Glucose homeostasis during the perinatal period in normal rats and rats with a glycogen storage disorder.

Gain, Kevin R.; Malthus, R. S.; Watts, Colin

doi:10.1172/jci110188

Cited by 18 publications

(9 citation statements)

References 21 publications

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“…It is unlikely to produce glucose from other sources because of the absence of gluconeogenesis in the fetus [12], In theory, the lower blood glucose con centrations and increased glycogenesis in the gsd/gsd fetuses compared with normal fe tuses could be due to higher levels of circulat ing insulin. However, this appears not to be so as we have shown recently that gsd/gsd fetuses at days 21 and 22 of gestation have lower blood immunoreactive insulin concen trations than normal controls [11], Despite the severe hypoglycemia experi enced by the gsd/gsd fetuses, they survive and appear to develop normally. They over come a restricted glucose supply and there fore future studies on alternative fuel sources will be of utmost importance to our under standing of fetal nutrition.…”

Section: Discussionmentioning

confidence: 84%

“…Girard et al [9] found that the normal fetal rat responds to induced hypoglycemia by a rise in circulating glucagon and, more recently, have shown that this is associated with a fall in liver glycogen [10]. We have recently shown in studies on the blood glu cose in the gsd/gsd rat immediately after birth [11] that utilization of liver glycogen is obligatory for maintenance of blood glucose in animals before the onset of gluconeogenesis. The present studies suggest that this ap plies also to the fetus before birth.…”

Section: Discussionmentioning

confidence: 94%

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Blood Glucose of Mother and Fetus during Late Pregnancy of Rats with a Glycogen Storage Disorder

Watts¹,

Gain²,

Malthus³

1982

Neonatology

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The gsd/gsd rat is unable to mobilize liver glycogen due to an absence of phosphorylase b kinase activity. Unlike the normal rat, the maternal gsd/gsd rat cannot maintain its blood glucose concentration in late pregnancy, and values of 3.25 ± 0.22 mM were found just before birth. The blood glucose of the gsd/gsd fetus falls to 1.76 ± 0.09 raMat day 19 of gestation and does not rise appreciably again before birth. In contrast, normal fetal rats show a steady rise in blood glucose from hypoglycemic levels at day 19 to a value of 5.70 ± 0.12 mM on the day of birth. These results indicate that the normal fetal rat contributes towards the regulation of its own blood glucose in late gestation by utilizing its liver glycogen stores.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 94%

Blood Glucose of Mother and Fetus during Late Pregnancy of Rats with a Glycogen Storage Disorder

Watts¹,

Gain²,

Malthus³

1982

Neonatology

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“…We preferred this low glucose condition to a complete lack of glucose which is unlikely to occur in vivo . Since standard DMEM/F12 contains a glucose concentration of 17.5 mM, which is approximately 3.5 fold higher than mean plasma rat (and human) glucose, which averages about 5 mM (Gain et al, 1981), and approximately 17 fold higher than what occurs within the rat brain, which averages about 1 mM and ranges between 0.5 mM to 1.5 mM (Song and Routh, 2006), we used a glucose-deficient DMEM and supplemented it with the appropriate amount of D-glucose to create a “normal glucose DMEM” (glucose concentration of 1 mM) and a “low glucose DMEM” (glucose concentration of 0.25 mM, as would be present in the brain during symptomatic hypoglycemia (Canabal et al, 2007). We also cultured cells in standard DMEM/F12 as a comparison to determine what affect the change from DMEM/F12 to “normal glucose DMEM” would have on CTX8 cell differentiation.…”

Section: Resultsmentioning

confidence: 97%

Glutamate dehydrogenase 1 and SIRT4 regulate glial development

Komlos

Mann

Yang

et al. 2012

Glia

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Congenital hyperinsulinism/hyperammonemia (HI/HA) syndrome is caused by an activation mutation of glutamate dehydrogenase 1 (GDH1), a mitochondrial enzyme responsible for the reversible interconversion between glutamate and α-ketoglutarate. The syndrome presents clinically with hyperammonemia, significant episodic hypoglycemia, seizures, and a frequent incidences of developmental and learning defects. Clinical research has implicated that although some of the developmental and neurological defects may be attributed to hypoglycemia, some characteristics cannot be ascribed to low glucose and as hyperammonemia is generally mild and asymptomatic, there exists the possibility that altered GDH1 activity within the brain leads to some clinical changes. GDH1 is allosterically regulated by many factors, and has been shown to be inhibited by the ADP-ribosyltransferase sirtuin 4 (SIRT4), a mitochondrially localized sirtuin. Here we show that SIRT4 is localized to mitochondria within the brain. SIRT4 is highly expressed in glial cells, specifically astrocytes, in the postnatal brain and in radial glia during embryogenesis. Furthermore, SIRT4 protein decreases in expression during development. We show that factors known to allosterically regulate GDH1 alter gliogenesis in CTX8 cells, a novel radial glial cell line. We find that SIRT4 and GDH1 overexpression play antagonistic roles in regulating gliogenesis and that a mutant variant of GDH1 found in HI/HA patients accelerates the development of glia from cultured radial glia cells.

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“…Despite the absence of Ppp1r3b, there were no compensatory changes in liver mRNA expression of Ppp1r3a and Ppp1r3c, and muscle glycogen content and incorporation of plasma glucose into muscle glycogen were unaffected. It has been previously suggested that liver glycogen is essential for neonatal survival until gluconeogenesis is fully established in the newborn liver (24). The Alb-Cre has been shown to drive incomplete deletion at birth, with progressively complete ablation over the first 6 weeks of life (25,26), which is presumably what permitted the survival of the Ppp1r3b ⌬hep pups.…”

Section: Discussionmentioning

confidence: 99%

Hepatic protein phosphatase 1 regulatory subunit 3B (Ppp1r3b) promotes hepatic glycogen synthesis and thereby regulates fasting energy homeostasis

Mehta

Shewale

Sequeira

et al. 2017

Journal of Biological Chemistry

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Maintenance of whole-body glucose homeostasis is critical to glycemic function. Genetic variants mapping to chromosome 8p23.1 in genome-wide association studies have been linked to glycemic traits in humans. The gene of known function closest to the mapped region, (protein phosphatase 1 regulatory subunit 3B), encodes a protein (G) that regulates glycogen metabolism in the liver. We therefore sought to test the hypothesis that hepatic is associated with glycemic traits. We generated mice with either liver-specific deletion ( ) or liver-specific overexpression of The deletion significantly reduced glycogen synthase protein abundance, and the remaining protein was predominantly phosphorylated and inactive. As a consequence, glucose incorporation into hepatic glycogen was significantly impaired, total hepatic glycogen content was substantially decreased, and mice lacking hepatic had lower fasting plasma glucose than controls. The concomitant loss of liver glycogen impaired whole-body glucose homeostasis and increased hepatic expression of glycolytic enzymes in mice relative to controls in the postprandial state. Eight hours of fasting significantly increased the expression of two critical gluconeogenic enzymes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, above the levels in control livers. Conversely, the liver-specific overexpression of enhanced hepatic glycogen storage above that of controls and, as a result, delayed the onset of fasting-induced hypoglycemia. Moreover, mice overexpressing hepatic Ppp1r3b upon long-term fasting (12-36 h) were protected from blood ketone-body accumulation, unlike control and mice. These findings indicate a major role for in regulating hepatic glycogen stores and whole-body glucose/energy homeostasis.

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Glucose homeostasis during the perinatal period in normal rats and rats with a glycogen storage disorder.

Cited by 18 publications

References 21 publications

Blood Glucose of Mother and Fetus during Late Pregnancy of Rats with a Glycogen Storage Disorder

Blood Glucose of Mother and Fetus during Late Pregnancy of Rats with a Glycogen Storage Disorder

Glutamate dehydrogenase 1 and SIRT4 regulate glial development

Hepatic protein phosphatase 1 regulatory subunit 3B (Ppp1r3b) promotes hepatic glycogen synthesis and thereby regulates fasting energy homeostasis

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