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Scientists at Lund University, Sweden showed that it is possible to prevent type 2 diabetes in mice by inhibiting a protein known as VDAC1. This inhibitor might be employed in treating this disease in humans [1].

Abstract

Type 2 diabetes (T2D) develops after years of prediabetes during which high glucose (glucotoxicity) impairs insulin secretion. We report that the ATP conducting mitochondrial outer membrane voltage dependent anion channel-1 (VDAC1) is upregulated in islets from T2D and non-diabetic organ donors under glucotoxic conditions. This is caused by a glucotoxicity-induced transcriptional program, triggered during years of prediabetes with suboptimal blood glucose control. Metformin counteracts VDAC1 induction. VDAC1 overexpression causes its mistargeting to the plasma membrane of the insulin secreting β cells with loss of the crucial metabolic coupling factor ATP. VDAC1 antibodies and inhibitors prevent ATP loss. Through direct inhibition of VDAC1 conductance, metformin, like specific VDAC1 inhibitors and antibodies, restores the impaired generation of ATP and glucose-stimulated insulin secretion in T2D islets. Treatment of db/db mice with VDAC1 inhibitor prevents hyperglycemia, and maintains normal glucose tolerance and physiological regulation of insulin secretion. Thus, β cell function is preserved by targeting the novel diabetes executer protein VDAC1.

Type 2 diabetes

Type 2 diabetes is a metabolic disorder characterized by insulin resistance, low insulin production, and high blood sugar. Insulin is a hormone responsible for lowering glucose blood levels by stimulating its absorption into cells to be used as an energy source. Insulin is secreted by beta cells in the pancreas; in type 1 diabetic patients, its levels are significantly lower due to an autoimmune destruction of beta cells, whereas in type 2, this depletion is significantly less and autoimmunity is not involved. High blood sugar levels are observed in both conditions, but in the case of type 2, this is due primarily to insulin resistance rather than a lack of insulin, as is the case in type 1 diabetes.

While there exist genetic risk factors for type 2 diabetes, the disease occurs primarily as the result of obesity, a lack of exercise, and a diet high in carbohydrates and simple sugars. It may lead to heart disease, stroke, kidney failure, retinopathies that may cause blindness, and poor blood flow in the limbs that may lead to amputation.

The study

The researchers conducted a small study on beta cells sampled from six deceased donors who were affected by type 2 diabetes. They found an overexpression of VDAC1—a protein normally located on the surfaces of mitochondrial membranes, where it acts as a channel to allow mitochondria to release energy into the cytoplasm in the form of adenosine triphosphate (ATP).

The researchers observed that the protein was also found on cellular membranes and that this caused cells to lose ATP to such a degree that cell death eventually occurred, leading to a decreased secretion of insulin; the scientists hypothesized that the presence of VDAC1 on the cellular membrane might be due to its overexpression.

By employing a VDAC1 inhibitor on the cells, the authors of the study managed to prevent ATP leakage, preventing cell death and restoring normal insulin secretion. The same technique was then tried on mice that were genetically modified to develop type 2 diabetes. Blocking VDAC1 to prevent the disease, despite the genetic predisposition, maintained insulin levels normal throughout the experiment; suspending the treatment led to an increase in glucose levels.

The researchers further observed that the same effect could be obtained by using metformin, a well-known diabetes drug old enough to be off patent. They explained that this effect might be caused by a possible effect of metformin on VDAC1.

Conclusion

The researchers acknowledge that this study is small and that it is too early to jump to conclusions; further studies will be needed to demonstrate the effects of blocking VDAC1 in cells of different tissues. However, their results are promising enough for them to patent the VDAC1 inhibitor for use in treating diabetes.

Literature

[1] Zhang, E., Mohammed Al-Amily, I., Mohammed, S., Luan, C., Asplund, O., Ahmed, M., … Salehi, A. (2018). Preserving Insulin Secretion in Diabetes by Inhibiting VDAC1 Overexpression and Surface Translocation in β Cells. Cell Metabolism.

About the author

Nicola Bagalà

Nicola is a bit of a jack of all trades—a holder of an M.Sc. in mathematics; an amateur programmer; a hobbyist at novel writing, piano and art; and, of course, a passionate life extensionist. After his interest in the science of undoing aging arose in 2011, he gradually shifted from quiet supporter to active advocate in 2015, first launching his advocacy blog Rejuvenaction before eventually joining LEAF. These years in the field sparked an interest in molecular biology, which he actively studies. Other subjects he loves to discuss to no end are cosmology, artificial intelligence, and many others—far too many for a currently normal lifespan, which is one of the reasons he’s into life extension.
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