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Diabetes: mitochondria become available and metformin stands strong

Diabetes is one of the main widespread diseases, affecting over 400 million people worldwide. About 200 million people have diabetes without knowing it. The disease is caused by genetics and lifestyle. An improved diet and more exercise can be enough treatment for some, while others need medications. Like other forms of diabetes, type 2 diabetes can lead to cardiovascular disease and complications. There are connections between type 2 diabetes, dementia and Alzheimer’s disease. Researchers at Lund University in Sweden believe that a drug, which inhibits the VDAC1 protein, may play a role in the future development of drugs for the treatment of type 2 diabetes. The study authors point out that there is also a link between VDAC1 and disease of Alzheimer’s, since high levels of VDAC1 can be found in the brain cells of parts of the brain that are affected at an early stage of the disease. “We believe that the substance can also have a good effect on these patients, preventing brain cells from dying and thus improving the cognitive abilities of patients,” says Dr. Albert Salehi.

Pre-diabetics may experience elevated blood glucose levels for many years before developing type 2 diabetes. High glucose levels initiate a series of negative processes. Among other things, they increase the production of VDAC1, a so-called channel protein inside cells that, with the help of a substance, ATP, releases energy from the cell’s power plants, the mitochondria, to other parts of the cell to be used for the secretion of insulin. At high and constant glucose levels, however, VDAC1 protein levels increase, causing VDAC1 to also attach to the cell surface. The energy (ATP), therefore, escapes from the cell and causes cell death due to the lack of energy. This, in turn, leads to altered glycemic control which ultimately causes organic complications, such as cardiovascular disease, kidney disease, blindness and stroke. When the researchers blocked VDAC1 in the beta cells of organ donors with type 2 diabetes, the energy supply was restored and insulin secretion was normalized.

The experiments were subsequently repeated on mice, which are known to develop genetically conditioned diabetes. As a result, the disease did not develop and insulin production was maintained for five weeks, at which point the treatment was stopped and glucose levels increased. Further studies are needed to demonstrate how the blockade of VDAC1 affects tissues such as kidneys, heart muscles and fat. “But pursuing results and conducting human studies requires more funding, “says Albert Salehi. In addition to the specific VDAC1 antibodies and VDAC1 inhibitors obtained in collaboration with Israeli researchers, the researchers also used the drug against diabetes, metformin, and had the same effect. This is a completely new mechanism for how metformin works on beta cells. The fact that metformin not only functions outside the pancreas but also protects beta cells and improves insulin secretion in people with diabetes Type 2 has recently been demonstrated by a Canadian research group. The effect is probably achieved through an impact on VDAC1, as scientists think.

In most tissues and cells studied, VDAC1 is more prevalent than VDAC2. Both VDAC1 and VDAC2 function as ion channels that allow ATP to penetrate. In beta cells, however, VDAC2 is more prevalent, indicating that it plays an important role in beta cells. However, the islets (with beta cells) donated by deceased people with type 2 diabetes have more VDAC1 and less VDAC2, compared to the islets of healthy donors. The proteins acts as reciprocally opposite: when VDAC1 increases, VDAC2 decreases and viceversa. Using confocal microscopes, the researchers were able to localize VDAC1 but not VDAC2 on the surface of beta cells in type 2 diabetics. In healthy cells and in the cells of people treated with metformin, the protein was located rather within the mitochondria. This was confirmed by immunofluorescence staining of the pancreas of non-diabetics and type 2 diabetics.

Associate professor and research team leader Albert Salehi, who led the study together with Professor Claes Wollheim, commented on the aims of the work: “The goal is to be able to administer the drug to newly diagnosed type 2 diabetics. allow beta cells that produce insulin to maintain their function or, even better, to give it to pre-diabetics to prevent the onset of type 2 diabetes. It is a small study based on donations of cells of six people who died with diabetes from Type 2, as well as a limited number of experiments on animal models Further studies are needed to demonstrate how to block VDAC1 for example on renal, cardiac, muscular and fatty tissue, but the results so far have been so promising that they have patented the use of the principle active for diabetes, we are very happy and this initial study would not have been possible without the financial support of the Forget Foundation”.

  • edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Zhang E et al., Salehi A. Cell Metab. 2018 Oct 1.

Tubbs E et al. Mol Cell Endocrinol. 2018; 461:205-14.

Ahmed M et al. Salehi A. Islets 2010; 2(5):283-92.

Dott. Gianfrancesco Cormaci
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di un brevetto sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of a patent concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (leader of the R&D for the partnership CoFood s.r.l.) - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica, salute e benessere sui siti web salutesicilia.com e medicomunicare.it