Fetal Programming of Perivenous Glucose Uptake Reveals a Regulatory Mechanism Governing Hepatic Glucose Output During Refeeding

Abstract

Increased hepatic gluconeogenesis maintains glycemia during fasting and has been considered responsible for elevated hepatic glucose output in type 2 diabetes. Glucose derived periportally via gluconeogenesis is partially taken up perivenously in perfused liver but not in adult rats whose mothers were protein-restricted during gestation (MLP rats)-an environmental model of fetal programming of adult glucose intolerance exhibiting diminished perivenous glucokinase (GK) activity. We now show that perivenous glucose uptake rises with increasing glucose concentration (0 -8 mmol/l) in control but not MLP liver, indicating that GK is fluxgenerating. The data demonstrate that acute control of hepatic glucose output is principally achieved by increasing perivenous glucose uptake, with rising glucose concentration during refeeding, rather than by downregulation of gluconeogenesis, which occurs in different hepatocytes. Consistent with these observations, glycogen synthesis in vivo commenced in the perivenous cells during refeeding, MLP livers accumulating less glycogen than controls. GK gene transcription was unchanged in MLP liver, the data supporting a recently proposed posttranscriptional model of GK regulation involving nuclear-cytoplasmic transport. The results are pertinent to impaired regulation of hepatic glucose output in type 2 diabetes, which could arise from diminished GK-mediated glucose uptake rather than increased gluconeogenesis. Diabetes 52:1326 -1332, 2003 T he precise mechanism(s) by which the liver normally switches rapidly from glucose production during fasting to glucose uptake and glycogen synthesis after refeeding or a glucose load remain unclear. Net hepatic glycogenolysis is promptly curtailed during glucose infusion, but gluconeogenesis is not decreased (1). These and other observations (2) have contributed to the view that glycogen is mainly synthesized via an "indirect" pathway during the early postprandial phase, in which gluconeogenic glucose-6-phosphate (G6P) is diverted to glycogen (3,4), rather than via the "direct" pathway from glucose to glycogen. Experiments in humans and in rats have demonstrated that if insulin is maintained at constant levels but glycemia is increased by glucose administration, then hepatic glucose output is rapidly suppressed and hepatic glucose uptake rises (1,5-8); postprandial hyperglycemia in type 2 diabetes is partly caused by failure of this mechanism. Hyperglycemia per se has no significant effect on hepatic gluconeogenic flux (1), and refeeding does not suppress rat liver G6P (9) in the time frame in which glucose production is switched off in individuals without diabetes (6,7). These observations raise the problem of how the balance between glycogen synthesis, gluconeogenesis, and glucose output is regulated from a generally assumed common pool of G6P.However, none of these studies takes account of metabolic heterogeneity along the radius of the hepatic lobule. If glucose output and uptake occurred in different hepatocytes, then a relatively simple explan...

Low Birth Weight and Zygosity Status Is Associated With Defective Muscle Glycogen and Glycogen Synthase Regulation in Elderly Twins

“…The significant positive association between birth weight and muscle glycogen content in elderly twins in the present study is consistent with studies reporting reduced muscle and liver glycogen contents in rats exposed to protein restriction during fetal life (20,21). It is likely that the lack of association between birth weight and GS activity and regulation in previous human studies may be explained by a relatively small number of study subjects, differences in age, and perhaps most importantly by the failure to adjust for genetic influence (18,19).…”

To: Krebs M, Brehm A, Krssak M et al. (2003) Direct and indirect effects of amino acids on hepatic glucose metabolism in humans. Diabetologia 46:917?925

“…In these papers, total gluconeogenesis is estimated by subtracting net glycogenolysis (measured by tracking hepatic glycogen content using nuclear magnetic resonance) from endogenous glucose production (EGP) (measured isotopically using [6,6-2 H 2 ]glucose). We have pointed out [2] that this calculation ignores the possible effect of hepatic intralobular functional heterogeneity.…”

“…As blood passes down the hepatic sinusoid, the specific activity of its glucose content is diluted by unlabelled glucose. During the subsequent passage through the perivenous zone, uptake of glucose [2,3] reduces the amount of this decreased specific-activity glucose that eventually reaches the assumed single compartment volume of glucose distribution. Thus this compartment receives a lower amount of diminished specific-activity glucose than it would in the absence of perivenous glucose uptake (PVGU), and EGP is underestimated to varying degrees, depending on the conditions.…”

“…The alternative explanation is that increases in EGP could be due to failure of PVGU, rather than increased gluconeogenesis. An example of this mechanism is seen in adult rats fetally programmed by maternal protein restriction to develop glucose intolerance; their perfused livers overproduce glucose, largely because of failure of perivenous glucose uptake as a result of localised perivenous depletion of glucokinase [2,3]. In these studies measurements of hepatic glucose uptake, gluconeogenesis and glycogen were made directly, by methods not involving isotopic dilution.…”

Comment on: Nyirenda MJ, Dean S, Lyons V, Chapman KE, Seckl JR (2006) Prenatal programming of hepatocyte nuclear factor 4a in the rat: a key mechanism in the ‘foetal origins of hyperglycaemia’? Diabetologia 49: 1412–1420, and on: McCurdy CE, Friedman JE (2006) Early foetal programming of hepatic gluconeogenesis: glucocorticoids strike back. Diabetologia 49:1138–1141

“…Glucokinase transcription, however, is unchanged in these programmed offspring, suggesting an effect on nucleo-cytoplasmic transport of glucokinase, which resides in the nucleus in the starved state but translocates to the cytosol postprandially. The difficulty in attributing control of gluconeogenesis to transcriptional events is that they are too slow [4] to provide the rapid switch-off of hepatic glucose output and the hepatic storage of glucose as glycogen seen in the postprandial state. A further effect of rats fetally programmed by maternal protein restriction is that the hepatic acini are enlarged to about twice the normal volume.…”