Introduction: What they say
A study from the Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA shows that “Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction.” This research paper was published, in the 24 April 2017 issue of the journal “Nature Medicine” [One of the best research journals in “Molecular Medicine” with an I.F of 30.357], by Prof. and Chief Scientific Officer of Joslin Diabetes Center George L King , Weier Qi and others.
What we say:
On the foundation of this interesting finding, Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that: Molecular therapy for Diabetic nephropathy (DN): Atrasentan, a drug used in the treatment of diabetic kidney disease and cancer, increases Pyruvate kinase M2 (PKM2) expression, decreases toxic glucose metabolites, mitochondrial dysfunction and apoptosis, augments glycolytic flux and PGC-1α levels, improves metabolic abnormalities, albuminuria, glomerular pathology, and renal dysfunction and alleviates diabetic nephropathy via down regulation of its target gene
From significance of the study to Public health relevance:
Given that: (1) more than 387 million people worldwide’re affected by Diabetes mellitus (DM); (2) Diabetes is going to be one of the top 10 causes of death by 2030; (3) diabetic disease results in a number of health complications, including diabetic nephropathy (DN), diabetic retinopathy, and diabetic neuropathy; (4) one third of people with diabetes suffer from diabetic kidney disease (DKD); and one third of them will develop kidney failure; (5) life-long painful injection/drug treatment is required to treat DM; (3) the global economic cost spent for diabetes treatment in 2014 was little more than 600 billion US dollars, there is an urgent need to find: (i) a way to induce regeneration of adult ß-cells that were lost in DM; (ii) remove accumulation of lipid in different tissues, such as skeletal muscle, liver and kidney, that improve insulin signalling and sensitivity; (iii) a cheaper alternative to the existing expensive weight-loss drugs; (iv) a side-effect-free natural product-based drug; and (v) a way to cure, not just treat, diabetes.
What is known?
Prof.George L King‘s research team has recently shown that:(1) Pyruvate kinase M2 (PKM2) expression and activity were upregulated in mice with diabetes; (2) Sulfenylation decreases PKM2 tetramer formation in diabetic and hyperglycemic conditions; (3) Knockdown of PKM2 in mice increases toxic glucose metabolites, mitochondrial dysfunction and programmed cell death; (4) Knockdown of PKM2 in mice with diabetes worsen albuminuria and glomerular pathology; (5) activation of PKM2 decreases toxic glucose metabolites and mitochondrial dysfunction by increasing glycolytic flux and PGC-1α levels; (6) activation of PKM2 also results in alleviation of metabolic abnormalities, mitochondrial dysfunction and renal pathology, suggesting that increasing the expression of PKM2 in Diabetic Nephropathy (DN) patients may alleviate DN-associated pathophysiologies.
From research findings to Therapeutic opportunity:
This study suggests, for the first time, that 14,15-Epoxyeicosatrienoic acid, by decreasing the expression of its target genes, it may increase the expression of Pyruvate kinase M2 (PKM2) (Fig 1). Thereby, it may: (1) decrease sulfenylation of PKM2 tetramer; (2) promote PKM2 tetramer formation; (3) reduce toxic glucose metabolites, mitochondrial dysfunction and apoptosis; (4) increase glycolytic flux and PGC-1α levels; (5) improve metabolic abnormalities, mitochondrial dysfunction, albuminuria and glomerular pathology; (6) ameliorate Diabetic nephropathy (DN)-associated pathophysiologies; and (7) improve renal dysfunction (Fig.1).
Thus, pharmacological formulations encompassing “14,15-Epoxyeicosatrienoic acid or its analogues, either alone or in combination with other drugs,” may be used in the treatment of DN.
Details of the research findings:
Idea Proposed/Formulated (with experimental evidence) by:
Dr L Boominathan Ph.D.
Terms & Conditions apply http://genomediscovery.org/registration/terms-and-conditions/
Undisclosed mechanistic information: How does Atrasentan increase the expression of Pyruvate kinase M2 (PKM2) to prevent diabetic neuropathy (DN)?
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Citation: Boominathan, L., Molecular therapy for Diabetic nephropathy (DN): Atrasentan, a drug used in the treatment of diabetic kidney disease and cancer, increases Pyruvate kinase M2 (PKM2) expression, decreases toxic glucose metabolites, mitochondrial dysfunction and apoptosis, augments glycolytic flux and PGC-1α levels, improves metabolic abnormalities, albuminuria, glomerular pathology, and renal dysfunction and alleviates diabetic nephropathy via down regulation of its target gene, 21/January/2018, 11.00 pm, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org
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