The influence of genetic background on expression of mutations at the diabetes locus in the mouse. I. C57BL/KsJ and C57BL/6J strains

Hummel, Katharine P.; Coleman, D L; Lane, Priscilla W.

doi:10.1007/bf00487005

Cited by 248 publications

(168 citation statements)

References 7 publications

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“…The Zucker obese rats and the Koletsky obese rats are phenotypically very different; therefore, f and fa may be two different alleles. However, the Zucker rat and the Koletsky rat were on different diets and have entirely different strain backgrounds which may greatly affect the expression of the same allele (Hummel, Coleman and Lane, 1972;Coleman and Hummel, 1973). The Koletsky rats are hypertensive whereas the Zucker rats are not.…”

Section: Resultsmentioning

confidence: 99%

Genetics of obesity in zucker rats and koletsky rats

Yen

Shaw

1977

Heredity

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Section: Resultsmentioning

confidence: 99%

Genetics of obesity in zucker rats and koletsky rats

Yen

Shaw

1977

Heredity

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“…For example, the db mutation in C57/B6 mice results in severe insulin resistance and obesity but without the beta-cell failure that is observed on the C57BLKS/J background. 45 As a result, the C57/B6 mice do not experience a decline in insulin, only develop mild hyperglycemia, and continue gaining weight throughout their life.…”

Section: Glp-1 Gene Therapy For Type II Diabetes Gb Parsons Et Almentioning

confidence: 99%

Ectopic expression of glucagon-like peptide 1 for gene therapy of type II diabetes

Parsons¹,

Souza²,

Wu³

et al. 2006

Gene Ther

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Glucagon-like peptide 1 (GLP-1) is a promising candidate for the treatment of type II diabetes. However, the short in vivo half-life of GLP-1 has made peptide-based treatments challenging. Gene therapy aimed at achieving continuous GLP-1 expression presents one way to circumvent the rapid turnover of GLP-1. We have created a GLP-1 minigene that can direct the secretion of active GLP-1 (amino acids 7-37). Plasmid and adenoviral expression vectors encoding the 31-amino-acid peptide linked to leader sequences required for secretion of GLP-1 yielded sustained levels of active GLP-1 that were significantly greater than endogenous levels. Systemic administration of expression vectors to animals using two diabetic rodent models, db/db mice and Zucker Diabetic Fatty (ZDF) rats, yielded elevated GLP-1 levels that lowered both the fasting and random-fed hyperglycemia present in these animals. Because the insulinotropic actions of GLP-1 are glucose dependent, no evidence of hypoglycemia was observed. Improved glucose homeostasis was demonstrated by improvements in %HbA1c (glycated hemoglobin) and in glucose tolerance tests. GLP-1-treated animals had higher circulating insulin levels and increased insulin immunostaining of pancreatic sections. GLP-1-treated ZDF rats showed diminished food intake and, in the first few weeks following vector administration, a diminished weight gain. These results demonstrate the feasibility of gene therapy for type II diabetes using GLP-1 expression vectors.

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“…Indeed, Hummel et al (9) and Coleman and Hummel (14) have shown that when mutations in leptin found in the ob/ob mouse are bred into different backgrounds, there is a difference in the severity of obesity and diabetes. A more recent strategy to define the role of genetic alterations and candidate genes for type 2 diabetes has been the creation of transgenic and knockout mice with alterations in insulin action (15) and in insulin secretion (16).…”

mentioning

confidence: 99%

Impact of Genetic Background on Development of Hyperinsulinemia and Diabetes in Insulin Receptor/Insulin Receptor Substrate-1 Double Heterozygous Mice

et al. 2003

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Type 2 diabetes is a complex disease in which genetic and environmental factors interact to produce alterations in insulin action and insulin secretion, leading to hyperglycemia. To evaluate the influence of genetic background on development of diabetes in a genetically susceptible host, we generated mice that are double heterozygous (DH) for knockout of the insulin receptor and insulin receptor substrate-1 on three genetic backgrounds (C57BL/6 [B6], 129Sv, and DBA). Although DH mice on all backgrounds showed insulin resistance, their phenotypes were dramatically different. B6 DH mice exhibited marked hyperinsulinemia and massive islet hyperplasia and developed early hyperglycemia, with 85% overtly diabetic by 6 months. By contrast, 129Sv DH mice showed mild hyperinsulinemia and minimal islet hyperplasia, and <2% developed diabetes. DBA mice had slower development of hyperglycemia, intermediate insulin levels, and evidence of islet degeneration, with 64% developing diabetes. Thus, mice carrying the same genetic defects on different backgrounds exhibited the full spectrum of abnormalities observed in humans with type 2 diabetes, which allowed for identification of potential loci that promote development of the diabetic phenotype. Diabetes 52: 1528 -1534, 2003 S everal common human disorders, including obesity, diabetes, hyperlipidemia, atherosclerosis, and hypertension, have complex patterns of inheritance with superimposed effects created by diet, level of exercise, and other environmental factors (1-3). Several monogenic forms of diabetes, including mutations in genes for insulin (4), the insulin receptor (5), maturity-onset diabetes of the young (6), and mitochondrial diabetes (7), have been identified and constitute Ͻ5% of all cases of type 2 diabetes. The genetic basis for the more common form(s) of type 2 diabetes remains elusive but is thought to be the result of interactions between genes controlling insulin resistance and ␤-cell function, environmental factors, and variations in other background genes (8).One approach toward defining the primary and background genes involved in type 2 diabetes and obesity is the use of naturally occurring rodent models (9,10) and inbred strains of mice (11-13). Indeed, Hummel et al. (9) and Coleman and Hummel (14) have shown that when mutations in leptin found in the ob/ob mouse are bred into different backgrounds, there is a difference in the severity of obesity and diabetes. A more recent strategy to define the role of genetic alterations and candidate genes for type 2 diabetes has been the creation of transgenic and knockout mice with alterations in insulin action (15) and in insulin secretion (16). Whereas knockout and transgenic mice often show diabetic or insulin-resistant phenotypes, by their very nature, the development of knockout mice leads to progeny that are born with a mixed genetic background and provide a unique tool for evaluation of the impact of background genes on phenotype (17,18).We have reported the creation and characterization of mice double h...

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The influence of genetic background on expression of mutations at the diabetes locus in the mouse. I. C57BL/KsJ and C57BL/6J strains

Cited by 248 publications

References 7 publications

Genetics of obesity in zucker rats and koletsky rats

Genetics of obesity in zucker rats and koletsky rats

Ectopic expression of glucagon-like peptide 1 for gene therapy of type II diabetes

Impact of Genetic Background on Development of Hyperinsulinemia and Diabetes in Insulin Receptor/Insulin Receptor Substrate-1 Double Heterozygous Mice

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