Didactically, DM is classified as type 1 (T1DM), which has an autoimmune component, or type 2 (T2DM), which is genetically inherited and is associated with well-known risk factors, such as age, obesity, and activity level.

Diabetic kidney disease (DKD) is one of the chronic complications of DM, forming part of a spectrum of the disease’s systemic impact together with vision and circulation problems, neuropathy, and cardio-cerebrovascular events.

It is the world’s leading reason for renal replacement therapy and is diagnosed in a lab by a reduction in the rate of glomerular filtration and the presence of albuminuria, both indicators of kidney problems.

Developing therapies that prevent DKD from progressing to its most advanced stages is of utmost importance to reducing the morbidity and mortality of the disease.

The most effective of the current treatment options include nonpharmacological measures, such as adopting a healthy lifestyle, and pharmacological measures that aim to manage blood glucose, albuminuria, blood pressure, and dyslipidemia (an imbalance in blood lipid levels).

The pillars of pharmacological therapy for DKD include its pathophysiological bases, aiming to control metabolic, hemodynamic, and inflammatory dysfunction.

The approach includes a combination of renin-angiotensin-aldosterone system (RAAS) inhibitors, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and mineralocorticoid receptor antagonists.

This pharmacological and nonpharmacological therapeutic arsenal can help to substantially limit the progression of DKD and reduces other complications, particularly cardio-cerebrovascular events.

Numerically, in DKD patients who use SRAA and iSGLT2 inhibitors, glomerular filtration rate decline is reduced from approximately 10 ml/min/1.73 m² to 2-3 ml/min/1.73 m². However, the decline still occurs faster than in the general population for people over 40 years of age (~0.7-0.9 ml/min/1.73 m²).

New treatment options

New therapies are thus needed to reduce the impact of DM on various organs and to improve the quality of life of patients affected by the disease.

For T1DM, studies into the differentiation of human embryonic and pancreatic cells have established a scientific basis for more recent research involving autologous fibroblasts, reprogrammed to differentiate into insulin producing cells, with promising early results.

The therapeutic potential of cells derived from bone marrow, including hematopoietic and mesenchymal cells, has been studied in relation to their rich secretome (the set of proteins and molecules secreted from the cell surface) and their impact on the modulation of pathways dysregulated by DM. 

However, analyses of the safety and efficacy of cell therapy for T1DM, especially in the long term, are still in the early stages. Another approach involves using pancreatic islets from deceased donors to restore the pool of insulin-producing cells.

Several advances have been documented, such as adaption of the number of islets, their encapsulation to mitigate the effect of the immune system, the evaluation of different infusion sites, and more.

At the same time, T1DM treatment has been largely refined with the use of effective regimens of long-acting insulin combined with fast-acting or ultra-fast-acting insulins, carbohydrate counting, and the availability of insulin pumps.

Real-time glucose monitoring has improved the safety and effectiveness of glycemic control while allowing treatment to be tailored to the individual.

Other technological innovations include weekly insulin administration and automated insulin infusion systems, also known as “artificial pancreases,” which deliver the ideal dose of insulin needed to control glucose levels.

Among T2DM patients, the effect of insulin is initially resisted, so antidiabetics are administered orally or subcutaneously. The therapeutic regimen for these patients only begins to include insulin in more advanced stages of the disease.

When it comes to cell therapy for patients with DM2, especially involving mesenchymal stem cells, there are still major challenges to overcome.

These cells can be obtained from various sources, such as bone marrow, adipose tissue, and umbilical cords, among others. However, T2DM patients are generally older than patients with T1DM and usually have multiple comorbidities when DKD is diagnosed.

As a result, the biological properties of mesenchymal stem cells may be less effective, limiting their therapeutic potential in clinical practice. Chronic hyperglycemia also leads to genetic, structural, and functional alterations in the mesenchymal stem cell niche, further restricting its therapeutic potential.

However, mesenchymal stem cells are devoid of class II HLAs (human leukocyte antigens), allowing them to be “immune privileged,” meaning they are not rejected when obtained from another healthy individual. They also do not significantly differentiate into other cell types after infusion.

Cell banks

These characteristics allow for the prospect of mesenchymal stem cell banks, which could be used to treat various diseases “off-the-shelf.”

Initial studies of these cells in patients with DKD and T2DM demonstrated safety and efficacy in preserving renal function. However, several aspects have been debated in the literature, such as the ideal number of cells and infusions, the infusion interval, and the administration route.

Guidelines standardizing how the cells are used have enabled adequate comparison between studies and regulation of safety and efficacy analyses.

Thus, infection parameters and chromosomal stability are not only analyzed, they are also characterized through immunophenotyping, differentiation, and power.

The potential of mesenchymal stem cells can also be increased by pre-infusion conditioning, including reduced oxygen conditions (hypoxia), medication, growth factor, and gene transfection.

Using the secretome of these cells (exosomes and microvesicles) has been explored in the context of DM and DKD.

Our research group at the Albert Einstein Teaching & Research Institute is investigating the therapeutic potential of mesenchymal stem cells and medications commonly used in patients with T2DM (empagliflozin and semaglutide) based on understanding the modulation of signaling pathways for inflammation, oxidative stress, cell death, and autophagy.

We used a model of T2DM and obesity in genetically modified rodents, which present similar structural and functional renal alterations to humans, making them the ideal model for evaluating the safety and efficacy of new therapies.

A greater biological understanding of the modulation of signaling pathways that are dysregulated in T2DM and obesity, with the use of multitarget therapy, will help advance human trials in preclinical research.

This research platform thus reinforces the importance of bench-to-bedside-to-bench studies to determine the best therapeutic approach for complex and multifaceted diseases such as DM and DKD.

Érika Bevilaqua Rangel is a physician with a master’s degree and doctorate in nephrology. She is a professor on the postgraduate program at the Albert Einstein Teaching & Research Institute, where she researches stem cells and heads the Einstein Intelligence Center (NIE), created to generate clear and reliable information about COVID-19 for health professionals and the public. She is also head of the Department of Renal Physiology and Pathophysiology at the Brazilian Society of Nephrology and is an assistant professor of nephrology at the School of Medicine of the Federal University of São Paulo (UNIFESP).

Opinion articles do not necessarily reflect the views of Science Arena or Hospital Israelita Albert Einstein.

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These are the findings of a study that examined data from the 2019 Global Burden of Diseases, Injuries, and Risk Factors Study (GBD 2019). The article was published this year in the journal Cell Metabolism.

The analysis revealed that the number of cases increased most significantly in countries with a high sociodemographic index, but the highest mortality rates occurred in countries with medium and low sociodemographic indices. The most affected region was the Eastern Mediterranean, which includes Afghanistan, Pakistan, Qatar, Iran, Egypt, and Lebanon, among others.

The results indicate that the prevalence of metabolic diseases has been rising at a stable rate over the last two decades. For type 2 diabetes, the increase was 1.56%. Hypertension and NAFLD rose by 0.20% and 0.83% respectively. In absolute numbers, there were an estimated 43.8 million cases of type 2 diabetes worldwide in 2019, in addition to 18.5 million cases of hypertension and 1.2 billion of NAFLD.

In terms of disability-adjusted life years (DALYs)—a measure of the amount of time lost to a disease—type 2 diabetes accounted for 19.95% among women and 17.97% among men in 2019. For hypertension, the rate was 6.93% among women and 5.44% among men, and for NAFLD, women were at a slight advantage, with 24.10% compared to 31.49% for men.

In the Americas, the sex most affected by metabolic disaeases reflected global trends, with type 2 diabetes accounting for 23.20% of DALYs among women and 21.58% among men; hypertension attributable to 4.51% among women and 4.24% among men; and NAFLD at 15.55% for women and 21.45% for men.

Obesity also followed the global pattern with women the most affected in the Americas, at 55.37% for women and 50.95% for men.

The proportion of deaths caused by certain metabolic diseases and risks was greater among women. Globally, type 2 diabetes accounts for 12.48% of deaths among women and 11.64% among men.

Hypertension, meanwhile, represents 10.87% of deaths for women and 8.08% for men, and for obesity the figure is 41.83% for women and 40.36% for men. Women are only less affected by hyperlipidemia, with 33.52% versus 38.45% among men. Similar proportions are seen in the Americas.

The study emphasizes that the increased prevalence of chronic noncommunicable diseases that cause premature death is an immediate global public health concern and that effective preventive and therapeutic measures need to be implemented both individually and community-wide, with a particular focus on regional and socioeconomic factors.

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One promising alternative therapy is the transplantation of isolated pancreatic cell islets from the pancreases of living but brain-dead donors. However, the health conditions of the donors, as well as technical issues involved in the conservation, transportation, and isolation of these cells, prevent the procedure from being carried out more often in Brazil, according to a study published in the journal Diabetology & Metabolic Syndrome by researchers from the School of Medicine at the University of São Paulo (FM-USP).

The authors, members of FM-USP’s Cellular and Molecular Therapy Research Center (NUCEL), carried out a retrospective analysis of pancreases received between January 2007 and January 2010 and the reasons why most of the organs were refused.

A total of 558 pancreases were offered by the São Paulo State Transplant Center in the period, 512 of which were rejected, with 46 accepted for islet isolation and transplantation.

The data suggest that hyperglycemia, technical issues, age, positive serology results, and hyperamylasemia are the leading reasons for organ refusal. Hyperamylasemia—an excess of the digestive enzyme amylase—may be associated with head trauma, one of the biggest causes of brain death in Brazil. It was the fifth most common reason for pancreas refusal in the study (8.2%).

Elevated glucose may be a consequence of the donor being admitted to an intensive care unit (ICU), where medication and parenteral nutrition can contribute to glucose instability.

Technical issues accounted for 8.7% of rejections, the second most common reason. The difficulties include insufficient numbers of personnel qualified to isolate islets, problems related to the availability of specific reagents and supplies, and organ transportation issues related to the long distances between the hospitals where donors are located and the transplant centers.

Finally, the advanced age of donors (8.5% of rejections) and positive serology results for a series of infections (8.4% of rejections) complete the list of obstacles to obtaining pancreatic islets.

“With respect to the supply of pancreases for islet transplantation in Brazil, our study highlights the need to concentrate efforts on improving the quality of donor organs in the ICU and minimizing technical problems,” wrote the study authors.

“We believe that the conclusions shown in this work could help to increase the availability of better-quality pancreases, leading to improved islet isolation and transplant outcomes,” they concluded.

In 2002, NUCEL became the first center in Brazil to perform a pancreatic islet transplant. Five patients underwent the procedure, which consists of one or more infusions of isolated cells into the bloodstream.

Only two other centers in the country perform islet isolation and transplantation: a laboratory at the Pontifical Catholic University (PUC) of Paraná, in Curitiba, and another at Hospital de Clínicas in Porto Alegre, Rio Grande do Sul.

In most cases, people with diabetes mellitus who undergo the treatment begin to produce their own insulin and rely less on hormone injections, in addition to reducing or eliminating episodes of hyperglycemia.

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