The Role of Insulin in the Regulation of PEPCK and Gluconeogenesis In Vivo

Abstract

The regulation of gluconeogenesis by insulin is complex and can involve insulin-mediated events in the liver, as well as in several non-hepatic tissues. Given the complexity of this regulation, it is no surprise that there is considerable debate regarding insulin’s ability to regulate the rate of gluconeogenic formation of glucose-6-phosphate (GNG flux to G6P)in vivo. Conventional ‘textbook’ teaching (based onin vitrostudies of rat liver) depicts that insulin can inhibit this pathway by suppressing the transcription of the enzyme phosphoenolpyruvate carboxykinase (PEPCK). PEPCK is widely considered to be a ‘rate-limiting’ enzyme with high control strength. Additionally, recent data in rodents have led to the conclusion that hyperinsulinemia in the brain can inhibit GNG flux to G6P, likely through transcriptional regulation of PEPCK. Recent data from the authors’ lab have confirmed that the molecular regulation of PEPCK messenger RNA (mRNA) and protein by insulin is conserved in large animals. Acute physiological hyperinsulinemia does not alter gluconeogenic formation of G6P, however, despite substantial reductions in PEPCK protein. This indicates that PEPCK has poor regulatory control over the pathwayin vivo. A physiological rise in insulin suppresses hepatic glucose production by inhibiting glycogenolysis and promoting glycogen synthesis, stimulating glycolytic flux, and redirecting gluconeogenically derived carbon to glycogen. This review documents the relevant ways in which insulin can regulate GNG flux to G6Pin vivo.

Interaction Between the Central and Peripheral Effects of Insulin in Controlling Hepatic Glucose Metabolism in the Conscious Dog

“…This finding fits with data from studies that showed that the gluconeogenic pathway was not suppressed by meal-associated hyperinsulinemia (23–25), despite insulin’s ability to suppress PEPCK protein expression (15). Thus, the rapid effects of insulin on hepatic glucose metabolism in the current study were the consequence of glycogenolytic inhibition and the redirection of gluconeogenic carbon into glycogen, not a reduction of gluconeogenic flux to glucose-6-phosphate (15,20,26,27). Interestingly, although brain-insulin signaling created differences in GK and GSK3β protein, those changes did not translate into an increase in hepatic glucose uptake, as was seen in the presence of selective brain hyperinsulinemia in our earlier study (12) or a decrease in EGP, as was shown in rodent studies (1–11).…”

“…That being said, we saw no impact of brain-insulin action on EGP even in the fourth hour of hyperinsulinemia, whereas in the rat, there was an ∼30% decrease at 2 h. Finally, glucose metabolism is different in rodents and large animals in several regards (e.g., the rodent has much higher basal rates of EGP, more complete glycogen depletion during fasting leading to an enhanced gluconeogenic contribution to EGP, differing hepatic neuroanatomy, etc.) (12,27,28), and it is possible that rodents have increased sensitivity of the gluconeogenic pathway to brain insulin–mediated inhibition compared with species with greater dependence on glycogenolysis.…”

Development of an in vitro human liver system for interrogating nonalcoholic steatohepatitis

“…This result was corroborated by upregulation of genes in the glycolysis/gluconeogenesis pathway ( Figure 4B and Supplemental Figure 4). Insulin normally inhibits gluconeogenesis by inhibiting transcription of phosphoenolpyruvate carboxykinase 1 (PCK1), which is important in catalyzing the first committed step in gluconeogenesis (22). However, PCK1 was upregulated by the lipotoxic milieu ( Figure 4B), suggesting that the cells have become unresponsive to insulin.…”

“…However, PCK1 was upregulated by the lipotoxic milieu ( Figure 4B), suggesting that the cells have become unresponsive to insulin. To determine if altered glucose regulation was due to reduced insulin sensitivity, we measured glucose output following an insulin challenge, as insulin should inhibit gluconeogenesis and promote glycolysis (22). Hepatocytes exposed to a lipotoxic milieu were unable to reduce their glucose secretion with an insulin challenge, while the hepatocytes exposed to a healthy milieu exhibited a 4-fold reduction in glucose secretion ( Figure 4C).…”

Evidence against a Physiologic Role for Acute Changes in CNS Insulin Action in the Rapid Regulation of Hepatic Glucose Production

“…Thus, it is unlikely that acute changes in brain insulin signaling, which appear to involve the genetic regulation of gluconeogenesis, would produce an effect on HGP during the time-course of a meal. Instead, it would appear that the non-genomic (post-translational) mechanisms are responsible for the rapid insulin-mediated suppression of HGP (Lin and Accili, 2011; Ramnanan et al, 2010a). …”