Therapeutic management of conditions associated with deficient insulin secretion has been globally identified as a challenge. For example, management of type-2 diabetes (T2D) currently is achieved by drugs that either reduce insulin resistance, reduce liver gluconeogenesis or elevate insulin secretion by β-cells in order to control blood glucose levels. Remarkable progress has been made in the last decade in deducing the mechanisms of fuel-stimulated insulin secretion (IS) in the pancreatic β-cell and while the role of enhanced Ca2+ influx in the triggering of KATP-dependent pathway of glucose stimulated insulin secretion (GSIS) is established, the signaling molecules implicated in the amplification of KATP-independent pathway(s) remain to be defined. Much support has been provided for the concept that lipid mediators and glycerolipid/free fatty acid (GL/FFA) cycling, which is glucose-responsive in the β-cell, play key role in GSIS. GL/FFA cycling refers to the cyclic process of FFA esterification with glycerol to synthesize GL, followed by its hydrolysis releasing the FFA that can be re-esterified.
GUFFA cycling is active in many cells allowing for continuous production of neutral (mono-, di- & tri-acylglycerols (MAG; DAG; TG)) and complex lipids and phospholipids (PL). Various intermediates of GL/FFA cycling including FFA, fatty acyl-CoAs (FACoA), DAG, etc., likely regulate GSIS, though the mechanisms by which they influence this process remain uncertain. The significance of GL/FFA cycling for insulin secretion became evident from studies showing curtailed GSIS in rat islets upon lipolysis inhibition by the pan-lipase inhibitors 3,5-dimethylpyrazole and orlistat, and also by the deletion of hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL). In the normoglycemic insulin resistant Zucker fatty rat, enhanced glucose-responsive GUFFA cycling has been proposed to contribute to the hyperinsulinemia associated with sustained β-cell compensation of this animal. Defective pancreatic islet GUFFA cycling at elevated glucose concentrations has been observed in various rodent models of type 2 diabetes. GL/FFA cycling intermediate, DAG, is thought to activate Munc-13-1, a vesicle priming protein, and also C-kinase enzymes, which play an important role in the exocytosis of insulin granules in GL/FFA cycling and lipolysis derived monoacylglycerols (MAG) act as regulators of insulin secretion.
As discussed in Madiraju, M. et al in PCT/CA2011/050295, agents capable of augmenting monoacylglyceride (MAG) level at the inner surface of the cytoplasmic membrane of a cell or a cellular membrane derived therefrom including but not limited to membranes of mitochondria, nucleus, endoplasmic reticulum, etc and/or inhibiting the activity of the MAG-hydrolyzing α/β-Hydrolase Domain 6 (ABHD6) may be useful for increasing insulin secretion and as such for treating or preventing a condition associated with an insufficient insulin secretion, like diabetes.
USPTO Backgrounds
USPTO Backgrounds