Mouse Genome Informatics
hm
    Leprdb/Leprdb
BKS.Cg-Dock7m +/+ Leprdb/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       
homeostasis/metabolism
• increased secreation of glucagon by pancreatic cells in culture
• brain derived neurotrophic factor (BDNF) causes a drop in blood glucose relative to controls 8 weeks after treatment (J:43162)
• affect of BDNF on blood glucose becomes progressively less as mice age (J:43162)
• neurotrophin 3 also causes a drop in blood glucose but the glucose levels return to normal by 24 hours after treatment (J:43162)
• glucose levels are reduced at all times tested when mice are placed on feeding restriction during the dark phase (J:91813)
• blood glucose shows a progressive increase from 5 through 33 weeks
• fasting blood glucose level is significantly higher than control at 26 weeks of age (J:135864)
• BDNF causes a 50% reduction in plasma insulin relative to controls (J:43162)
• morning insulin levels lowered when feeding is restricted during the dark phase (J:91813)
• Background Sensitivity: plasma lipid levels differ between young and old mutants unlike on the C57BL/6J background where levels are similar at both ages; 14-month old mice have lower triglycerides, HDL cholesterol and combined VLDL + LDL cholesterol levels than 14-week old mice, but have significantly higher plasma triglyceride levels
• fasting plasma total cholesterol concentration is increased 2 fold over controls
• triglyceride levels are reduced at all times tested when mice are placed on feeding restriction during the dark phase
• triglyceride levels are elevated 1.5- to 2-fold
• BDNF treatment causes a lower blood glucose level response in a glucose tolerance test
• in diabetic wounds, PGE2 level is consistently less than 50% of wild-type wounds at all times
• mutants treated with sRAGE do not show the increased albumin excretion seen in untreated mutants (0.11 ug albumin/ug creatinine vs 0.20 ug albumin/ ug creatinine); levels are not significantly different from control animals (0.08 ug albumin/ ug creatinine)
• moderate albuminuria is observed at 26 weeks of age
• wound healing is impaired, with an average wound closure time of 22 days, 7 days longer than in controls
• T26A, a prostaglandin transporter inhibitor, topically applied to wounds shortened wound closure to 16 days in mutants, similar to untreated controls; T26A increased re-epithelialization, neovascularization, and blood flow in wounds

growth/size
• body weight drops after 6 days on feeding restriction during the dark phase
• become progressively obese starting at 5 weeks of age
• weight reaches 2.5X that of control mice by 3 months of age

renal/urinary system
• mutants treated with sRAGE do not show the increased albumin excretion seen in untreated mutants (0.11 ug albumin/ug creatinine vs 0.20 ug albumin/ ug creatinine); levels are not significantly different from control animals (0.08 ug albumin/ ug creatinine)
• moderate albuminuria is observed at 26 weeks of age
• moderate mesangial expansion is observed in glomeruli at 26 weeks
• male mutants treated with sRAGE to achieve RAGE blockade display increased creatinine clearance (~5.1 ml/hour/100 x g body weight) compared to PBS-treated mutants (~3 ml/hour/100 x g body weight), approaching wild-type levels (6.7 ml/hour/100 x g body weight)

nervous system
• axonal growth cone extension fails to occur for neurons treated in culture with 100ng/ml of leptin
• myelinated fibers reduced in numbers at 25 weeks in the sural nerve
• unmyelinated fibers reduced in numbers at 25 weeks in the vagus nerve
• myelinated fiber density increases in most nerves (not the peroneal and phrenic nerves)
• unmyelinated fiber density increase in the sural, peroneal, and vagus nerves
• non significant shift toward smaller fiber diameter at 15 weeks of age
• significantly shifted to smaller diameter fibers by 25 weeks in ventral roots, dorsal roots, sural nerve
• smaller diameter nerve fibers in peroneal, phrenic and vagus nerves at 25 weeks but not significant
• small numbers of very large unmyelinated fibers (up to 1.6 micrometers)
• shift of unmyelinated fibers to smaller diameters
• number of myelin lamellae relative to nerve diameter is increased
• motor nerve conductance significantly lower than controls from 7 weeks of age onward
• velocity returns to and is maintained at prediabetic levels by 15 weeks of age whereas control mice show a continuous increase in velocity
• insulin treatment results in improved conductance but only for the duration of treatment and control levels of conductance are never restored
• no conductance improvement is seen in mice over 23 weeks in age due to insulin treatment
• CA1 hippocampal slices indicate brief post tetanic potentiation but no long term potentiation on recordings of excitatory post-synaptic potentials
• CA1 hippocampal slices indicate no long term depression on recordings of excitatory post-synaptic potentials

behavior/neurological
• daily locomotor pattern becomes attenuated in 6-8 week old mice but rhythmicity is retained
• daily locomotor activity rhythmicity severely diminished at 13-14 weeks, 75% fail to show significant rhythmicity
• daily locomotor rhythmicity restored by feeding restriction during dark phase
• food intake is about 60% of control level
• longer swimming distances than control mice in a Morris water maze test
• cross the original platform location less frequently than do controls in a Morris water maze test

vision/eye
• prolonged latency of the b-wave in the retina
• delays in oscillatory potentials 1, 2, 3 although only the delay in "OP1" is significant

endocrine/exocrine glands
• increased secreation of glucagon by pancreatic cells in culture

cardiovascular system
• dense bodies found in the smooth muscle of intramyocardial arteries
• presence of many lipid droplets
• dense bodies present in places normally occupied by mitochondria
• disrupted sarcomeres sometimes

muscle
• presence of many lipid droplets
• dense bodies present in places normally occupied by mitochondria
• disrupted sarcomeres sometimes

cellular
• axonal growth cone extension fails to occur for neurons treated in culture with 100ng/ml of leptin

Mouse Models of Human Disease
OMIM IDRef(s)
Diabetes Mellitus, Noninsulin-Dependent; NIDDM 125853 J:185546
Obesity 601665 J:6323