The mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK-M) and glucose homeostasis: Has it been overlooked?

Abstract

Background Plasma glucose levels are tightly regulated within a narrow physiologic range. Insulin-mediated glucose uptake by tissues must be balanced by the appearance of glucose from nutritional sources, glycogen stores, or gluconeogenesis. In this regard, a common pathway regulating both glucose clearance and appearance has not been described. The metabolism of glucose to produce ATP is generally considered to be the primary stimulus for insulin release from beta-cells. Similarly, gluconeogenesis from phosphoenolpyruvate (PEP) is believed to be the primarily pathway via the cytosolic isoform of phosphoenolpyruvate carboxykinase (PEPCK-C). These models cannot adequately explain the regulation of insulin secretion or gluconeogenesis. Scope of review A metabolic sensing pathway involving mitochondrial GTP (mtGTP) and PEP synthesis by the mitochondrial isoform of PEPCK (PEPCK-M) is associated with glucose-stimulated insulin secretion from pancreatic beta-cells. Here we examine whether there is evidence for a similar mtGTP-dependent pathway involved in gluconeogenesis. In both islets and the liver, mtGTP is produced at the substrate level by the enzyme succinyl CoA synthetase (SCS-GTP) with a rate proportional to the TCA cycle. In the beta-cell PEPCK-M then hydrolyzes mtGTP in the production of PEP that, unlike mtGTP, can escape the mitochondria to generate a signal for insulin release. Similarly, PEPCK-M and mtGTP might also provide a significant source of PEP in gluconeogenic tissues for the production of glucose. This review will focus on the possibility that PEPCK-M, as a sensor for TCA cycle flux, is a key mechanism to regulate both insulin secretion and gluconeogenesis suggesting conservation of this biochemical mechanism in regulating multiple aspects of glucose homeostasis. Moreover, we propose that this mechanism may be more important for regulating insulin secretion and gluconeogenesis compared to canonical nutrient sensing pathways. Major conclusions PEPCK-M, initially believed to be absent in islets, carries a substantial metabolic flux in beta-cells. This flux is intimately involved with the coupling of glucose-stimulated insulin secretion. PEPCK-M activity may have been similarly underestimated in glucose producing tissues and could potentially be an unappreciated but important source of gluconeogenesis. General Significance The generation of PEP via PEPCK-M may occur via a metabolic sensing pathway important for regulating both insulin secretion and gluconeogenesis.

A Role for Mitochondrial Phosphoenolpyruvate Carboxykinase (PEPCK-M) in the Regulation of Hepatic Gluconeogenesis

“…Previously, strong arguments have favored a role for PEPCK-M in lactate gluconeogenesis, and repeated calls to further study PEPCK-M have been made (10,14,(25)(26)(27). Nevertheless, PEPCK-M deletion was predicted to be "unlikely to have a relevant metabolic impact" at least in rodents (10).…”

“…Contemporary views of PEPCK-M would argue its elimination would be inconsequential to gluconeogenesis (14). Previously, strong arguments have favored a role for PEPCK-M in lactate gluconeogenesis, and repeated calls to further study PEPCK-M have been made (10,14,(25)(26)(27).…”

“…1E). The NADH made by LDH during lactate metabolism is consumed by glyceraldehyde-3-phosphate dehydrogenase (GAPDH) during gluconeogenesis and thus favors PEPCK-M to maintain a balanced cytosolic redox state (14,(25)(26)(27). In contrast, pyruvate depends on cytosolic malate dehydrogenase (rather than LDH) to supply GAPDH with NADH and thus favors PEPCK-C metabolism.…”

“…The importance of PEPCK-C to human diabetes has recently come under additional scrutiny because PEPCK-C mRNA, protein, and activity from liver biopsy of humans with type 2 diabetes do not correlate with EGP (16). Nevertheless, although substantial indirect data support a diminished role for PEPCK-M, loss of function has never been directly assessed (14).…”

“…PEPCK-C gluconeogenesis has been studied almost to the complete exclusion of PEPCK-M (10,14). PEPCK-M lacks the strong transcriptional regulation that is characteristic of PEPCK-C (9).…”