Differential beta cell responses to hyperglycaemia and insulin resistance in two novel congenic strains of diabetes (FVB- Lepr (db)) and obese (DBA- Lep (ob)) mice.
OBJECTIVE
Our goal was to identify genetic variants that determine the response to insulin resistance and hyperglycaemia. This report documents the diabetes syndrome of two new congenic strains of mice generated by the transfer of the Lepr(db) mutation to the FVB/NJ strain and the Lep(ob) mutation to the DBA/2J strain.


METHODS
Mice were characterised by measures of blood metabolites and hormones along with challenges with glucose and insulin injections. Histological examinations of the endocrine pancreas and the kidneys were also carried out.


RESULTS
Obese mice of the FVB-db congenic strain show long-term hyperglycaemia that is primarily due to severe insulin resistance. The hyperglycaemia in the fed state persists despite escalating secretion of insulin and massive increase of pancreatic beta cells. Obese FVB-db mice show evidence of mesangial matrix expansion, a hallmark of diabetic nephropathy. Leptin-deficient mice of the DBA-ob strain have variable obesity-diabetes. In mice with high insulin (>10 ng/ml), DBA-ob/ob mice maintain their increased adiposity and have a large increase in beta-cell number. In mice with low insulin (<1 ng/ml) DBA-ob/ob mice have greatly diminished adiposity. These mice have atrophied islets with evidence of increased beta-cell neogenesis from the ductal epithelium.


CONCLUSIONS
The strain-specific responses suggest the existence of genetic variants that control insulin sensitivity and beta-cell responses in the strains described in this report. These new models of obesity-diabetes should prove useful in dissecting the genetic control of beta-cell responses to hyperglycaemia and insulin resistance.
Division of Molecular Genetics and New York Obesity Research Center, Department of Pediatrics, Columbia University, New York, USA. sc569@columbia.edu
S
S
Chua
S Mei
SM
Liu
Q
Q
Li
L
L
Yang
V T
VT
Thassanapaff
P
P
Fisher
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003433:Crosses, Genetic; D005260:Female; D005951:Glucose Tolerance Test; D006943:Hyperglycemia / Q000473:pathology / Q000503:physiopathology*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D007668:Kidney / Q000473:pathology; D007678:Kidney Glomerulus / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008817:Mice, Mutant Strains; D008820:Mice, Obese; D010179:Pancreas / Q000473:pathology; D012727:Sex Characteristics; D013045:Species Specificity
D001786:Blood Glucose; D007328:Insulin