Studying rare genetic disorders, associating type 2 diabetes, is a valuable approach to decipher disease origins as a specific causal gene can be linked to the diabetic phenotype. Understanding the related protein functions favors the discovery of new pathways, hence the design of new therapies. We focused on an ultra-rare genetic disorder, the Alström syndrome, associated with severe early-onset type 2 diabetes, obesity, steatosis and generalized fibrosis and for which a unique gene is consistently found mutated in ALMS patients, ALMS1 gene. Combining clinical, multiomics and in vivo mouse data, we discovered that ALMS1 regulates the ultimate steps of insulin signaling in the adipocyte, controlling fusion of GLUT4 sorting vesicles with the plasma membrane. ALMS1 binds to αPKC in the GLUT4 sorting vesicles vicinity and, under insulin stimulus, releases αPKC to trigger GLUT4 plasma membrane entry and glucose absorption. ALMS1 inactivation specifically inhibits adipocyte’s glucose absorption. In mice, the diabetic, steatotic and fibrotic phenotypes were linked to switching adipocyte energy tropism from glucose to lipids corelated with fatty acid transporters’ upregulation like FATP2 in the adipocyte; also observed in ALMS patients’ adipocytes. This change in fuel source in the adipocyte is the underlying cause for the observed metabolic disorders in vivo; primarily mediated through lipid signaling. Insulin-independent glucose absorption was achieved in normal adipocytes using a cell-penetrant, stapled peptide termed PATAS that targets ALMS1/αPKC protein interaction and in vivo can restore physiological adipocyte’s glucose energy tropism. Several in-house and outsourced experiments have demonstrated that PATAS administration significantly improves glucose intolerance, fasting blood glucose levels, liver steatosis and fibrosis in different mouse and rat models thereby making PATAS a potential novel drug to treat type 2 diabetes and its associated complications.

Disclosure

V. Marion: Research Support; Self; Rhythm Pharmaceuticals, Inc. Stock/Shareholder; Self; ALMS THERAPEUTICS.

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