High-Fat, Carbohydrate-Free Diet Markedly Aggravates Obesity but Prevents β-Cell Loss and Diabetes in the Obese, Diabetes-Susceptible &lt;i&gt;db/db&lt;/i&gt; Strain

Mirhashemi, F.; Kluth, Oliver; Scherneck, Stephan; Vogel, Heike; Kluge, Reinhart; Schürmann, Annette; Joost, Hans‐Georg; Neschen, Susanne

doi:10.1159/000176064

Cited by 13 publications

(12 citation statements)

References 33 publications

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“…GLUT2 under-expression has been reported in the β-cells of Zucker (fa/fa) rats [40] and db/db mice, models of spontaneously occurring T2D with antecedent obesity [41]. Significant decreases in both GLUT2 and glucokinase (GK) were also found in rats fed high fat diets (HFD) [42].…”

Section: Discussionmentioning

confidence: 99%

Glycolytic and Mitochondrial Metabolism in Pancreatic Islets from MSG-Treated Obese Rats Subjected to Swimming Training

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Ferreira

Rickli

et al. 2013

Cell Physiol Biochem

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Backgrounds/Aims: Obese rats obtained by neonatal monosodium glutamate (MSG) administration present insulin hypersecretion. The metabolic mechanism by which glucose catabolism is coupled to insulin secretion in the pancreatic β-cells from MSG-treated rats is understood. The purpose of this study was to evaluate glucose metabolism in pancreatic islets from MSG-treated rats subjected to swimming training. Methods: MSG-treated and control (CON) rats swam for 30 minutes (3 times/week) over a period of 10 weeks. Pancreatic islets were isolated and incubated with glucose in the presence of glycolytic or mitochondrial inhibitors. Results: Swimming training attenuated fat pad accumulation, avoiding changes in the plasma levels of lipids, glucose and insulin in MSG-treated rats. Adipocyte and islet hypertrophy observed in MSG-treated rats were attenuated by exercise. Pancreatic islets from MSG-treated obese rats also showed insulin hypersecretion, greater glucose transporter 2 (GLUT2) expression, increased glycolytic flux and reduced mitochondrial complex III activity. Conclusion: Swimming training attenuated islet hypertrophy and normalised GLUT2 expression, contributing to a reduction in the glucose responsiveness of pancreatic islets from MSG-treated rats without altering glycolytic flux. However, physical training increased the activity of mitochondrial complex III in pancreatic islets from MSG-treated rats without a subsequent increase in glucose-induced insulin secretion.

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Section: Discussionmentioning

confidence: 99%

Glycolytic and Mitochondrial Metabolism in Pancreatic Islets from MSG-Treated Obese Rats Subjected to Swimming Training

Leite

Ferreira

Rickli

et al. 2013

Cell Physiol Biochem

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“…The protective effect of the carbohydrate-free diet has been observed in two mouse strains, NZO and db / db [ 17 – 19 ]. In both strains, beta cell failure was associated with a marked decrease in the immunoreactivity of the GLUT2 [ 18 , 19 ]. Internalisation and reduced abundance of GLUT2 in beta cells of NZO mice and in other models of diabetes (Chinese hamster and Psammomys obesus ) has been reported earlier to precede the loss of insulin immunoreactivity [ 32 , 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, lipotoxicity does not appear to be sufficient for the destruction of the beta cell. Carbohydrate-restricted diets fully prevented beta cell destruction in both NZO and db/db mice [ 17 , 18 ] despite an extreme insulin resistance and a marked inflammatory state of adipose tissue [ 19 ]. This finding is consistent with a previously suggested scenario in which postprandial hyperglycaemia (‘glucotoxicity’) plays an essential role in the pathogenesis of islet cell failure [ 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Dissociation of lipotoxicity and glucotoxicity in a mouse model of obesity associated diabetes: role of forkhead box O1 (FOXO1) in glucose-induced beta cell failure

et al. 2010

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Aims/hypothesisCarbohydrate-free diet prevents hyperglycaemia and beta cell destruction in the New Zealand Obese (NZO) mouse model. Here we have used a sequential dietary regimen to dissociate the effects of obesity and hyperglycaemia on beta cell function and integrity, and to study glucose-induced alterations of key transcription factors over 16 days.MethodsMice were rendered obese by feeding a carbohydrate-free diet for 18 weeks. Thereafter, a carbohydrate-containing diet was given. Plasma glucose, plasma insulin and total pancreatic insulin were determined, and forkhead box O1 protein (FOXO1) phosphorylation and the transcription factors pancreatic and duodenal homeobox 1 (PDX1), NK6 homeobox 1 protein (NKX6.1) and v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A (avian) (MAFA) were monitored by immunohistochemistry for 16 days.ResultsDietary carbohydrates produced a rapid and continuous increase in plasma glucose in NZO mice between day 2 and 16 after the dietary challenge. Hyperglycaemia caused a dramatic dephosphorylation of FOXO1 at day 2, followed by a progressive depletion of insulin stores. The loss of beta cells was triggered by apoptosis (detectable at day 8), associated with reduction of crucial transcription factors (PDX1, NKX6.1 and MAFA). Incubation of isolated islets from carbohydrate-restricted NZO mice or MIN6 cells with palmitate and glucose for 48 h resulted in a dephosphorylation of FOXO1 and thymoma viral proto-oncogene 1 (AKT) without changing the protein levels of both proteins.Conclusions/interpretationThe dietary regimen dissociates the effects of obesity (lipotoxicity) from those of hyperglycaemia (glucotoxicity) in NZO mice. Obese NZO mice are unable to compensate for the carbohydrate challenge by increasing insulin secretion or synthesising adequate amounts of insulin. In response to the hyperglycaemia, FOXO1 is dephosphorylated, leading to reduced levels of beta cell-specific transcription factors and to apoptosis of the cells.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-010-1973-8) contains supplementary material, which is available to authorised users.

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“…Interestingly, restriction of carbohydrates protects diabetes-prone mice (NZO, db/db on C57BLKS background) from hyperglycemia, but re-exposure to carbohydrates causes rapid development of hyperglycemia and beta-cell apoptosis within a few days [ 9 – 11 ]. We have recently developed a dietary intervention which allowed a very fast and synchronized beta-cell failure in NZO-mice.…”

Section: Introductionmentioning

confidence: 99%

Identification of Four Mouse Diabetes Candidate Genes Altering β-Cell Proliferation

et al. 2015

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Beta-cell apoptosis and failure to induce beta-cell regeneration are hallmarks of type 2-like diabetes in mouse models. Here we show that islets from obese, diabetes-susceptible New Zealand Obese (NZO) mice, in contrast to diabetes-resistant C57BL/6J (B6)-ob/ob mice, do not proliferate in response to an in-vivo glucose challenge but lose their beta-cells. Genome-wide RNAseq based transcriptomics indicated an induction of 22 cell cycle-associated genes in B6-ob/ob islets that did not respond in NZO islets. Of all genes differentially expressed in islets of the two strains, seven mapped to the diabesity QTL Nob3, and were hypomorphic in either NZO (Lefty1, Apoa2, Pcp4l1, Mndal, Slamf7, Pydc3) or B6 (Ifi202b). Adenoviral overexpression of Lefty1, Apoa2, and Pcp4l1 in primary islet cells increased proliferation, whereas overexpression of Ifi202b suppressed it. We conclude that the identified genes in synergy with obesity and insulin resistance participate in adaptive islet hyperplasia and prevention from severe diabetes in B6-ob/ob mice.

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High-Fat, Carbohydrate-Free Diet Markedly Aggravates Obesity but Prevents β-Cell Loss and Diabetes in the Obese, Diabetes-Susceptible <i>db/db</i> Strain

Cited by 13 publications

References 33 publications

Glycolytic and Mitochondrial Metabolism in Pancreatic Islets from MSG-Treated Obese Rats Subjected to Swimming Training

Glycolytic and Mitochondrial Metabolism in Pancreatic Islets from MSG-Treated Obese Rats Subjected to Swimming Training

Dissociation of lipotoxicity and glucotoxicity in a mouse model of obesity associated diabetes: role of forkhead box O1 (FOXO1) in glucose-induced beta cell failure

Identification of Four Mouse Diabetes Candidate Genes Altering β-Cell Proliferation

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