Chromosomal mapping of pancreatic islet morphological features and regulatory hormones in the spontaneously diabetic (Type 2) Goto-Kakizaki rat.
Insulin resistance and altered endocrine pancreas function are central pathophysiological features of type 2 diabetes mellitus (T2DM). The Goto-Kakizaki (GK) rat is a model of spontaneous T2DM characterised by reduced beta cell mass and genetically determined glucose intolerance and altered insulin secretion. To identify genetic determinants of endocrine pancreas histopathology, we carried out quantitative trait locus (QTL) mapping of histological phenotypes (beta cell mass -BCM and insulin-positive cell area -IPCA) and plasma concentration of hormones and growth factors in a F2 cohort derived from GK and normoglycemic Brown Norway rats. Although IPCA and BCM in the duodenal region of the pancreas were highly positively correlated (P < 10(-6)), and similarly in the splenic region, both measures were poorly correlated when comparing duodenal and splenic phenotypes. Strongest evidence of linkage to pancreas morphological traits was obtained between BCM and chromosome 10 (LOD 3.2). Evidence of significant linkage (LOD 4.2) to plasma corticosterone was detected in a region of chromosome 1 distal to other QTLs previously identified in the GK. Male-specific genetic effects were detected, including linkages (LOD > 4) to growth hormome (GH) on chromosome 6 and prolactin on chromosome 17. These data suggest independent genetic control of the structure and function of ontologically different regions of the endocrine pancreas. Novel QTLs for corticosterone, prolactin and GH may contribute to diabetes in the GK. The QTLs that we have identified in this, and previous genetic studies collectively underline the complex and multiple mechanisms involved in diabetes in the GK strain.
Finlay
Clare
C
The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7BN, UK.
Argoud
Karène
K
Wilder
Steven P
SP
Ouali
Fetta
F
Ktorza
Alain
A
Kaisaki
Pamela J
PJ
Gauguier
Dominique
D
D000818:Animals; D001786:Blood Glucose; D002874:Chromosome Mapping; D003345:Corticosterone / Q000097:blood; D003433:Crosses, Genetic; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D013006:Growth Hormone / Q000097:blood / Q000235:genetics; D007328:Insulin / Q000097:blood / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D010179:Pancreas / Q000473:pathology; D010641:Phenotype; D011388:Prolactin / Q000097:blood / Q000235:genetics; D040641:Quantitative Trait Loci; D051381:Rats; D011914:Rats, Inbred BN
D001786:Blood Glucose; D005819:Genetic Markers; D007328:Insulin; D011388:Prolactin; D013006:Growth Hormone; D003345:Corticosterone