Pathomechanisms and therapy of a human TXNIP-dependent glycogenosis

• Applicant: Dr. Christian Schlein
• Subject Area: Endocrinology, Diabetology, Metabolism ; Human Genetics
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 464628025

Glycogenoses are hereditary storage disorders in which the synthesis or metabolism of glucose derivatives is impaired. The symptoms include e.g. recurrent hypoglycaemia, lactic acidosis, dyslipidemia, hepatomegaly and muscle weakness. In glycogenosis, the synthesis and breakdown of glycogen components usually are impaired. However, the form of glycogenosis caused by a pathologically increased uptake of glucose, which is presented here, has not yet been described. The disease was diagnosed in a 31-year-old patient suffering from hypertrophic cardiomyopathy, progressive impairment, loss of strength and recurrent hypoglycaemia. In whole exome sequencing we found a homozygous missense mutation in the TXNIP gene, which encodes the thioredoxin interacting protein. Recent mouse studies on the function of TXNIP have shown that TXNIP is important for the endocytosis of the insulin-dependent glucose transporter GLUT4. The TXNIP-mediated endocytosis of this transporter would thus limit the glucose flux into the muscle, so that the lack of this mechanism leads to pathological glycogen and lipid accumulation in the muscle and in the liver. Preliminary data from muscle and liver biopsies show that the patient exhibits pathologically increased lipid synthesis and subsequent secondary dyslipidemia, which role remains unclear so far. Functional TXNIP loss, like any other glycogenosis, has not been able to be treated in a targeted manner pharmacologically. In this project, we evaluated for the first time a pharmacological therapy with a clinically available GLUT-antagonist to reduce life-threatening hypoglycaemia by reduction of the uptake of glucose and thus achieving a higher blood sugar level. For this purpose, the mechanism of drug therapy with Ritonavir, an HIV protease inhibitor, will be demonstrated in preclinical models. Studies have shown that Ritonavir is a specific GLUT4 (and to a lesser extent also GLUT2) antagonist, which causes the spectrum of side effects of therapy-associated HIV lipodystrophy and an increase in blood sugar levels. In order to investigate whether this spectrum of side effects of Ritonavir can act as a therapy option for (TXNIP-associated) glycogenosis, this anti-hypoglycemic, anti-dyslipidemic option is to be mechanistically worked up on the basis of patient fibroblasts and on the TXNIP-deficient animal model. Furthermore, a planned, clinically indicated off-label therapy intervention with Ritonavir for the Hamburg patient is to be scientifically supervised and processed.

• DFG Programme: Research Grants