| Authors |
Hinder LM, Vincent AM, Hayes JM, McLean LL, Feldman EL
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| Submitted By |
Eva Feldman on 1/30/2013 |
| Status |
Published |
| Journal |
Experimental neurology |
| Year |
2013 |
| Date Published |
1/1/2013 |
| Volume : Pages |
239 : 102 - 110 |
| PubMed Reference |
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| Abstract |
Dyslipidemia has been identified as an important pathogenic risk factor for
diabetic neuropathy, but current animal models do not adequately reproduce the
lipid profile observed in human diabetics (increased triglycerides with an
elevated LDL-cholesterol and reduced HDL-cholesterol). High fat feeding of mice
produces hyperlipidemia, but mice are resistant to increases in the LDL to HDL
ratio, reducing the potential for peripheral lipid deposits to impact
neuropathy, as is postulated to occur in human subjects. Genetic manipulations
provide an alternative approach to reproducing a neuropathic plasma lipid
profile. Based on findings from the atherosclerosis literature, we began with
knockout of ApoE. Since knockout of ApoE alone only partially mimics the human
diabetic lipid profile, we examined the impact of its combination with a
well-characterized model of type 2 diabetes exhibiting neuropathy, the db/db
mouse. We added further gene manipulations to increase hyperlipidemia by using
mice with both ApoE and ApoB48 knockout on the ob/+ (leptin mutation) mice. In
all of these models, we found that either the db/db or ob/ob genotypes had
increased body weight, hyperlipidemia, hyperglycemia, and evidence of neuropathy
compared with the control groups (db/+ or ob/+, respectively). We found that
ApoE knockout combined with leptin receptor knockout produced a lipid profile
most closely modeling human dyslipidemia that promotes neuropathy. ApoE knockout
combined with additional ApoB48 and leptin knockout produced similar changes of
smaller magnitude, but, notably, an increase in HDL-cholesterol. Our data
suggest that the overall effects of ApoE knockout, either directly upon nerve
structure and function or indirectly on lipid metabolism, are insufficient to
significantly alter the course of diabetic neuropathy. Although these models
ultimately do not deliver optimal lipid profiles for translational diabetic
neuropathy research, they do present glycemic and lipid profile properties of
value for future therapeutic investigations.
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