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  • 1
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    Online Resource
    Distinguishing Covariation From Causation in Diabetes
    American Diabetes Association ; 2004
    In:  Diabetes Vol. 53, No. 1 ( 2004-01-01), p. 240-244
    Details
    In: Diabetes, American Diabetes Association, Vol. 53, No. 1 ( 2004-01-01), p. 240-244
    Abstract: Protein disulfide isomerase (Pdi) is reported to be an insulin-regulated gene whose expression level is increased in the livers of rats with streptozotocin-induced diabetes. We found that Pdi mRNA is ∼20-fold more abundant in the diabetes-susceptible BTBR mouse strain relative to the diabetes-resistant C56BL/6 (B6) strain. A genetic analysis was carried out to determine whether there is a causal relationship between elevated Pdi expression and diabetes phenotype in BTBR-ob/ob mice. We mapped Pdi mRNA abundance as a quantitative trait in 108 (B6 × BTBR)F2-ob/ob mice segregating for diabetes. We detected a single linkage at the telomeric end of chromosome 11, where the Pdi gene itself resides (logarithm of odds score & gt;30.0). No linkage was detected for the Pdi mRNA trait in the regions where we have previously identified quantitative trait loci for diabetes traits. Sequencing of the Pdi promoter and cDNA revealed several single nucleotide polymorphisms between these two mouse strains. We conclude that in our experimental model, elevated Pdi expression is cis regulated and is not linked to diabetes susceptibility. Genetic analysis is a powerful tool for distinguishing covariation from causation in expression array studies of disease traits.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/diabetes.53.1.240
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2004
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  • 2
    Online Resource
    Online Resource
    An Enhancer Within Abcb11 Regulates G6pc2 in C57BL/6 Mouse Pancreatic Islets
    American Diabetes Association ; 2023
    In:  Diabetes ( 2023-08-08)
    Details
    In: Diabetes, American Diabetes Association, ( 2023-08-08)
    Abstract: G6PC2 is predominantly expressed in pancreatic islet beta cells where it encodes a glucose-6-phosphatase catalytic subunit that modulates the sensitivity of insulin secretion to glucose by opposing the action of glucokinase, thereby regulating fasting blood glucose (FBG). Prior studies have shown that the G6pc2 promoter alone is unable to confer sustained islet-specific gene expression in mice, suggesting the existence of distal enhancers that regulate G6pc2 expression. Using information from both mice and humans, and knowledge that single nucleotide polymorphisms (SNPs) both within and near G6PC2 are associated with variations in FBG in humans, we identified several putative enhancers 3' of G6pc2. One region, herein referred to as enhancer I, resides in the 25th intron of Abcb11 and binds multiple islet-enriched transcription factors. CRISPR-mediated deletion of enhancer I in C57BL/6 mice had selective effects on the expression of genes near the G6pc2 locus: in isolated islets G6pc2 and Spc25 expression were reduced ~50%, and Gm13613 expression was abolished, whereas Cers6 and Nostrin expression were unaffected. This partial reduction in G6pc2 expression enhanced islet insulin secretion at basal glucose concentrations but did not affect FBG or glucose tolerance in vivo, consistent with the absence of a phenotype in G6pc2 heterozygous C57BL/6 mice.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db23-0215
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
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  • 3
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    Online Resource
    Loss of Stearoyl-CoA Desaturase-1 Improves Insulin Sensitivity in Lean Mice but Worsens Diabetes in Leptin-Deficient Obese Mice
    American Diabetes Association ; 2007
    In:  Diabetes Vol. 56, No. 5 ( 2007-05-01), p. 1228-1239
    Details
    In: Diabetes, American Diabetes Association, Vol. 56, No. 5 ( 2007-05-01), p. 1228-1239
    Abstract: The lipogenic gene stearoyl-CoA desaturase (SCD)1 appears to be a promising new target for obesity-related diabetes, as mice deficient in this enzyme are resistant to diet- and leptin deficiency–induced obesity. The BTBR mouse strain replicates many features of insulin resistance found in humans with excess visceral adiposity. Using the hyperinsulinemic-euglycemic clamp technique, we determined that insulin sensitivity was improved in heart, soleus muscle, adipose tissue, and liver of BTBR SCD1-deficient mice. We next determined whether SCD1 deficiency could prevent diabetes in leptin-deficient BTBR mice. Loss of SCD1 in leptinob/ob mice unexpectedly accelerated the progression to severe diabetes; 6-week fasting glucose increased ∼70%. In response to a glucose challenge, Scd1−/− leptinob/ob mice had insufficient insulin secretion, resulting in glucose intolerance. A morphologically distinct class of islets isolated from the Scd1−/− leptinob/ob mice had reduced insulin content and increased triglycerides, free fatty acids, esterified cholesterol, and free cholesterol and also a much higher content of saturated fatty acids. We believe the accumulation of lipid is due to an upregulation of lipoprotein lipase (20-fold) and Cd36 (167-fold) and downregulation of lipid oxidation genes in this class of islets. Therefore, although loss of Scd1 has beneficial effects on adiposity, this benefit may come at the expense of β-cells, resulting in an increased risk of diabetes.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db06-1142
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2007
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  • 4
    Online Resource
    Online Resource
    Gene Expression Profiles of Nondiabetic and Diabetic Obese Mice Suggest a Role of Hepatic Lipogenic Capacity in Diabetes Susceptibility
    American Diabetes Association ; 2003
    In:  Diabetes Vol. 52, No. 3 ( 2003-03-01), p. 688-700
    Details
    In: Diabetes, American Diabetes Association, Vol. 52, No. 3 ( 2003-03-01), p. 688-700
    Abstract: Obesity is a strong risk factor for the development of type 2 diabetes. We have previously reported that in adipose tissue of obese (ob/ob) mice, the expression of adipogenic genes is decreased. When made genetically obese, the BTBR mouse strain is diabetes susceptible and the C57BL/6J (B6) strain is diabetes resistant. We used DNA microarrays and RT-PCR to compare the gene expression in BTBR-ob/ob versus B6-ob/ob mice in adipose tissue, liver, skeletal muscle, and pancreatic islets. Our results show: 1) there is an increased expression of genes involved in inflammation in adipose tissue of diabetic mice; 2) lipogenic gene expression was lower in adipose tissue of diabetes-susceptible mice, and it continued to decrease with the development of diabetes, compared with diabetes-resistant obese mice; 3) hepatic expression of lipogenic enzymes was increased and the hepatic triglyceride content was greatly elevated in diabetes-resistant obese mice; 4) hepatic expression of gluconeogenic genes was suppressed at the prediabetic stage but not at the onset of diabetes; and 5) genes normally not expressed in skeletal muscle and pancreatic islets were expressed in these tissues in the diabetic mice. We propose that increased hepatic lipogenic capacity protects the B6-ob/ob mice from the development of type 2 diabetes.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/diabetes.52.3.688
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2003
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  • 5
    Online Resource
    Online Resource
    Identification of Major Quantitative Trait Loci Controlling Body Weight Variation in ob/ob Mice
    American Diabetes Association ; 2004
    In:  Diabetes Vol. 53, No. 1 ( 2004-01-01), p. 245-249
    Details
    In: Diabetes, American Diabetes Association, Vol. 53, No. 1 ( 2004-01-01), p. 245-249
    Abstract: The adipocyte hormone leptin constitutes an important component of the regulation of energy homeostasis; leptin-deficient animals, such as obese mice, are strikingly overweight. The seemingly uninhibited weight gain in obese mice belies the fact that control of energy homeostasis remains under precise, heritably modifiable control. Herein, we report large, heritable differences in body weight and food intake between BTBR-ob/ob and B6-ob/ob mice. We have identified two loci, called modifier of obese (Moo1 and Moo2), that explain the majority of the heritable variance in (BTBR × B6) F2-ob/ob mice. Using interval-specific congenic mouse lines, we mapped Moo1 to an 8-Mb segment of chromosome 2 and demonstrated that Moo1 exerts its effects primarily by regulating total fat mass. Although null alleles of leptin are rare, the majority of overweight adults are leptin resistant, suggesting that leptin-independent pathways, such as those studied here, are important regulators of energy homeostasis. Thus, the identification of these loci may provide important new insights into the pathogenesis of human obesity.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/diabetes.53.1.245
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2004
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