The fact that individuals with type 2 diabetes have elevated fasting glucose levels is among the most perplexing factors for them. This is due to the fact that in these insulin-resistant individuals, the liver produces glucose, a process that still raises many unanswered issues for scientists.
The most significant developments in our knowledge of this mechanism
are now presented in a review paper that was published in the journal Trends in
Endocrinology & Metabolism. In the battle against type 2 diabetes mellitus,
which the World Health Organization (WHO) lists as one of the pandemics of the
twenty-first century, it also aids in the discovery of novel therapeutic
targets.
The UB Institute of Biomedicine (IBUB), the Sant Joan de Deu
Research Institute (IRSJD), the Faculty of Pharmacy and Food Sciences at the
University of Barcelona, the Centre for Biomedical Research Network on Diabetes
and Associated Metabolic Diseases (CIBERDEM), and Professor Manuel
Vazquez-Carrera are the study's leaders. Experts Emma Barroso, Javier
Jurado-Aguilar, and Xavier Palomer (UB-IBUB-IRJSJD-CIBERDEM) as well as
Professor Walter Wahli from the University of Lausanne (Switzerland) are
involved in the work.
Type 2 diabetes mellitus is an increasingly common chronic disease
that results in high levels of circulating glucose -- the cellular energy fuel
-- due to a deficient insulin response in the body. It can cause severe organ
damage and is estimated to be under-diagnosed in a high percentage of the
affected population worldwide.
In patients, the glucose synthesis pathway in the liver
(gluconeogenesis) is hyperactivated, a process that can be controlled by drugs
such as metformin. "Recently, new factors involved in the control of
hepatic gluconeogenesis have been identified. For example, a study by our group
revealed that growth differentiation factor (GDF15) reduces the levels of proteins
involved in hepatic gluconeogenesis", says Professor Manuel
Vazquez-Carrera, from the UB's Department of Pharmacology, Toxicology and
Therapeutic Chemistry.
To make progress in the fight against this pathology, it will also
be necessary to further study pathways such as TGF-b, which is involved in the
progression of metabolic dysfunction-associated fatty liver disease (MASLD), a
very prevalent pathology that often coexists with type 2 diabetes mellitus.
"TGF-b plays a very relevant role in the progression of liver fibrosis and
has become one of the most important factors that may contribute to increased
hepatic gluconeogenesis and, therefore, to type 2 diabetes mellitus. Therefore,
studying the involvement of the TGF-b pathway in the regulation of hepatic
gluconeogenesis could help to achieve better glycaemic control", stresses
Vazquez-Carrera.
However, acting on a single factor to improve the regulation of
gluconeogenesis does not seem to be a sufficient therapeutic strategy to
adequately control the disease.
"It would be important to be able to design combination
therapies that could consider the different factors involved to improve the
approach to type 2 diabetes mellitus", Vazquez-Carrera says.
"Today there are several molecules -- TGF-b, TOX3, TOX4, etc.
-- that could be considered therapeutic targets for designing future strategies
to improve patients' well-being. Their efficacy and safety will determine their
therapeutic success. We cannot lose sight of the fact that controlling the
overactivation of hepatic gluconeogenesis in type 2 diabetes mellitus has an
additional difficulty: it is a key pathway for making glucose available in
fasting situations, it is finely modulated by numerous factors and this makes
regulation difficult", he adds.
Interestingly, other factors involved in the control of
gluconeogenesis have also been identified in patients hospitalised with
COVID-19 who showed high glucose levels. "Hyperglycaemia was very
prevalent in patients hospitalised with COVID-19, which seems to be related to
the ability of SARS-CoV-2 to induce the activity of proteins involved in
hepatic gluconeogenesis", the expert notes.
The mechanisms of action of metformin, the most commonly
prescribed drug for the treatment of type 2 diabetes, which reduces hepatic
gluconeogenesis, are still not fully understood. It has now been discovered
that the drug decreases gluconeogenesis via inhibition of complex IV of the
mitochondrial electron transport chain. This is a mechanism independent of the
classical effects known until now through activation of the AMPK protein, a
sensor of the cell's energy metabolism.
"Inhibition of mitochondrial complex IV activity by metformin
-- not complex I as previously thought -- reduces the availability of
substrates required for hepatic glucose synthesis", says Vazquez-Carrera.
In addition, metformin can also reduce gluconeogenesis through its
effects on the gut, leading to changes that ultimately attenuate hepatic
glucose production in the liver. "Thus, metformin increases glucose uptake
and utilisation in the gut, and generates metabolites capable of inhibiting
gluconeogenesis when they reach the liver via the portal vein. Finally,
metformin also stimulates the secretion of GLP-1 in the intestine, a hepatic
gluconeogenesis inhibitory peptide that contributes to its anti-diabetic
effect", he explained.
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