Expression of Human Fructose-1,6-Bisphosphatase in the Liver of Transgenic Mice Results in Increased Glycerol Gluconeogenesis

Lamont, Benjamin J.; Visinoni, Sherley; Fam, Barbara C; Kebede, Melkam A.; Weinrich, B; Papapostolou, Stavroula; Massinet, Helene; Proietto, Joseph; Favaloro, Jenny M.; Andrikopoulos, Sofianos

doi:10.1210/en.2005-1498

Cited by 40 publications

(49 citation statements)

References 60 publications

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“…In addition, there was also a trend for increased glucose uptake in muscle, which together with the normal suppression of EGP contributed to the normal plasma glucose and insulin concentrations and glucose tolerance. Interestingly, the maintenance of normal glucose tolerance in the face of increased GNG is a phenomenon that our group also reported in hemizygous, liver-specific FBPase overexpressing mice (Lamont et al 2006). Taken together, our results suggest that in rats genetically geared towards increased glucose production, glucose intolerance does not develop simply due to glucose excess.…”

Section: Discussionsupporting

confidence: 83%

“…Intraperitoneal glucose tolerance tests (IPGTT) were performed as described previously (Lamont et al 2006, but modified for rats. Briefly, rats (nZ10-15 PVG/c; nZ10-15 PEPCK) were fasted overnight and anaesthetised with i.p.…”

Section: Intraperitoneal Tolerance Testsmentioning

confidence: 99%

“…However, this relationship is challenged when one considers that not all models of increased GNG develop this abnormality. For example, we have generated a liver-specific FBPase transgenic mouse that is characterised by normal glucose tolerance and plasma glucose concentrations (Lamont et al 2006). This inconsistency raises the possibility that a single genetic defect leading to elevated GNG will not necessarily lead to glucose intolerance.…”

Section: Introductionmentioning

confidence: 99%

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A primary defect in glucose production alone cannot induce glucose intolerance without defects in insulin secretion

Mangiafico

Lim²,

Neoh³

et al. 2011

Journal of Endocrinology

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Increased glucose production is associated with fasting hyperglycaemia in type 2 diabetes but whether or not it causes glucose intolerance is unclear. This study sought to determine whether a primary defect in gluconeogenesis (GNG) resulting in elevated glucose production is sufficient to induce glucose intolerance in the absence of insulin resistance and impaired insulin secretion. Progression of glucose intolerance was assessed in phosphoenolpyruvate carboxykinase (PEPCK) transgenic rats, a genetic model with a primary increase in GNG. Young (4-5 weeks of age) and adult (12-14 weeks of age) PEPCK transgenic and Piebald Virol Glaxo (PVG/c) control rats were studied. GNG, insulin sensitivity, insulin secretion and glucose tolerance were assessed by intraperitoneal and intravascular substrate tolerance tests and hyperinsulinaemic/euglycaemic clamps. Despite elevated GNG and increased glucose appearance, PEPCK transgenic rats displayed normal glucose tolerance due to adequate glucose disposal and robust glucose-mediated insulin secretion. Glucose intolerance only became apparent in the PEPCK transgenic rats following the development of insulin resistance (both hepatic and peripheral) and defective glucose-mediated insulin secretion. Taken together, a single genetic defect in GNG leading to increased glucose production does not adversely affect glucose tolerance. Insulin resistance and impaired glucose-mediated insulin secretion are required to precipitate glucose intolerance in a setting of chronic glucose oversupply.

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Section: Discussionsupporting

confidence: 83%

Section: Intraperitoneal Tolerance Testsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A primary defect in glucose production alone cannot induce glucose intolerance without defects in insulin secretion

Mangiafico

Lim²,

Neoh³

et al. 2011

Journal of Endocrinology

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“…ITTs were performed as previously described (Lamont et al 2006). Mice were administered with 0.5 IU/kg of Actrapid insulin intraperitoneally and glucose measurements from the tail were taken at 15, 30, 45 and 60 min.…”

Section: Insulin Tolerance Testmentioning

confidence: 99%

Identification of ABCC8 as a contributory gene to impaired early-phase insulin secretion in NZO mice

Andrikopoulos

Fam

Holdsworth

et al. 2015

Journal of Endocrinology

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Type 2 diabetes (T2D) is associated with defective insulin secretion, which in turn contributes to worsening glycaemic control and disease progression. The genetic cause(s) associated with impaired insulin secretion in T2D are not well elucidated. Here we used the polygenic New Zealand Obese (NZO) mouse model, which displays all the cardinal features of T2D including hyperglycaemia to identify genes associated with b-cell dysfunction. A genomewide scan identified a major quantitative trait locus (QTL) on chromosome 7 associated with defective glucose-mediated insulin secretion. Using congenic strains, the locus was narrowed to two candidate genes encoding the components of the KATP channel: Abcc8 (SUR1) and Kcnj11 (Kir6.2). The NZO Abcc8 allele was associated with a w211 bp deletion in its transcript and reduced expression of SUR1. Transgenic NZO mice were generated that expressed the WT Abcc8/Kcnj11 genes and displayed significant improvements in early-phase glucosemediated insulin secretion and glucose tolerance, confirming Abcc8 as a causative gene. Importantly, we showed that despite improving b-cell function in the NZO transgenic mice, there was no enhancement of insulin sensitivity or body weight. This study provides evidence for a role of Abcc8 in early-phase glucose-mediated insulin secretion and validates this gene as a contributor to b-cell dysfunction in T2D.

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“…We have previously shown that FBPase is upregulated in the liver of mice or rats fed a high-fat diet (14,15) and in the New Zealand Obese (NZO) mouse, an obese model of type 2 diabetes (14,16). We have recently demonstrated that transgenic mice with specific overexpression of FBPase in the liver displayed increased glycerol gluconeogenesis (17).…”

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confidence: 99%

Fructose-1,6-Bisphosphatase Overexpression in Pancreatic β-Cells Results in Reduced Insulin Secretion

et al. 2008

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OBJECTIVE-Fructose-1,6-bisphosphatase (FBPase) is a gluconeogenic enzyme that is upregulated in islets or pancreatic ␤-cell lines exposed to high fat. However, whether specific ␤-cell upregulation of FBPase can impair insulin secretory function is not known. The objective of this study therefore is to determine whether a specific increase in islet ␤-cell FBPase can result in reduced glucose-mediated insulin secretion. RESEARCH DESIGN AND METHODS-To test this hypothesis, we have generated three transgenic mouse lines overexpressing the human FBPase (huFBPase) gene specifically in pancreatic islet ␤-cells. In addition, to investigate the biochemical mechanism by which elevated FBPase affects insulin secretion, we made two pancreatic ␤-cell lines (MIN6) stably overexpressing huFBPase.RESULTS-FBPase transgenic mice showed reduced insulin secretion in response to an intravenous glucose bolus. Compared with the untransfected parental MIN6, FBPase-overexpressing cells showed a decreased cell proliferation rate and significantly depressed glucose-induced insulin secretion. These defects were associated with a decrease in the rate of glucose utilization, resulting in reduced cellular ATP levels.CONCLUSIONS-Taken together, these results suggest that upregulation of FBPase in pancreatic islet ␤-cells, as occurs in states of lipid oversupply and type 2 diabetes, contributes to insulin secretory dysfunction.

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Expression of Human Fructose-1,6-Bisphosphatase in the Liver of Transgenic Mice Results in Increased Glycerol Gluconeogenesis

Cited by 40 publications

References 60 publications

A primary defect in glucose production alone cannot induce glucose intolerance without defects in insulin secretion

A primary defect in glucose production alone cannot induce glucose intolerance without defects in insulin secretion

Identification of ABCC8 as a contributory gene to impaired early-phase insulin secretion in NZO mice

Fructose-1,6-Bisphosphatase Overexpression in Pancreatic β-Cells Results in Reduced Insulin Secretion

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