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5 results on '"Gudrun Brockmann"'

1. Identification of Novel Potential Type 2 Diabetes Genes Mediating β-Cell Loss and Hyperglycemia Using Positional Cloning

Author

Heja Aga, Nicole Hallahan, Pascal Gottmann, Markus Jaehnert, Sophie Osburg, Gunnar Schulze, Anne Kamitz, Danny Arends, Gudrun Brockmann, Tanja Schallschmidt, Sandra Lebek, Alexandra Chadt, Hadi Al-Hasani, Hans-Georg Joost, Annette Schürmann, and Heike Vogel

Subjects
type 2 diabetes, β-cell loss, insulin, positional cloning, transcriptomics, haplotype, Genetics, QH426-470
Abstract

Type 2 diabetes (T2D) is a complex metabolic disease regulated by an interaction of genetic predisposition and environmental factors. To understand the genetic contribution in the development of diabetes, mice varying in their disease susceptibility were crossed with the obese and diabetes-prone New Zealand obese (NZO) mouse. Subsequent whole-genome sequence scans revealed one major quantitative trait loci (QTL), Nidd/DBA on chromosome 4, linked to elevated blood glucose and reduced plasma insulin and low levels of pancreatic insulin. Phenotypical characterization of congenic mice carrying 13.6 Mbp of the critical fragment of DBA mice displayed severe hyperglycemia and impaired glucose clearance at week 10, decreased glucose response in week 13, and loss of β-cells and pancreatic insulin in week 16. To identify the responsible gene variant(s), further congenic mice were generated and phenotyped, which resulted in a fragment of 3.3 Mbp that was sufficient to induce hyperglycemia. By combining transcriptome analysis and haplotype mapping, the number of putative responsible variant(s) was narrowed from initial 284 to 18 genes, including gene models and non-coding RNAs. Consideration of haplotype blocks reduced the number of candidate genes to four (Kti12, Osbpl9, Ttc39a, and Calr4) as potential T2D candidates as they display a differential expression in pancreatic islets and/or sequence variation. In conclusion, the integration of comparative analysis of multiple inbred populations such as haplotype mapping, transcriptomics, and sequence data substantially improved the mapping resolution of the diabetes QTL Nidd/DBA. Future studies are necessary to understand the exact role of the different candidates in β-cell function and their contribution in maintaining glycemic control.

Published
2020
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5. Strain, Sex, and Diet Dependent Responses to American and Ketogenic Diets in Mice

Author

David W. Threadgill, Gudrun Brockmann, Anna C. Salvador, and Danny Arends

Subjects
medicine.medical_specialty, Nutrition and Dietetics, Cholesterol, Diet therapy, medicine.medical_treatment, Strain (biology), Medicine (miscellaneous), Biology, Steroid hormone, chemistry.chemical_compound, Chronic disease, Endocrinology, chemistry, Nutrient-Gene Interactions, Internal medicine, medicine, Steroid Hormone Biosynthesis, Genotype determination, Food Science, Ketogenic diet
Abstract

OBJECTIVES: Carbohydrate restriction is a widely used dietary intervention to treat chronic diseases like metabolic syndrome. The ketogenic diet represents a severe type of carbohydrate restriction and is being rapidly adopted by metabolically healthy individuals. Recently, different responses to American (35% of energy from fat, 50% from carbohydrate) and ketogenic (80% of energy from fat, and 0% from carbohydrate) were observed between C57BL/6 J and FVB/NJ mice suggesting that genetic background effects response and non-response to carbohydrate restriction. METHODS: To further investigate the apparent response and non-response to carbohydrate restriction, we generated a C57BL/6 J x FVB/NJ intercross (F2) population (250 females and 264 males) to identify quantitative trait loci (QTL) involved in response to these two high fat diets. All animals were genotyped on the Mouse Universal Genotyping Array. RESULTS: Genetic analyses for fat gain during 3 months on diet revealed a diet and sex dependent (p(diet: Chr5 )= 0.0013, p(sex: Chr5 )= 0.0087) QTL on Chromosome (Chr) 5 at 73.7 Mb that results in a male-specific response to the ketogenic diet. There is an additional QTL on distal Chr1 at 191.6 Mb for fat mass gain in both males and females, on on both diets that overlaps with a QTL for serum HDL cholesterol concentration after 3 months on diet at 168.6 Mb. CONCLUSIONS: This distal locus on Chr1 has previously been associated with Apoa2 and serum HDL cholesterol concentration in these strains. Additional candidate genes in these regions include Hsd11b1 and Srd5a3 and are associated with steroid hormone biosynthesis. These candidates are of primary interest given the relationship between cholesterol and synthesis of steroid hormones. These results demonstrate that the response to American and ketogenic diets is strain and sex specific. Our ongoing efforts to validate the regulatory role of these loci in response to carbohydrate restriction will be used to assess the utility of the relevant genotypes and analytes as biomarkers for response to carbohydrate restriction. FUNDING SOURCES: National Institutes of Health.

Published
2020

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