Diabetes mellitus (DM) is one of the main public health problems globally, with 463 million affected – six million in Spain . Their number has doubled in the last thirty years and it is estimated that by 2045 the number of diabetics will exceed 700 million. Although there are different types of diabetes, all of them are characterized by high blood glucose levels –hyperglycemia–, due to a defect in insulin production, resistance to the action of this hormone or a combination of both causes.
Its effects are slow, but inexorable. Apart from the high vital risk and the compromised quality of life of patients, diabetes involves a high healthcare cost. Not only because of the disease itself, but because of the associated complications, such as retinopathy, nephropathy, neuropathy, diabetic foot and cardiovascular problems.
The situation is especially serious in Europe due to the aging of the population. And another fact to keep in mind: half of diabetics have not been diagnosed.
The key is in the beta cells of the pancreas, which are located in the so-called islets of Langerhans and are highly specialized in the production of insulin. This hormone travels through the bloodstream to its target tissues – mainly muscle and adipose tissue – where it promotes the passage of glucose from the blood to the interior of the cells, thus maintaining a balance between sugar and insulin levels. in the body.
Types of diabetes
There are two main types of diabetes. Type 1 (DM1) is an autoimmune disease, because beta cells are destroyed by the immune system itself; and type 2 (DM2), the most common, characterized by the progressive loss of function of beta cells and the appearance of resistance to the action of insulin in the tissues.
“Until recently, it was thought that, in DM1, beta cells disappeared completely”, explains Eduard Montanya, scientific director of CIBERDEM (Center for Biomedical Research in Diabetes and Associated Metabolic Diseases Network), in Madrid. “However, and thanks to very sensitive detection systems, it has been possible to verify that, in very advanced patients, there is still a small activity of these cells. The question is whether it is a small population that survives autoimmune aggression, or a continuous attempt by the body to regenerate them ”, adds Dr. Montanya.
The causes of the autoimmune process are not fully understood. There is a genetic predisposition, although the existence of environmental factors, not fully identified, that trigger it is suspected: environmental pollution, type of diet, childhood obesity or viral infections, among others. Thus, recently, a team from the National Cancer Research Center in Madrid has discovered that infection by coxsackievirus – a virus of the Enterovirus genus that lives in the intestine – could trigger the onset of diabetes.
The scientists observed that the infection triggers a cascade of molecular events that ends with the silencing of the Pdx1 gene, which is critical for insulin production. “This causes the loss of identity and function of beta cells, which become similar to alpha cells, which are in charge of increasing blood glucose levels, leading to hyperglycemia and diabetes, regardless of the immune response ”Explains Nabil Djouder, lead author of the work published in Cell Reports Medicine .
In type 2 diabetes, the pancreas produces insulin, but the target tissue cells do not recognize it, causing an increase in blood glucose. This is known as insulin resistance. To compensate, the pancreas continues to produce more and more hormones, without achieving the desired effect. If this process is not stopped, there may come a time when the body can no longer generate more insulin and diabetes appears. In the most extreme cases, patients must self-administer the hormone.
“It was believed that insulin resistance caused the beta cell to end up giving up and dying due to mechanisms of apoptosis or cell death,” says Dr. Montanya. But what we have discovered is that some of these cells undergo a dedifferentiation process, that is, they return to a less mature state, more similar to that of their stem cells, the result of which is the loss of insulin secretion. In his opinion, “these studies open a very interesting path to the possibility of being able to reverse the immature state to recover functional beta cells”.
Factors that determine the appearance of diabetes
Although a family predisposition for dm2 has been found, there are two determining factors: sedentary lifestyle and being overweight or obese, especially visceral fat that accumulates around internal organs. This type of fat is different from the normal one found just under the skin – the typical michelin. It is considered very high risk, because it produces chemicals called adipokines, which promote pro-inflammatory states that contribute to the development of insulin resistance.
There is no better prevention of DM2 than a balanced diet and regular physical activity that stimulates the sensitivity of cells to insulin, in addition to preventing overweight and obesity. “We have an incredible therapeutic tool that will never be outdone: lifestyle. Numerous studies and evidences confirm that a weight loss of 5% and the practice of moderate exercise –walking 30 minutes a day– prevents the progression of the disease in 60% of the cases . Without a doubt, no other medicine achieves such beneficial results ”, observes Dr. Antonio Pérez, president of the Spanish Diabetes Society (SED).
A sedentary lifestyle and the progressive abandonment of the Mediterranean diet seem to be behind the increase in diabetes in countries such as Spain, Greece and Portugal. And, although the solution seems simple, “changing habits is not easy, it costs a lot and goes beyond the health field,” warns Dr. Pérez. It also points out that there should be campaigns aimed at the general population, such as those made with tobacco.
Against this background, the incidence of DM2 has not stopped growing. It can remain undiagnosed for many years, as hyperglycemia develops gradually and in the early stages is not severe enough to be detected. Identification of patients at high risk of developing diabetes is essential to design prevention strategies and control risk factors for the disease.
Diagnostic tests
The traditional diagnostic tests are the basal blood glucose test, which is performed on an empty stomach; the oral glucose tolerance test; where fasting blood glucose is measured and two hours after the intake of a drink with 75 g of glucose; and the measurement of glycosylated hemoglobin. However, these tests show certain limitations, and they are not accurate enough. In recent years, new biomarkers have been identified that have improved sensitivity and specificity, and increased predictive value. “One of the objectives is to try to define in the heterogeneous group of people with DM2 what we would call the profile or phenotype of the patients, which will contribute to personalizing the treatment,” says Dr. Pérez. The paradigm is cancers, for which there are different markers that help choose the most appropriate therapy for each type of tumor.
This year marks the centenary of the discovery of insulin by researchers at the University of Toronto (Canada), a crucial finding for people with diabetes, who have been able to survive thanks to the administration of this hormone.
In recent decades, efforts have focused on creating insulins with the most physiological action profiles possible, which mimic the function of the pancreas. This gland, located behind the stomach and in front of the spine, continuously secretes a certain amount of basal insulin so that the body’s cells can capture glucose from the blood and use it as a source of energy.
Thus, as Dr. Pérez points out, “advances in therapy have been spectacular. The insulins that we have now have nothing to do with those of the last century. Today we have what we call long-acting analogs, which reproduce basal insulin secretion; and the fast and ultra-fast acting analogs, which are used to cover the insulin response after a meal ”.
There are antidiabetics that are not insulin or prick, such as metformin. This drug, in pill form, reduces glucose production in the liver and increases glucose uptake in the muscle cell. It is an effective, safe and inexpensive drug that has been on the market for 90 years and remains the first choice for most patients with type 2 diabetes.
At present, treatment is not exclusively aimed at glycemic control, but also at preventing possible complications. Fortunately, we have drugs with cardiovascular and renal benefits independent of glycemic control. These new molecules include glucagon-like peptide 1 (GLP-1) analogues, which improve insulin secretion, slow gastric emptying rate and stimulate the feeling of satiety, reducing body weight. of other effects, such as control of blood pressure and lipid profile.
Another family of drugs are sodium-glucose co-transporter-2 (SGLT2) inhibitors, which increase excretion of glucose in the urine, reduce blood glucose, body weight, blood pressure, and renal and cardiovascular irrigation.
Due to its protein nature, insulin is digested by gastric juices. And, being a large molecule, it is difficult for it to pass through the mucous membranes. For this reason, it has been administered by subcutaneous injection.
People with DM1, both children and adults, require several daily doses with an exhaustive control of glycemia – also with finger pricks. This implies an invasive therapy that causes, on many occasions, that patients abandon the medication due to boredom, pain or needle phobia.
For Dr. Pérez, one of the great problems that diabetes has is that “its treatment is very cumbersome and interferes in the daily life of patients, who have to make decisions several times a day, from what they eat and when , to the activity they are going to develop, and calculate the insulin doses to be taken at all times. With the aggravating circumstance that some of these decisions are not adequate, which is demoralizing. Therefore, anything that simplifies and automates the process will be essential to improve the lack of adhesion ”.
New treatments
The first non-invasive insulin delivery alternative was approved for sale in 2006. It was an inhaled powder formulation that had to be withdrawn from the market due to its adverse effects – cough and impaired lung function. In 2014, a new preparation for adults was approved that is absorbed from the lungs after inhalation. Currently, a phase II clinical trial is underway to establish its tolerance and safety in children and adolescents between four and seventeen years old with type 1 diabetes.
Another possible route of administration is intranasal, although the problems in this case are the barrier posed by the mucosa to the passage of large molecules such as insulin, rapid mucociliary clearance and pulmonary adverse effects, among others. Phase II clinical trials are underway with children and adolescents at risk of developing DM1.
However, the truth is that the oral route would be ideal for its simplicity. The problem is that doses up to ten times higher are needed to achieve similar efficiency, which seriously compromises production capacity and increases costs.
Insulin patches that adhere to the skin and allow the drug to be released in a controlled manner into the capillary bed have also been studied . Smart patches with microneedles that release insulin in response to sugar levels have been successfully tested in experimental animals. But, once again, its biggest limitation is the poor permeability of the tissues, which decreases the availability of the hormone.
In fact, weekly injectables are also being tested, with phase III clinical trials. Patients with DM2 would take a dose of this insulin and forget about it for a week. Type 1 patients would also need to cover each meal with the administration of a rapid insulin.
Meanwhile, insulin delivery systems have undergone spectacular evolution. From the first metal and glass syringes, with needles of considerable length and thickness, there was a move to disposable plastic syringes. Today those known as pens or pens are used, equipped with small needles covered with a sliding material that reduces the pain of the puncture. They come pre-filled and exist for all types of insulin. The most advanced are the smart ones. Via bluetooth they communicate with a mobile application that has functions to manage diabetes: dose and administration time registration, hormone temperature, dose or bolus calculator, and reserve insulin indicator. This information can be shared with doctors and caregivers.
On the other hand, there are insulin delivery ports. They are systems with a subcutaneous catheter whose Teflon cannula requires a small needle for insertion. They allow the administration of multiple doses, reducing the number of punctures.
Another modality is insulin pumps, small devices the size of a mobile phone that deliver insulin continuously. They consist of an infuser – a microcomputer programmed to infuse insulin continuously 24 hours a day – and a connecting catheter – a thin plastic tube that connects the pump to the subcutaneous tissue. For meals or in case of hyperglycemia, they administer boluses, the dose of which must be calculated by the patient based on the amount of carbohydrates and the activity to be carried out.
Artificial pancreas
Although, without a doubt, one of the greatest advances is the artificial pancreas. It consists of a sensor for continuous measurement of glucose in the blood, an information transmitter, an intelligent control algorithm and an insulin pump. Blood glucose data is received every five minutes, and the algorithm allows the required doses to be constantly recalculated without the patient having to go around counting carbohydrate servings or giving up meals. At the moment, there are clinical studies with more than twenty systems in the world, each one with its particularities. They are differentiated by the level of automation –hybrid or fully automatic–, the type of control algorithm and the hormones used –insulin or a combination of insulin and glucagon. Most of the commercialized systems, yes, are the hybrids, designed to control, fundamentally, the basal levels, although the patient has to continue informing the system of the meals and the activity that they are going to carry out.
Within regenerative medicine, transplantation of islets of Langerhans – clusters of cells that are responsible for producing insulin and glucagon – seems the most logical treatment for diabetes, because it replaces cells that have been destroyed with new ones and is a relatively simple that is carried out by means of an injection. The problem is that they are obtained from the pancreas of donors who have died, the source is therefore limited and, in addition, it is necessary to resort to immunosuppressants to avoid rejection.
Obtaining alternative sources of stem cells is currently the focus of many lines of research. Among them, the obtaining of embryonic or adult stem cells from which insulin-producing cells, such as beta cells, would be derived for implantation in the patient. This is precisely what Dr. Montanya’s work focuses on. “Despite the enormous advances in this field, it is unlikely that in the near future we will have an unlimited number of these cells for clinical use, so islet transplantation will remain, in the short term, the only cell therapy clinically applicable substitute for the treatment of diabetes ”, says the specialist.
