NIDDM genes in mice: deleterious synergism by both parental genomes contributes to diabetogenic thresholds

Leiter, Edward H.; Reifsnyder, Peter C.; Partke, Hans-Joachim; Junger, E.; Herberg, L.

doi:10.2337/diabetes.47.8.1287

Cited by 59 publications

(90 citation statements)

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“…With outcross populations, a threshold body weight (45 g at 12 weeks) is required for the development of diabetes [8,12,28,29]. In the presence of dietary carbohydrate, an increase of dietary fat accelerated the development of diabetes (Fig.…”

Section: Discussionmentioning

confidence: 99%

Development of diabetes in obese, insulin-resistant mice: essential role of dietary carbohydrate in beta cell destruction

et al. 2007

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Aims/hypothesis The role of dietary carbohydrate in the pathogenesis of type 2 diabetes is still a subject of controversial debate. Here we analysed the effects of diets with and without carbohydrate on obesity, insulin resistance and development of beta cell failure in the obese, diabetesprone New Zealand Obese (NZO) mouse. Materials and methods NZO mice were kept on a standard diet (4% [w/w] fat, 51% carbohydrate, 19% protein), a high-fat diet (15, 47 and 17%, respectively) and a carbohydrate-free diet in which carbohydrate was exchanged for fat (68 and 20%, respectively). Body composition and blood glucose were measured over a period of 22 weeks. Glucose tolerance tests and euglycaemichyperinsulinaemic clamps were performed to analyse insulin sensitivity. Islet morphology was assessed by immunohistochemistry. Results Mice on carbohydrate-containing standard or high-fat diets developed severe diabetes (blood glucose >16.6 mmol/l, glucosuria) due to selective destruction of pancreatic beta cells associated with severe loss of immunoreactivity of insulin, glucose transporter 2 (GLUT2) and musculoaponeurotic fibrosarcoma oncogene homologue A (MafA). In contrast, mice on the carbohydrate-free diet remained normoglycaemic and exhibited hyperplastic islets in spite of a morbid obesity associated with severe insulin resistance and a massive accumulation of macrophages in adipose tissue. Conclusions/interpretation These data indicate that the combination of obesity, insulin resistance and the inflammatory response of adipose tissue are insufficient to cause beta cell destruction in the absence of dietary carbohydrate.

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Section: Discussionmentioning

confidence: 99%

Development of diabetes in obese, insulin-resistant mice: essential role of dietary carbohydrate in beta cell destruction

et al. 2007

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“…Thus, an immunophenotype assumed to be H2 z -controlled in NZW can now be compared in NZO to establish the extent to which interactions with non-MHC loci are required to produce the phenotype. Genetic outcrosses between NZO and other (unrelated) inbred strains (NON/Lt, SJL/J) have not shown an MHC requirement for "diabesity" (Leiter et al, 1998;Plum et al, 2000). Hence, there is no basis for assuming that there is a primary role for autoimmunity in diabetes pathogenesis in NZO mice as there clearly is in the NOD mouse model for T cell-mediated type 1 diabetes (Serreze and Leiter, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…We found previously that the penetrance of diabetes in NZO/Hl and NZO/HlLt males could be increased from 50% to 90% to 100% by intercrossing with the unrelated Swiss-derived NON/Lt strain (Leiter et al, 1998). However, outcross of NZO/Hl to SWR, another Swiss-derived strain, suppressed diabetogenesis (Plum et al, 2000).…”

Section: Synergism Between Nzo/hllt and Nzb/blnj Genomes To Precipitamentioning

confidence: 99%

“…NZO mice have been studied primarily as a mouse model of obesity-induced insulin resistance (Proietto and Larkins, 1993). Interestingly, transition from obesityinduced insulin resistance and impaired glucose tolerance to overt type 2 diabetes ("diabesity") appears to be a colony-dependent phenomenon, with mice of the NZO substrain in Australia (NZO/Wehi) currently showing little development of clinical disease (Thorburn et al, 2000), whereas NZO/Hl and NZO/HlLt males develop diabetes at a frequency of 40% to 50% (Leiter et al, 1998). NZO/Hl females in Düsseldorf and NZO/HlLt females in Bar Harbor develop marked obesity, but remain diabetesfree (Leiter et al, 1998).…”

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The Diabetes-Prone NZO/HlLt Strain. I. Immunophenotypic Comparison to the Related NZB/BlNJ and NZW/LacJ Strains

Haskell

Flurkey

Duffy

et al. 2002

Laboratory Investigation

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SUMMARY:New Zealand Obese (NZO)/HlLt male mice exhibit a polygenic obesity and approximately 50% develop type 2 diabetes. This strain is known to produce a variety of autoantibodies, including autoantibodies to the insulin receptor. Because of their relatedness to the autoimmune-predisposed New Zealand Black (NZB) and New Zealand White (NZW) inbred strains, we compared NZO to its two related strains for shared hematologic and immunologic characteristics. Comparison of the three strains by serotyping and genotyping methods indicated that NZO shared with NZW the rare (recombinant) H2 z haplotype at the major histocompatibility complex. Similar to the NZB and NZW strains, spleens from NZO mice contained increased numbers of CD19 ϩ CD43 ϩ IgM ϩ B-1 B cells, a phenotype associated with natural autoantibody production. NZO mice developed a progressive microcytic anemia that was distinguished from NZB hemolytic anemia by absence of demonstrable antierythrocyte antibodies in the former. Outcross of NZO females with NZB males accelerated development of obesity and diabetes in F1 males. NZO males made B-lymphocyte-deficient by a disrupted immunoglobulin heavy chain gene did not become diabetic. These results suggest that NZO mice should be useful to investigators interested in studying the genetic contributions to autoimmunity made by the related NZW and NZB strains. Further, these results, combined with the pancreatic histopathology contained in the companion manuscript, suggest that B lymphocytes may be important contributors to diabetes pathogenesis in the NZO mouse. (Lab Invest 2002, 82:833-842).

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“…NZO mice originate from a colony of agouti mice selected for obesity which was subsequently fixed by inbreeding (Bielschowsky and Goodall 1970). NZO mice have been used in outcross studies aimed to locate genes responsible for obesity, insulin resistance and diabetes (Joost 2010;Joost and Schurmann 2014;Leiter et al 1998). Quantitative trait loci (QTLs) affecting adiposity and blood glucose have been identified on a number of chromosomes and different loci (Plum et al 2002;Taylor et al 2001;Vogel et al 2009Vogel et al , 2012Vogel et al , 2013 confirming the polygenic nature of obesity and diabetes development in this mouse model.…”

Section: Introductionmentioning

confidence: 90%

Skeletal muscle mitochondrial uncoupling prevents diabetes but not obesity in NZO mice, a model for polygenic diabesity

et al. 2015

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Induction of skeletal muscle (SM) mitochondrial stress by expression of uncoupling protein 1 (UCP1) in mice results in a healthy metabolic phenotype associated with increased secretion of FGF21 from SM. Here, we investigated whether SM mitochondrial uncoupling can compensate obesity and insulin resistance in the NZO mouse, a polygenic diabesity model. Male NZO mice were crossed with heterozygous UCP1 transgenic (tg) mice (mixed C57BL/6/CBA background) and further backcrossed to obtain F1 and N2 offspring with 50 and 75 % NZO background, respectively. Male F1 and N2 progeny were fed a high-fat diet ad libitum for 20 weeks from weaning. Blood glucose was reduced, and diabetes (severe hyperglycemia [300 mg/dl) was fully prevented in both F1-and N2-tg progeny compared to a diabetes prevalence of 15 % in F1 and 42 % in N2 wild type. In contrast, relative body fat content and plasma insulin were decreased, and glucose tolerance was improved, in F1-tg only. Both F1 and N2-tg showed decreased lean body mass. Accordingly, induction of SM stress response including FGF21 expression and secretion was similar in both F1 and N2-tg mice. In white adipose tissue, expression of FGF21 target genes was enhanced in F1 and N2-tg mice, whereas lipid metabolism genes were induced in F1-tg only. There was no evidence for induction of browning in either UCP1 backcross. We conclude that SM mitochondrial uncoupling induces FGF21 expression and prevents diabetes in mice with a 50-75 % NZO background independent of its effects on adipose tissue.

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NIDDM genes in mice: deleterious synergism by both parental genomes contributes to diabetogenic thresholds

Cited by 59 publications

References 0 publications

Development of diabetes in obese, insulin-resistant mice: essential role of dietary carbohydrate in beta cell destruction

Development of diabetes in obese, insulin-resistant mice: essential role of dietary carbohydrate in beta cell destruction

The Diabetes-Prone NZO/HlLt Strain. I. Immunophenotypic Comparison to the Related NZB/BlNJ and NZW/LacJ Strains

Skeletal muscle mitochondrial uncoupling prevents diabetes but not obesity in NZO mice, a model for polygenic diabesity

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