Phenotypes for Lepr MGI:3694548 MGI Mouse

• increased secreation of glucagon by pancreatic cells in culture

abnormal circulating glucose level ( J:43162 )

decreased circulating glucose level ( J:43162 , J:91813 )

• 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)

increased circulating glucose level ( J:6323 )

• blood glucose shows a progressive increase from 5 through 33 weeks

hyperglycemia ( J:135864 , J:185546 )

• fasting blood glucose level is significantly higher than control at 26 weeks of age (J:135864)

decreased circulating insulin level ( J:43162 , J:91813 )

• 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)

abnormal circulating lipid level ( J:18161 )

• 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

abnormal circulating cholesterol level ( J:18161 )

increased circulating cholesterol level ( J:18161 )

• fasting plasma total cholesterol concentration is increased 2 fold over controls

increased circulating HDL cholesterol level ( J:18161 )

increased circulating LDL cholesterol level ( J:18161 )

increased circulating VLDL cholesterol level ( J:18161 )

decreased circulating triglyceride level ( J:91813 )

• triglyceride levels are reduced at all times tested when mice are placed on feeding restriction during the dark phase

increased circulating triglyceride level ( J:18161 )

• triglyceride levels are elevated 1.5- to 2-fold

improved glucose tolerance ( J:43162 )

• BDNF treatment causes a lower blood glucose level response in a glucose tolerance test

decreased prostaglandin level ( J:185546 )

• in diabetic wounds, PGE2 level is consistently less than 50% of wild-type wounds at all times

decreased urine albumin level ( J:82491 )

• 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)

albuminuria ( J:135864 )

• moderate albuminuria is observed at 26 weeks of age

abnormal enzyme/coenzyme activity ( J:302677 )

• Lypla1 (APT-1) enzyme activity is decreased in lung endothelial cells

delayed wound healing ( J:185546 )

• 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

weight loss ( J:91813 )

• body weight drops after 6 days on feeding restriction during the dark phase

increased body weight ( J:135864 )

obese ( J:6323 )

• become progressively obese starting at 5 weeks of age

• weight reaches 2.5X that of control mice by 3 months of age

decreased urine albumin level ( J:82491 )

• 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)

albuminuria ( J:135864 )

• moderate albuminuria is observed at 26 weeks of age

expanded mesangial matrix ( J:135864 )

• moderate mesangial expansion is observed in glomeruli at 26 weeks

increased creatinine clearance ( J:82491 )

• 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)

abnormal nervous system morphology ( J:6323 )

abnormal axon extension ( J:112680 )

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

decreased motor neuron number ( J:6323 )

• 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

abnormal axon morphology ( J:6323 )

• 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

abnormal myelin sheath morphology ( J:6323 )

• number of myelin lamellae relative to nerve diameter is increased

abnormal nerve conduction ( J:6323 )

• 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

abnormal CNS synaptic transmission ( J:109401 )

reduced long-term potentiation ( J:109401 )

• CA1 hippocampal slices indicate brief post tetanic potentiation but no long term potentiation on recordings of excitatory post-synaptic potentials

absent long-term depression ( J:109401 )

• CA1 hippocampal slices indicate no long term depression on recordings of excitatory post-synaptic potentials

abnormal learning/memory/conditioning ( J:109401 )

abnormal spatial learning ( J:109401 )

• longer swimming distances than control mice in a Morris water maze test

abnormal spatial reference memory ( J:109401 )

• cross the original platform location less frequently than do controls in a Morris water maze test

abnormal food intake ( J:43162 )

• food intake is about 60% of control level

abnormal locomotor circadian rhythm ( J:91813 )

• 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

abnormal eye electrophysiology ( J:103714 )

• prolonged latency of the b-wave in the retina

• delays in oscillatory potentials 1, 2, 3 although only the delay in "OP1" is significant

increased glucagon secretion ( J:6264 )

• increased secreation of glucagon by pancreatic cells in culture

abnormal aorta morphology ( J:302677 )

• aortic tissue shows increased retention of insoluble fibronectin

abnormal vascular development ( J:6115 )

• dense bodies found in the smooth muscle of intramyocardial arteries

abnormal myocardial fiber morphology ( J:6115 )

• presence of many lipid droplets

• dense bodies present in places normally occupied by mitochondria

• disrupted sarcomeres sometimes