Antecedent Hyperglycemia, Not Hyperlipidemia, Is Associated With Increased Islet Triacylglycerol Content and Decreased Insulin Gene mRNA Level in Zucker Diabetic Fatty Rats

Harmon, Jamie S.; Gleason, Catherine E.; Tanaka, Yoshito; Poitout, Vincent; Robertson, R. Paul

doi:10.2337/diabetes.50.11.2481

Cited by 131 publications

(99 citation statements)

References 48 publications

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“…The deleterious effect of high glucose is well established [2,3], but increased NEFA at physiological glucose concentrations were also able to significantly alter GSIS and insulin content. These results are in accordance with previous studies [6,10,33], but argue against the hypothesis that increased glucose is a prerequisite for the deleterious effect of NEFA on betacell function [11,12,13,14]. We also found that in-action is, at least in part, mediated by modifications in gene expression [9,17].…”

Section: Discussionsupporting

confidence: 91%

“…However, whether glucose and NEFA alter beta-cell function synergistically or separately, remains controversial. Some authors have shown that beta-cell failure was induced by increased glucose alone [2,9] or increased NEFA alone [6,10], while others have suggested that excess glucose or NEFA are not deleterious separately, but synergize in causing glucolipotoxicity [11,12,13,14].…”

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confidence: 99%

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Non-esterified fatty acids are deleterious for human pancreatic islet function at physiological glucose concentration

et al. 2004

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Aims/hypothesis. Whether excess glucose (glucotoxicity) and excess non-esterified fatty acids (lipotoxicity) act synergistically or separately to alter beta-cell function on Type 2 diabetes remains controversial. We examined the influence of non-esterified fatty acids, with or without concomitant increased glucose concentrations, on human islet function and on the expression of genes involved in lipid metabolism. Methods. Human islets isolated from non-diabetic and non-obese donors were cultured with 5.5, 16 or 30 mmol/l glucose, and when appropriate with 1 or 2 mmol/l non-esterified fatty acids. After 48 h, glucose-stimulated insulin secretion, insulin content, triglyceride content and expression of different genes were evaluated. Results. Non-esterified fatty acids decreased glucosestimulated insulin secretion, insulin content and increased triglyceride content of human isolated islets, independently from the deleterious effect of glucose. Increased glucose concentrations also decreased glucosestimulated insulin secretion and insulin content, but had no influence on triglyceride content. Glucose-stimulated insulin secretion of islets appeared to be significantly correlated with their triglyceride content. Glucose and non-esterified fatty acids modified the gene expression of carnitine palmitoyltransferase-I, acetyl-CoA carboxylase, acyl-CoA oxidase and uncoupling protein 2. Conclusion/interpretation. In our model of isolated human islets, increased glucose and non-esterified fatty acids separately reproduced the two major beta-cell alterations observed in vivo, i.e. loss of glucose-stimulated insulin secretion and reduction in islet insulin content. Our results also suggest that this deleterious effect was, at least in part, mediated by modifications in lipid metabolism gene expression. [Diabetologia (2004) 47:463-469]

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Section: Discussionsupporting

confidence: 91%

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confidence: 99%

Non-esterified fatty acids are deleterious for human pancreatic islet function at physiological glucose concentration

et al. 2004

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“…Previously it has been shown that inhibition of fatty acid oxidation by an inhibitor of CPT1 reduces basal hypersecretion in ZDF rats, such that the maintenance of fatty acid oxidation may also be important in compensation processes [38]. Islets of the ZF rat displayed none of the well-described features of lipotoxicity [7,[39][40][41][42][43]. The TG content was mildly decreased rather than dramatically increased [7,40].…”

Section: Discussionmentioning

confidence: 93%

Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling

et al. 2006

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Aims/hypothesis The aim of this study was to determine the role of fatty acid signalling in islet beta cell compensation for insulin resistance in the Zucker fatty fa/fa (ZF) rat, a genetic model of severe obesity, hyperlipidaemia and insulin resistance that does not develop diabetes. Materials and methods NEFA augmentation of insulin secretion and fatty acid metabolism were studied in isolated islets from ZF and Zucker lean (ZL) control rats. Results Exogenous palmitate markedly potentiated glucosestimulated insulin secretion (GSIS) in ZF islets, allowing robust secretion at physiological glucose levels (5-8 mmol/l).Exogenous palmitate also synergised with glucagon-like peptide-1 and the cyclic AMP-raising agent forskolin to enhance GSIS in ZF islets only. In assessing islet fatty acid metabolism, we found increased glucose-responsive palmitate esterification and lipolysis processes in ZF islets, suggestive of enhanced triglyceride-fatty acid cycling. Interruption of glucose-stimulated lipolysis by the lipase inhibitor Orlistat (tetrahydrolipstatin) blunted palmitate-augmented GSIS in ZF islets. Fatty acid oxidation was also higher at intermediate glucose levels in ZF islets and steatotic triglyceride accumulation was absent. Conclusions/interpretationThe results highlight the potential importance of NEFA and glucoincretin enhancement of insulin secretion in beta cell compensation for insulin resistance. We propose that coordinated glucose-responsive fatty acid esterification and lipolysis processes, suggestive of triglyceride-fatty acid cycling, play a role in the coupling mechanisms of glucose-induced insulin secretion as well as in beta cell compensation and the hypersecretion of insulin in obesity.

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“…It is well documented that LEPR-deficiency, independent of strain, causes a defect in glucose-stimulated insulin secretion, both in the intact rodent [38] and in isolated islets [39]. Moreover, the increased insulin concentrations in the fed and fasting states of obese mice of both strains indicate that insulin resistance is the primary cause of glucose intolerance in LEP-and LEPR-deficient mice ( Table 1 ).…”

Section: Discussionmentioning

confidence: 94%

Differential beta cell responses to hyperglycaemia and insulin resistance in two novel congenic strains of diabetes (FVB-Lepr db ) and obese (DBA-Lep ob ) mice

Chua¹,

Liu

et al. 2002

Diabetologia

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Aims. Our goal was to identify genetic variants that determine the response to insulin resistance and hyperglycaemia. This report documents the diabetes syndrome of two new congenic strains of mice generated by the transfer of the Lepr db mutation to the FVB/NJ strain and the Lep ob mutation to the DBA/2J strain. Methods. Mice were characterised by measures of blood metabolites and hormones along with challenges with glucose and insulin injections. Histological examinations of the endocrine pancreas and the kidneys were also carried out. Results. Obese mice of the FVB-db congenic strain show long-term hyperglycaemia that is primarily due to severe insulin resistance. The hyperglycaemia in the fed state persists despite escalating secretion of insulin and massive increase of pancreatic beta cells. Obese FVB-db mice show evidence of mesangial matrix expansion, a hallmark of diabetic nephropathy.Leptin-deficient mice of the DBA-ob strain have variable obesity-diabetes. In mice with high insulin (>10 ng/ml), DBA-ob/ob mice maintain their increased adiposity and have a large increase in betacell number. In mice with low insulin (<1 ng/ml) DBA-ob/ob mice have greatly diminished adiposity. These mice have atrophied islets with evidence of increased beta-cell neogenesis from the ductal epithelium. Conclusions. The strain-specific responses suggest the existence of genetic variants that control insulin sensitivity and beta-cell responses in the strains described in this report. These new models of obesity-diabetes should prove useful in dissecting the genetic control of beta-cell responses to hyperglycaemia and insulin resistance. [Diabetologia (2002) [6,7], SHR [8], and LA [9]. In rats, it seems that only obese males are subject to developing severe hyperglycaemia and contraction of beta-cell numbers.The loss of beta cells in these obesity-diabetes models is not mediated by the immune system. Studies have shown that C57BLKS/J db/db (K-db) mice develop their characteristic diabetes phenotype independent of a functional immune system [10]. The response of the beta cell in these obese rodents is subject to dietary influences. When placed on a completely carbohydrate-free diet (CHO-free diet), obese C57BLKS/J db/db mice are able to maintain near-euglycaemia and preserve their pancreatic beta-cell mass [11].While these strain-specific phenotypes have been documented [4], some of the congenic strains have been lost. This report describes the generation and characterisation of several new congenic mouse strains carrying mutations of Lep or Lepr. The FVB congenic strains (FVB-db and FVB-ob) provide a new diabetes phenotype that has not been described previously. Obese FVB mice suffer a prolonged period of hyperglycaemia that produces massive expansion of beta-cell mass. We show data that the early onset of severe insulin resistance probably accounts for the hyperglycaemia of these strains. The islet hyperplasia of obese FVB mice suggests that prolonged hyperglycaemia does not eventually lead to complete betacell atro...

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Antecedent Hyperglycemia, Not Hyperlipidemia, Is Associated With Increased Islet Triacylglycerol Content and Decreased Insulin Gene mRNA Level in Zucker Diabetic Fatty Rats

Cited by 131 publications

References 48 publications

Non-esterified fatty acids are deleterious for human pancreatic islet function at physiological glucose concentration

Non-esterified fatty acids are deleterious for human pancreatic islet function at physiological glucose concentration

Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling

Differential beta cell responses to hyperglycaemia and insulin resistance in two novel congenic strains of diabetes (FVB-Lepr db ) and obese (DBA-Lep ob ) mice

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