Diabetes has hepatic origins

Obesity increases the risk of developing metabolic conditions, and primarily type 2 diabetes. The molecular mechanisms by which obesity predisposes people to the development of insulin resistance are so far poorly understood. By deciphering how the protein PTPR-γ, which is increased in obesity, inhibits insulin receptors located at the surface of liver cells, the scientists open the door to potential news therapeutic strategies.

The expansion of fat cells, a characteristic of obesity, leads to an increase in inflammatory signals that have effects on the liver as well as on several other organs. Obesity-induced inflammation triggers the activation of a transcription factor called NF-kβ, which seems to be instrumental in the development of diabetes. Researchers examined various human cohorts-these human studies indicated that PTPR-γ content in liver increases upon inflammation, an effect that could directly affect insulin receptors by inhibiting insulin action.

The scientists modified the levels of PTPR-γ expression in mice, by either suppressing, normally expressing or overexpressing it, and observed the effect on insulin resistance. The mice totally lacking PTPR-γ, when put on a high-calorie diet, did develop obesity. But they did not show any sign of insulin resistance and seemed to be entirely protected from diet-induced diabetes. They also administered lipopolysaccharide, a toxin pertaining to certain bacteria of the gut microbiota associated with obesity and insulin resistance. Once again, the animals lacking PTPR-γ did not develop insulin resistance.

They reconstituted the expression of PTPR-γ at normal levels, but only in hepatocytes (liver cells ). The mice were again prone to insulin resistance, indicating the pivotal role of the liver. Moreover, a two-fold overexpression in the liver (mimicking the natural pathophysiology of obesity was sufficient to cause insulin resistance. The metabolic functions of this protein were never characterized; this discovery therefore opens the door for potential new therapies.

The very form of this protein allows for potential inhibition strategies: when two independent PTPR-γ molecules are brought together by a ligand, they cannot act any more. The researchers are now working on identifying the endogenous ligand produced by the body, or on developing molecules that could mimic its function.
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Mepsevii for treating inherited metabolic condition

The U.S. Food and Drug Administration has approved Mepsevii (vestronidase alfa-vjbk) to treat pediatric and adult patients with an inherited metabolic condition called mucopolysaccharidosis type VII (MPS VII), also known as Sly syndrome. MPS VII is an extremely rare, progressive condition that affects most tissues and organs.

MPS VII is an inherited, rare genetic condition and impacts less than 150 patients worldwide. The features of MPS VII vary widely from patient to patient, but most patients have various skeletal abnormalities that become more pronounced with age, including short stature. Affected individuals can also develop heart valve abnormalities, enlarged liver and spleen, and narrowed airways which can lead to lung infections and trouble breathing.

The life expectancy of individuals with MPS VII depends on the severity of symptoms. Some affected individuals do not survive infancy, while others may live into adolescence or adulthood. Heart disease and airway obstruction are major causes of death in people with MPS VII. Affected individuals may have developmental delay and progressive intellectual disability.

The safety and efficacy of Mepsevii were established in clinical trial and expanded access protocols enrolling a total of 23 patients ranging from 5 months to 25 years of age. Patients received treatment with Mepsevii at doses up to 4 mg/kg once every two weeks for up to 164 weeks. Efficacy was primarily assessed via the six-minute walk test in ten patients who could perform the test. After 24 weeks of treatment, the mean difference in distance walked relative to placebo was 18 meters.

Additional follow-up for up to 120 weeks suggested continued improvement in three patients and stabilization in the others. Two patients in the Mepsevii development program experienced marked improvement in pulmonary function. Overall, the results observed would not have been anticipated in the absence of treatment. The most common side effects after treatment with Mepsevii include infusion site reactions, diarrhea, rash and anaphylaxis.
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