A 45-year-old man is referred to an endocrinologist for newly diagnosed diabetes mellitus. A week ago, his primary care physician noted an elevated fasting serum glucose level. The endocrinologist discusses the different treatment options available, including oral and injectable medications. He recommends treatment with a medication that alters glucose metabolism within the liver by increasing the concentration of fructose 2,6-bisphosphate within hepatocytes. Which of the following conversions will be inhibited by high intracellular concentrations of this metabolite?
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Fructose 2,6-bisphosphate helps control the balance between gluconeogenesis and glycolysis through inverse regulation of phosphofructokinase-1 (PFK-1) and fructose 1,6-bisphosphatase. Fructose 2,6-bisphosphate activates PFK-1, the main regulatory enzyme involved in glycolysis, which converts fructose 6-phosphate to fructose 1,6-bisphosphate. The opposite reaction (fructose 1,6-bisphosphate to fructose-6-phosphate) occurs in gluconeogenesis and is catalyzed by the enzyme fructose-1,6-bisphosphatase (inhibited by fructose 2,6-bisphosphate).
The interconversion of fructose-6-phosphate and fructose 2,6-bisphosphate is achieved by a bifunctional enzyme complex composed of PFK-2 (increases fructose 2,6-bisphosphate levels) and fructose 2,6-bisphosphosphatase (decreases fructose 2,6-bisphosphate levels). Insulin causes activation of PFK-2, leading to increased fructose 2,6-bisphosphate levels and augmented glycolysis. High concentrations of fructose 2,6-bisphosphate also inhibit gluconeogenesis, leading to decreased conversion of alanine and other gluconeogenic substrates to glucose.
(Choice A) Fatty acid synthesis is upregulated by insulin and high citrate levels (which increase when acetyl-CoA is abundant, as with active glycolysis). Therefore, fatty acid synthesis is likely to be upregulated in metabolic states in which fructose 2,6-bisphosphate concentration is increased.
(Choice C) The conversion of fructose-6-phosphate to fructose-1,6-bisphosphate is catalyzed by the enzyme PFK-1. This enzyme is allosterically activated by high levels of fructose-2,6-bisphosphate, and so conversion would be increased.
(Choice D) Glycogen formation is stimulated by increased levels of insulin and glucose-6-phosphate. Because elevated insulin levels also increase fructose 2,6-bisphosphate formation, the rise of fructose 2,6-bisphosphate levels in hepatocytes is typically concurrent with increased glycogen synthesis.
(Choice E) The rise in fructose-2,6-bisphosphate accelerates glycolysis, leading to increased conversion of NAD+ to NADH.
Educational objective:
Fructose 2,6-bisphosphate (F2,6BP) activates phosphofructokinase-1 (increasing glycolysis) and inhibits fructose 1,6-bisphosphatase (decreasing gluconeogenesis). F2,6BP concentration is regulated by a bifunctional enzyme complex: phosphofructokinase-2 increases F2,6BP levels in response to insulin, and fructose 2,6-bisphosphatase decreases F2,6BP levels in response to glucagon.