Pancreatic β-cells in diabetes mellitus

Endoplasmic reticulum stress; role of mitochondria

Energy production by mitochondria is associated with the work of 2 mechanisms: the respiratory electron transport chain (ETC);
oxidative phosphorylation.

They compete with the processes of proton and electron transfer. The latter contribute to the formation of reactive oxygen species.

Reactive oxygen species include:

free radicals: superoxide ion (O−2);

hydroxyl radical (OH−);

nitric oxide (NO−);

molecular forms:

hydrogen peroxide (H2O2);

atomic oxygen (O2);

hypochlorous acid (HOCl);

peroxynitrite (NO−3).

It is believed that basal levels of ROS may serve as a physiological signal.

However, if the production of reactive oxygen species exceeds the normal limits determined by the cellular capacity; they can significantly damage cellular components, including mitochondria, by:

lipid peroxidation;

protein oxidation;

DNA mutations.

In the pancreas, ROS mediate β-cell death through:

damage to structures that provide insulin synthesis;

depletion of ATP reserves necessary for this process.

Experiments on animals have established a relationship between the presence of type 2 diabetes and the production of free forms of oxygen.

In vitro studies have revealed other signs of β-cell failure:

a significant decrease in ATP reserves;

cell death.

Many clinical studies suggest a correlation between the presence of hyperglycemia and ROS production; β—cells, in particular, have low resistance to oxidative stress due to the lowest expression of antioxidants:

superoxide dismutase (SOD);

catalase;

glutathione peroxidase.

Moreover, overexpression of antioxidants such as glutathione peroxidase-1 (Gpx-1) in animals with T2DM is known to provide protection against hyperglycemia-induced oxidative stress.

Some animal and in vitro studies suggest that certain antioxidants may reduce cell damage in diabetes.

More specifically, through its effects on mitochondria, the antioxidant mitoquinone (MitoQ) protects β cells from apoptosis caused by glucose toxicity.

Mitoquinone is a representative of a new class of antioxidants whose pharmacological targets are mitochondria: ubiquinone derivatives accumulate in high concentrations in the mitochondrial matrix.

Another substance that affects mitochondria is b - an oral protein kinase C inhibitor (PKCI). The effect of these drugs on the risk of diabetes complications has been studied.

Ruboxistaurine is reported to be effective in preventing the development of retinopathy, nephropathy and peripheral neuropathy.

However, data on the effectiveness of ruboxistaurine are mixed. There are studies that examined the effects of this drug along with other non-specific antioxidants: vitamins C, E, co-enzyme Q10, alpha-lipoic acid, L-carnitine, but no significant clinical benefits were noted during their use.

The pharmacodynamics of PRCIs have not been sufficiently studied to date.

Ruboxystaurine is not yet FDA-registered as further research and evidence of its effectiveness is required.

Doubts regarding the effectiveness of PKCI are also based on the fact that kinases are involved in the implementation of almost all cellular functions, while the search for a selective inhibitor of the isoenzyme seems to be a rather difficult task.

The role of protein kinase and the possibilities of inhibitors of this enzyme in β-cells have not yet been fully studied.

However, it is believed that overexpression of PKC-delta enhances β-cell proliferation by increasing phosphorylation of p21.

Moreover, under stress conditions, PKC-delta performs a pro-apoptotic function and can cause β-cell death.

Diabetes and cancer of other organs - which organs are affected and what increases the risks?

Diabetes and cancer of other organs
Oncological diseases of other organs in diabetes develop as a result of both systemic and local carcinogenesis. Scientists conducted research not only in cases of liver and pancreatic cancer, but in tumors of other organs.

The kidneys are one of the target organs affected by CD-specific hyperglycemia. Kidney cancer has been shown to develop due to general factors - hyperinsulinemia, obesity, and specific factors, mainly hypertension and diabetic nephropathy.

Diabetics have a slightly higher incidence of bladder cancer. Hyperinsulinemia is not the only common factor in carcinogenesis in this case. Frequent urinary tract infections can also contribute to the development of cancer.

Cancers of the female reproductive system are also more common in women with diabetes. It has been proven that diabetics are more likely to develop breast and uterine cancer, regardless of whether they are obese or not. As you know, obesity is one of the main causes of breast cancer. But the development of these types of cancer is determined by several mechanisms, among which the action of sex hormones is important.

Hyperinsulinemia increases the level of bioactive estrogens in a woman’s blood because the concentration of hormone-binding protein decreases.
Excessive insulin concentration also stimulates the synthesis of androgens in the ovarian stroma.
Also, one of the mechanisms for the development of cancer of the reproductive organs of a woman is a delay in the first menstruation, especially in girls with type 1 diabetes. Such women are more prone to infertility, irregular menstruation and other fertility problems.

Most studies suggest that type 2 diabetes is associated with an increased incidence of colon carcinomas and adenomas. The risk of developing colorectal cancer is increased in both women and men.

When describing the mechanisms of pathogenesis, a number of reasons are mentioned:

hyperinsulinemia;
slower transit of contents in the intestines;
increased concentration of bile acid in the stool, which is typical for diabetes.

Based on the results of published large prospective cohort studies and case-control studies, diabetics were found to have a slightly higher likelihood of developing non-Hodgkin's lymphoma. This is explained by disruption of the immune system due to dysfunction of neutrophils and changes in cellular and humoral immunity in patients with diabetes.

Autophagy

Cellular damage and apoptosis are associated with autophagy, the process of removing damaged organelles from the cell through lysosomal degradation and the formation of new ones in their place.
Some diseases, including diabetes, are believed to have multiple etiologies. In particular, autophagy is called among the reasons.
Studies examining the relationship between diabetes and autophagy in humans have found that when β cells and islet cells of Langerhans are exposed to hyperglycemia or hyperlipidemia, autophagy stops.
This leads to the accumulation of oxidized, damaged or incorrectly folded proteins in cells.
β death is also observed as a result of oxidative stress.

The process of autophagy is regulated by various signals.
The mTOR signaling complexes 1 and 2 proteins (mTORC1 and mTORC2) are of particular importance in the mechanism.
These proteins are kinases involved in several cellular processes, for example: the formation of insulin resistance (IR);
adipogenesis;
angiogenesis;
autophagy.

The described kinases are thought to be upregulated in certain diseases and play a role in dysfunctional autophagy.

When β-cells are incubated with rapamycin, the process of autophagy is launched in them, and signs of impaired carbohydrate metabolism appear.

When β-cells are incubated with 3-methyladenine, an autophagy inhibitor, cell viability is restored.

Recent animal studies have shown that there are correlations between the manifestation of diabetes and:

improper protein folding;

abnormal autophagy;

endoplasmic reticulum (ER) stress.

Is there a connection between diabetes and prostate cancer?

Although diabetes is a risk factor for many organ cancers, epidemiological studies show that prostate cancer is less common among diabetics.

A meta-analysis of 14 studies where PSA levels were not used as an early diagnosis tool and 5 studies where PSA levels were used confirmed a statistically significant reduction in the risk of prostate cancer in men with diabetes.

The risk is reduced by an average of 16%. This is most likely due to decreased testosterone levels in diabetes. It has been suggested that other metabolic and hormonal factors, such as altered insulin and leptin levels, statin and metformin use, may influence this relationship.

Defective folding

In recent years, defective folding in the ER has been implicated as a cause of several chronic diseases, including: diabetes mellitus;
non-alcoholic fatty liver disease (NAFLD);
cancer;
Alzheimer's disease.

ER functions:

Ca deposition;

protein folding;

construction;

biosynthetic;

insulin synthesis (in the ER of β cells).

The idea that ER stress is part of the pathogenesis of diabetes mellitus arose after a series of trials.

They found that in the presence of prediabetes, proinsulin synthesis in β-cells occurs more actively, and due to this, protein folding is disrupted. Misfolded proteins accumulate in the ER, causing stress.

At the prediabetic stage, the following processes occur:

insulin resistance (IR);

overexpression of proinsulin;

unwound protein molecules in the ER lumen.

It is believed that the accumulation of proteins with a disrupted three-dimensional structure:

causes ER stress in β cells;

associated with autophagy dysfunction (inability to remove defective proteins);

associated with increased formation of reactive oxygen species;

leads to apoptosis and death of b-cells.

The stress factor activates the corresponding signaling molecules, which subsequently trigger the work of underlying structures - this process is called the unfolded protein reaction (UPR).

The transmembrane kinases IREI and PERK and the transcription factor ATF6 are recognized by membrane sensory formations; in case of stress, kinases signal the cessation of translation, increased protein folding, cellular autophagy and the need to initiate apoptosis.

The last of the listed processes is regulated through activation:

CCAAT/ homologous protein binding enhancer gene;

proapoptotic signaling kinases - with the help of them the body ensures cyclic transformations of damaged proteins.

All described mechanisms ensure regeneration in cells and preservation of their viability.

Understanding the essence of the processes occurring can be used for therapeutic purposes.

For example, the use of liraglutide allows one to resist ER stress (it prevents stress-associated β-cell apoptosis).

ER stress-induced cascades often result in hyperglycemia and increased release of FFAs and inflammatory cytokines.

Mitochondria and the ER are the main regulators of intracellular calcium levels.

Any impact on Ca stores or homeostasis activates a cascade of pathological processes that disrupts normal metabolism and leads to cell death.

When the intracellular calcium content changes, the functions characteristic of β-cells are disrupted. For example, the exocytosis of insulin in granules depends on the level of Ca, a mechanism that often does not work in diabetes.

The process of insulin secretion also depends on blood glucose levels and Ca levels.

The latter is recorded by Ca-dependent channels. With their help, some kinases are activated. In addition, the cascade regulating insulin secretion functions through Ca2+/calmodulin-dependent protein kinase II (CaMKII).

CaMKII activity strongly correlates with the presence of diabetes symptoms; inhibition of this enzyme complex causes impaired glucose tolerance.

Ca in β-cells is deposited in mitochondria and the ER—damage to these organelles significantly disrupts both Ca levels and insulin secretion.

Risks of developing cancer in patients with diabetes mellitus

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Risks of developing cancer

According to data provided by oncologists, diabetes increases the risk of damage to the liver, pancreas, colon, kidneys, bladder, uterine lining, breast and the development of non-Hodgkin's lymphoma.

There are two types of mechanisms that contribute to the development of malignant neoplasms in diabetes.

The first type
is general mechanisms that contribute to oncological processes in many organs. For example, hyperglycemia, hyperinsulinemia, the activity of drugs used in the treatment of diabetes, since they affect all tissues.
The second type
is certain mechanisms that influence carcinogenesis in only one of the organs.

Due to its chronic course without obvious symptoms, diabetes often goes undiagnosed for a long time. According to an epidemiological study conducted in the United States, 3-5% of adults have no diabetes. It has been proven that diabetes is one of the factors that increases the risk of developing malignant neoplasms - cancer is definitely more common among people with CD