Gluconeogenic Enzymes in β-Cells: Pharmacological Targets for Improving Insulin Secretion.

Pancreatic β-cells express the gluconeogenic enzymes glucose 6-phosphatase (G6Pase), fructose 1,6-bisphosphatase (FBP), and phosphoenolpyruvate (PEP) carboxykinase (PCK), which modulate glucose-stimulated insulin secretion (GSIS) through their ability to reverse otherwise irreversible glycolytic steps. Here, we review current knowledge about the expression and regulation of these enzymes in the context of manipulating them to improve insulin secretion in diabetics. Because the regulation of gluconeogenic enzymes in β-cells is so poorly understood, we propose novel research avenues to study these enzymes as modulators of insulin secretion and β-cell dysfunction, with especial attention to FBP, which constitutes an attractive target with an inhibitor under clinical evaluation at present. Glucose must be metabolized into pyruvate through the glycolytic pathway in β-cells for proper oscillatory and biphasic insulin secretion. Chronic impairment of glycolysis negatively impacts β-cell function, leading to hyperglycemia and diabetes. Functional gluconeogenic enzymes that reverse the glycolytic pathway are expressed in β-cells and modulate glucose-stimulated insulin secretion (GSIS). Dysregulation of gluconeogenic enzymes in β-cells is associated with impaired GSIS, so they constitute interesting pharmacological targets for intervention in insulin secretion. Deeper understanding of the regulation of gluconeogenic enzymes in β-cells is critical to unravel their physiological and pathological role and to discover new points of intervention for antidiabetic therapeutics. [ABSTRACT FROM AUTHOR]