Metabolic adaptations to chronic glucose infusion in rats

Topp, Brian; McArthur, MA; Finegood, Diane T.

doi:10.1007/s00125-004-1493-5

Cited by 63 publications

(65 citation statements)

References 47 publications

(78 reference statements)

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“…The lack of effects of glucose and Intralipid on insulin secretion is in marked contrast with the results of previous studies using continuous infusion protocols (15,21-29). While Sako and Grill (22) glucose infusion reduced GSIS, in other studies a marked enhancement was observed (27)(28)(29). Thibault et al (23) observed that sustained hyperglycemia enhances insulin secretion in both normal and hyperglycemic rats.…”

Section: Discussionmentioning

confidence: 91%

Cyclical and Alternating Infusions of Glucose and Intralipid in Rats Inhibit Insulin Gene Expression and Pdx-1 Binding in Islets

et al. 2008

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OBJECTIVE—Prolonged exposure of isolated islets of Langerhans to elevated levels of fatty acids, in the presence of high glucose, impairs insulin gene expression via a transcriptional mechanism involving nuclear exclusion of pancreas-duodenum homeobox-1 (Pdx-1) and loss of MafA expression. Whether such a phenomenon also occurs in vivo is unknown. Our objective was therefore to ascertain whether chronic nutrient oversupply inhibits insulin gene expression in vivo. RESEARCH DESIGN AND METHODS—Wistar rats received alternating 4-h infusions of glucose and Intralipid for a total of 72 h. Control groups received alternating infusions of glucose and saline, saline and Intralipid, or saline only. Insulin and C-peptide secretion were measured under hyperglycemic clamps. Insulin secretion and gene expression were assessed in isolated islets, and β-cell mass was quantified by morphometric analysis. RESULTS—Neither C-peptide secretion nor insulin sensitivity was different among infusion regimens. Insulin content and insulin mRNA levels were lower in islets isolated from rats infused with glucose plus Intralipid. This was associated with reduced Pdx-1 binding to the endogenous insulin promoter, and an increased proportion of Pdx-1 localized in the cytoplasm versus the nucleus. In contrast, MafA mRNA and protein levels and β-cell mass and proliferation were unchanged. CONCLUSIONS—Cyclical and alternating infusions of glucose and Intralipid in normal rats inhibit insulin gene expression without affecting insulin secretion or β-cell mass. We conclude that fatty acid inhibition of insulin gene expression, in the presence of high glucose, is an early functional defect that may contribute to β-cell failure in type 2 diabetes.

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Section: Discussionmentioning

confidence: 91%

Cyclical and Alternating Infusions of Glucose and Intralipid in Rats Inhibit Insulin Gene Expression and Pdx-1 Binding in Islets

et al. 2008

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“…In the present study, the expression of cytosolic PrP C in b-cells of Sprague Dawley rats decreased after the first 24 h of glucose challenge, and gradually returned to normal levels after 4 days. Topp et al 20 reported that blood glucose in the infused animals was highest (B25 mmol/l) on day 1 and 2 and decreased by day 3. Insulin increased B12-fold during the first 24 h and remained B8-fold higher than control values by day 5.…”

Section: Discussionmentioning

confidence: 99%

“…The degree of insulitis was evaluated on H&E stained pancreas sections as described previously. 19 Pancreatic sections from glucose-infused Sprague Dawley rats were from a study reported by Topp et al 20 The aim of this study was to evaluate the adaptation of b-cells to hyperglycemia that occurs during chronic glucose infusion. Briefly, male rats were maintained at 221C and 12 h lightdark cycle, with free access to food and water.…”

Section: Materials and Methods Animalsmentioning

confidence: 99%

“…Animals were killed while anesthetized with sodium pentobarbital 35 mg/kg i.p., and the pancreas was rapidly removed and fixed in Bouin's solution overnight. For additional details, refer to Topp et al 20 Antibodies and Immunostaining Pancreatic sections were heated in 10 mM citric acid buffer (pH 6.0) in a microwave oven for 10 min to retrieve antigen. All incubation steps with antibodies were performed at room temperature.…”

Section: Materials and Methods Animalsmentioning

confidence: 99%

“…To investigate whether PrP C expression in b-cells was linked to glucoregulation, we investigated the effect of hyperglycemia on PrP C expression in b-cells by analyzing pancreatic tissue from rats infused chronically with glucose, a model of b-cell adaptation to hyperglycemia. 20 We examined the expression pattern as well as cytosolic aggregation of PrP C in b-cells of male Sprague Dawley rats infused with either saline or 50% glucose (2 ml/h) for 0, 1, 2, 3, 4, 5 and 6 days (n ¼ 45 per group).…”

Section: Cytosolic Prpmentioning

confidence: 99%

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Pronounced cytosolic aggregation of cellular prion protein in pancreatic β-cells in response to hyperglycemia

Strom¹,

Wang²,

Reimer

et al. 2007

Laboratory Investigation

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Cellular prion protein (PrP C ), an N-linked glycoprotein, is expressed in a variety of tissues, but its functions remain unclear. PrP C is abundantly expressed in the endocrine pancreas, which regulates blood glucose homeostasis. Therefore, we investigated whether the expression of PrP C was altered in islets of Langerhans in a model of spontaneous type 1 diabetes, the diabetes-prone BioBreeding (BBdp) rat and a model of b-cell adaptation to hyperglycemia, the chronic glucose-infused Sprague Dawley rat. Pancreatic sections from animals aged 7-100 days were stained immunohistochemically and evaluated using light, fluorescence and confocal microscopy. PrP C was ubiquitously expressed in all four major endocrine cell types within islets. Surprisingly, cytosolic inclusions containing PrP C were identified exclusively in a subpopulation of insulin-producing b-cells. The inclusions exhibited different molecular characteristics from the PrP aggregates previously described in vitro in neurons. The frequency of b-cells with PrP C inclusions increased with age and was threefold greater in diabetes-prone rats than in controls at 100 days. Cytosolic PrP C expression in b-cells was suppressed whereas the number and size of PrP C inclusions markedly increased in response to hyperglycemia during the first 2 days of continuous glucose infusion in Sprague Dawley rats. In summary, this is the first report describing in vivo cytosolic PrP C aggregation. These unique PrP C inclusions were b-cell specific, more frequent in diabetes-prone animals, and responded to hyperglycemia in glucose-infused Sprague Dawley rats. These data suggest a potential dysfunction in b-cells of diabetes-prone rats, and point to new avenues for the study of diabetes pathogenesis.

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Mechanisms of β cell failure in the pathogenesis of Type 2 diabetes

Accili¹

2008

Drug Development Research

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ABSTRACTb cell failure plays a key role in the pathogenesis of type 2 diabetes. It consists of impaired insulin secretion and decreased b cell mass. Recent insight into the pathogenesis of diabetes-associated b cell failure has shown that (1) b cell compensation to insulin resistance occurs primarily via increased b cell replication; (2) commonly employed diabetes treatments are associated with a seemingly irreversible loss of b cell function; and (3) most diabetes-associated genes identified in recent genome-wide association studies appear to regulate b cell mass and/or function, as opposed to insulin action. Experimental studies in animal models have contributed to establishing the idea that pancreatic b cells are an ''insulin target tissue,'' in which insulin signaling links insulin secretion with cellular proliferation and survival. It is possible that b cell failure represents but another aspect of insulin resistance. Prevention of b cell dysfunction is a critical goal of diabetes therapy, and it will require the identification of ''druggable'' cellular pathways that can be enlisted in the clinic to achieve durability of treatment. Drug Dev Res 69: [111][112][113][114][115] 2008 r2008 Wiley-Liss, Inc.

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Metabolic adaptations to chronic glucose infusion in rats

Cited by 63 publications

References 47 publications

Cyclical and Alternating Infusions of Glucose and Intralipid in Rats Inhibit Insulin Gene Expression and Pdx-1 Binding in Islets

Cyclical and Alternating Infusions of Glucose and Intralipid in Rats Inhibit Insulin Gene Expression and Pdx-1 Binding in Islets

Pronounced cytosolic aggregation of cellular prion protein in pancreatic β-cells in response to hyperglycemia

Mechanisms of β cell failure in the pathogenesis of Type 2 diabetes

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