does not automatically resolve the most delicate issue: in type 1 diabetes, autoimmunity could also affect newly implanted cells again.
In fact, for a cell therapy to become truly feasible on a large scale, it is not enough to produce new beta cells: it is also necessary to protect them.
“The strategies under study include genetically modified cells to make them less recognizable by the immune system, with the aim of one day arriving at implants that do not require continuous immunosuppression. The first results in humans of some of these technologies represent a proof of principle, but not yet a consolidated solution. The duration of protection, the ability of the cells to maintain an effective function over time and the safety of genetic modifications remain to be verified. Avoid rejection and, at the same time, ensure that these ‘invisible’ cells to the immune system remain safe and controllable over time are indispensable conditions for transforming this promise into a therapy”
explains Piemonti.
Regenerate beta cells with drugs
Finally, alongside cell replacement, there is another path that aims to stimulate the proliferation of beta cells still present. It is a particularly interesting approach for type 2 diabetes, in which the loss of beta cell function is intertwined with insulin resistance, but which could potentially also be studied in combination with cell therapies.
Among the biological targets studied are the nuclear protein menin and the DYRK1A (Dual Specificity Tyrosine-Phosphorylation-Regulated Kinase 1A) protein, involved in the regulation of beta cell proliferation. The inhibition of DYRK1A and menin represents one of the most innovative lines of regenerative therapy for type 2 diabetes. Some molecules that act on these mechanisms are already in clinical trials, such as the menin inhibitor icovamenib (phase 2), while others, such as the menin inhibitor KO-7246 and the DYRK1A inhibitors, are still in the preclinical phase or in the very early stages of study in humans. The phase 2 data with icovamenib appear particularly interesting: after a 12-week treatment cycle, the reduction in glycated hemoglobin was maintained for months, especially in patients with marked insulin deficiency. Preclinical data and early clinical evidence also suggest that both classes of drugs could perform best in association with GLP-1 receptor agonists (‘cocktail effect’).
“The prospect is to stably increase the ability of the pancreas to produce insulin, through beta-cell regeneration, without the need to introduce new cells from the outside. However, this is still early research: stimulating cell proliferation requires rigorous control, because excessive or unregulated activity could entail non-negligible risks”
reports Piedmont.
Towards gene therapy
A further line of research explores the potential of gene therapy to optimize the way in which the body uses (and consumes) glucose. Among the strategies being studied is the introduction of insulin and glucokinase genes into the muscle, an enzyme involved in the metabolism of sugars at the level of various organs (liver, pancreas, muscle).
“Intramuscular gene therapy with KRIYA-839, developed for type 1 diabetes, represents one of the most innovative projects at an international level: rather than targeting the pancreas, this approach inserts the engineered insulin and glucokinase genes directly into the muscle. The goal is to transform the muscles into a system capable of detecting hyperglycemia (thanks to glucokinase) and immediately secreting the necessary insulin at a local level. The idea is to encourage the use of glucose by the muscle, thus contributing to the control of blood sugar levels. This possibility is also still experimental (so far the data comes from animal models and the first study in humans was announced only recently) and will have to demonstrate efficacy and safety.”
Piedmont says.
In the meantime, other pharmacological approaches aimed at activating glucokinase have been developed: dorzagliatin, for example, a new generation oral antidiabetic drug, first-in-class of the therapeutic class of glucokinase activators (GKA) was approved in China (2022), and this year also in Macao and Hong Kong, for type 2 diabetes, but is not available in Europe. The drug acts on the liver (promotes the storage of sugars in the form of glycogen and reduces the uncontrolled production of glucose by the fasting liver) and on the pancreas (stimulates the production of insulin in a manner dependent on blood sugar levels, with a low risk of hypoglycemia) and phase 3 clinical trials (SEED and DAWN) have demonstrated a significant and long-lasting reduction in glycated hemoglobin. This is the ‘pill’ pharmacological declination of the concept on which glucokinase gene therapy is based. The new molecule stimulates the enzyme already present, while gene therapy aims to insert new or enhanced copies of the glucokinase gene.
