Sammanfattning
Type 2 diabetes is caused by a combination of environmental and inherited factors influencing the progression of insulin resistance and impaired insulin secretion leading to chronically elevated blood glucose levels. The aim of this thesis was to functionally and genetically characterise the species-conserved diabetes locus Niddm1i of the GK rat encoding hyperglycaemia and defect insulin secretion.
High-resolution QTL mapping revealed that Niddm1i is a composite of at least four subloci influencing diabetes-associated phenotypes (Niddm1i1-Niddm1i4). Sorcs3 and Sorcs1 were positionally mapped as diabetes candidate genes within Niddm1i2 and Niddm1i3. Investigation of pancreatic islets and beta-cells identified two separately inherited insulin secretion defects. A 3-Mb region in the proximal part of Niddm1i encoded impaired beta-cell glucose metabolism and ATP production, and a 4.5-Mb region in the distal half of Niddm1i encoded impaired insulin exocytosis. These findings were in line with the observed decreased transcript levels of genes involved in cellular respiration and vesicle transport in young NIDDM1I rat pancreas. Niddm1i also caused increased transcriptional levels of genes involved in pancreatic immune response and inflammation. By use of congenic strains dissecting the 4.5-Mb region in the distal half of Niddm1i, impaired insulin secretion in islets was mapped to the same chromosomal region as Niddm1i4 encoding hyperglycaemia. Increased gene expression level of Adra2a was observed for the GK genotype in islets.
In conclusion, several loci and genes influencing glucose homeostasis and insulin secretion within Niddm1i were identified. Further studies of the identified candidate genes in human populations could establish their potential role in human type 2 diabetes.
High-resolution QTL mapping revealed that Niddm1i is a composite of at least four subloci influencing diabetes-associated phenotypes (Niddm1i1-Niddm1i4). Sorcs3 and Sorcs1 were positionally mapped as diabetes candidate genes within Niddm1i2 and Niddm1i3. Investigation of pancreatic islets and beta-cells identified two separately inherited insulin secretion defects. A 3-Mb region in the proximal part of Niddm1i encoded impaired beta-cell glucose metabolism and ATP production, and a 4.5-Mb region in the distal half of Niddm1i encoded impaired insulin exocytosis. These findings were in line with the observed decreased transcript levels of genes involved in cellular respiration and vesicle transport in young NIDDM1I rat pancreas. Niddm1i also caused increased transcriptional levels of genes involved in pancreatic immune response and inflammation. By use of congenic strains dissecting the 4.5-Mb region in the distal half of Niddm1i, impaired insulin secretion in islets was mapped to the same chromosomal region as Niddm1i4 encoding hyperglycaemia. Increased gene expression level of Adra2a was observed for the GK genotype in islets.
In conclusion, several loci and genes influencing glucose homeostasis and insulin secretion within Niddm1i were identified. Further studies of the identified candidate genes in human populations could establish their potential role in human type 2 diabetes.
| Originalspråk | engelska |
|---|---|
| Kvalifikation | Doktor |
| Tilldelande institution |
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| Handledare |
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| Tilldelningsdatum | 2007 jan. 12 |
| Förlag | |
| ISBN (tryckt) | 91-85559-72-5 |
| Status | Published - 2007 |
Bibliografisk information
Defence detailsDate: 2007-01-12
Time: 09:15
Place: Clinical Research Center (CRC) Lecture Hall, Malmö University Hospital, Sweden
External reviewer(s)
Name: Lejon, Kristina
Title: Docent
Affiliation: Department of Clinical Microbiology
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<div class="article_info">Charlotte Granhall, Hee-Bok Park, Hossein Fakhrai-Rad and Holger Luthman. <span class="article_issue_date">2006</span>. <span class="article_title">High-resolution QTL Analysis Reveals Multiple Diabetes Susceptibility Loci Mapped to Intervals less than 800-kb in the Species Conserved Niddm1i of the GK Rat.</span> <span class="journal_series_title">Genetics</span>, <span class="journal_volume">vol 174</span> <span class="journal_pages">pp 1565-1572</span>.</div>
<div class="article_info">Charlotte Granhall, Anders H. Rosengren, Erik Renström and Holger Luthman. <span class="article_issue_date">2006</span>. <span class="article_title">Separately inherited defects in insulin exocytosis and beta-cell glucose metabolism contribute to type 2 diabetes.</span> <span class="journal_series_title">Diabetes</span>, <span class="journal_volume">vol 55</span> <span class="journal_pages">pp 3494-3500</span>.</div>
<div class="article_info">Charlotte Granhall, Hemang Parikh, Leif Groop and Holger Luthman. <span class="article_issue_date"></span>. <span class="article_title">GK genotype within the species conserved diabetes locus Niddm1i causes downregulation of cellular respiration and vesicle transport in rat pancreas.</span> (manuscript)</div>
<div class="article_info">Charlotte Granhall and Holger Luthman. <span class="article_issue_date"></span>. <span class="article_title">The Niddm1i4 diabetes susceptibility locus encodes hyperglycaemia, impaired islet insulin secretion, and increased Adra2a RNA expression.</span> (manuscript)</div>
Ämnesklassifikation (UKÄ)
- Medicinsk genetik
