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Endocrinology Vol. 143, No. 4 1213-1217
Copyright © 2002 by The Endocrine Society

INSULIN-GLUCAGON-GI PEPTIDES-DIABETES MELLITUS

Sciatic Nerve Lipoprotein Lipase Is Reduced in Streptozotocin-Induced Diabetes and Corrected by Insulin

L. D. M. C.-B. Ferreira, P. U. Huey, B. E. Pulford, D. N. Ishii and R. H. Eckel

University of Colorado Health Sciences Center (L.D.M.C.-B.F., P.U.H., R.H.E.) and Colorado State University (B.E.P., D.N.I.), Denver, Colorado 80262

Address all correspondence and requests for reprints to: R. H. Eckel, M.D., University of Colorado Health Sciences Center, B-151, 4200 East Ninth Avenue, Denver, Colorado 80262. E-mail: . robert.eckel{at}uchsc.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The metabolic abnormalities underlying the cause of diabetic neuropathy have been the subject of much debate. Lipoprotein lipase (LPL) is a 56-kDa enzyme produced by several tissues in the body and has recently been shown in vitro to be expressed in cultured Schwann cells, where it is important in phospholipid synthesis. This suggests a role for LPL in myelin biosynthesis in the peripheral nervous system. The aim of this study was to determine if acute streptozotocin (STZ)-induced diabetes reduces the expression and regulation of sciatic nerve LPL in vivo. Adult Sprague Dawley rats were rendered diabetic via an sc injection of STZ. A decrease in sciatic nerve LPL activity was observed in the STZ-treated rats after just 2 d of diabetes and remained significantly reduced for at least 35 d. The decrease in LPL activity coincided temporally with a drop in motor nerve conduction velocity. Treatment with insulin for 4 d showed a normalization of sciatic nerve LPL activity. These results show that STZ-induced diabetes causes a decrease in LPL activity in the sciatic nerve that, as in other tissues, is reversible with insulin treatment. These data may suggest a role for LPL in the pathophysiology of diabetic neuropathy.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
LIPOPROTEIN LIPASE (EC 3.1.1.34, LPL) is a rate-limiting enzyme involved in the hydrolysis of triglyceride-rich lipoproteins (1) and also contributes to the nonhydrolytic uptake of lipoproteins by cells (2, 3). LPL has been shown to be expressed in several portions of the nervous system, such as the spinal cord and brain (4, 5, 6, 7). The exact function of LPL in the nervous system has yet to be elucidated. Work conducted in this laboratory has shown that inhibition of LPL activity in Schwann cells by a goat antirat LPL antibody eliminates most of the incorporation of lipoprotein-derived fatty acids into polar lipids, suggesting a role in myelin phospholipid biosynthesis (8).

Diabetes is associated with a decrease in LPL activity in most LPL-expressing tissues including adipose tissue (9), skeletal muscle (10, 11, 12), and the brain (13). Diabetes has been shown to affect both the peripheral nervous system (PNS) and the central nervous system (14, 15, 16). Peripheral neuropathy in humans with diabetes is characterized by neuroanatomical changes including segmental demyelination, axonal degradation, decreased fiber myelin density, and decreased nerve conduction velocity (17). Acute experimental diabetes in rats is accompanied by electrophysiological abnormalities in the peripheral nerve analogous to neuropathy in humans with diabetes (18).

The aim of this study was to determine if acute streptozotocin (STZ)-induced diabetes reduces the expression and regulation of sciatic nerve LPL in vivo, and whether this could be corrected by insulin.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
All animal experiments were approved by and conducted in accordance with guidelines set by the University of Colorado Health Science Center Committee on Animal Care. Adult male Sprague Dawley rats (350 g, Charles River Laboratories, Inc., Wilmington, MA) were divided randomly into two groups. Rats from the first group were rendered diabetic by the sc administration of 60 mg/kg of streptozotocin (STZ, Sigma in 10 mM citrate/0.9% saline buffer, pH 4.5), whereas those in the second group received vehicle only. Blood glucose was checked 24 h after injection using a One-Touch Glucometer (Lifescan, Milipitas, CA), and only rats with blood glucose greater than 15 mM were used in the group with diabetes. Animals had unlimited access to standard laboratory chow and water. Animals from both groups were chosen at random and euthanized at 0, 2, 4, 7, 14, 28, and 35 d after injection.

The sciatic nerve was sampled from both hindlimbs, with one nerve being used to measure heparin releasable LPL activity while the second nerve was quick frozen in liquid nitrogen and stored at -80 C for mRNA analysis conducted later. Blood was sampled (100–200 µl) via the aorta and centrifuged at 720 x g for 10 min. The supernatant (plasma) was then transferred to a 1.5 ml tube that was kept at -20 C until further analysis was conducted.

To ensure that STZ did not have a neurotoxic effect on the sciatic nerve independent of the hyperglycemia, a separate experiment was conducted. Rats were rendered diabetic as previously described above. These rats were further subdivided into two groups, whereby one group would receive insulin twice daily to keep them euglycemic and the second group would not receive any glucose lowering medication. Twenty-four hours after STZ injection, animals were checked for hyperglycemia and then kept euglycemic for 3 d. The animals were euthanized at d 4, and LPL activity was measured in the sciatic nerve. Animals had unlimited access to standard laboratory chow and water up to the time of euthanasia.

LPL activity
Heparin-releasable LPL activity in the sciatic nerve was measured in a method slightly modified from that described (19). Briefly, excised nerves were rinsed with ice cold Krebs-Ringer phosphate buffer and minced with a pair of scissors, then blotted dry and weighed. The minced tissue was then incubated in 200 µl Krebs-Ringer phosphate buffer and 3 µg/ml heparin for 45 min at 37 C. A 75-µl aliquot was removed and incubated with 75 µl of a [14C]triolein phosphatidylcholine stabilized substrate. After another 45-min incubation at 37 C, the reaction was solubilized, and 14C-labeled fatty acids were partitioned according to the method of Belfrage and Vaughn (20). A 1.5-ml aliquot of the resulting aqueous supernatant was counted by ß-scintillation (Beckman Coulter, Inc., Fullerton, CA; LS6000TA). LPL activity was expressed as nanomoles of FFA released per minute per gram tissue.

Motor nerve conduction velocity (MNCV) measurement
MNCV was measured according to Carsten et al. (18). MNCV was measured 2 d after induction of STZ diabetes. Rats were anesthetized ip with a combination of 90 mg/kg ketamine and 20 mg/kg xylazine. Conduction velocities were calculated by dividing the distance between the stimulating and recording electrodes by the latency. Motor nerve conduction velocities were all normalized to 35 C.

mRNA analysis
Total RNA from diabetic and control nerves was isolated by homogenization in TRIzol reagent (Life Technologies, Inc., Carlsbad, CA) and processed according to the manufacturer’s instructions. One microgram total RNA was used for semiquantitative RT-PCR as described earlier (21). The RT reactions were subjected to duplex PCR amplification using primers specific for rat LPL (forward primer = 5'-GAGATTTCTCTGTATGGCACA-3' and reverse primer = 5'-CTGCAGATGAGAAACTTTCTC-3') and a competimer/primer mix specific for 18S rRNA (QuantumRNA kit; Ambion, Inc., Austin, TX). The PCR products were separated by electrophoresis in 2.5% agarose and visualized with ethidium bromide staining. A digital image of the gel was obtained with an Alphaimager 2000 (Alpha Innotech Corp., San Leandro, CA) and was analyzed for band pixel density using the SigmaGel program (SPSS, Inc., Chicago, IL).

Statistics
Data were analyzed using a one-way ANOVA, a two-way ANOVA, or t test (SPSS, Inc.) to compare differences among groups. A forward stepwise regression was conducted on the LPL activity, plasma glucose, and weight change data to assess relationships between the variables. A P value less than 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
LPL activity time course
Administration of STZ resulted in hyperglycemia in all of the diabetic groups over the 35 d of the experiment (Table 1Go, P < 0.001 vs. vehicle-treated group). Diabetes has been shown to be associated with a decrease in levels of LPL activity in the majority of LPL expressing tissues. In these experiments, a decrease in sciatic nerve LPL activity was observed in the STZ-treated rats after just 2 d (from 5.3 ± 0.5 nmol FFA/min·g to 3.2 ± 0.7 nmol FFA/min·g, P = 0.021, Fig. 1Go) and remained significantly reduced for at least 35 d. Vehicle-treated control rats showed no change in sciatic nerve LPL activity over the 35 d of the experiment (n = 5 per group). A forward stepwise regression analysis demonstrated a strong relationship between LPL activity and corresponding plasma glucose values (r2=0.388, P < 0.001, Fig. 2Go). It should be noted that no correlation between LPL activity and plasma glucose was observed within vehicle-treated controls or within diabetic rats when both groups were looked at individually.


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  		Table 1. Plasma glucose values for LPL time course experiments

 


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  		Figure 1. Effect of duration of STZ-induced diabetes on sciatic nerve LPL activity. Control rats are shown by dark dots, rats with diabetes are shown by white dots. *, P < 0.05 compared with STZ treated group on corresponding day using a two-way ANOVA followed by a Tukey a posteriori test (n = 5 rats/group).

 


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  		Figure 2. Relationship between sciatic nerve LPL activity and plasma glucose. Both control rats and rats with STZ diabetes are shown.

 
LPL mRNA
Steady-state LPL mRNA levels in the sciatic nerve were measured and analyzed by RT-PCR. LPL mRNA values were normalized to the 18S rRNA values band for standardization of each reaction. Relative LPL mRNA levels were constant over the 35 d of the experiment in the control rats. No differences were detected in relative LPL mRNA levels in the sciatic nerve in response to STZ induced diabetes (Fig. 3Go) for the duration of the experiment (35 d) (n = 5 per group).



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  		Figure 3. Effect of duration of diabetes on relative sciatic nerve LPL mRNA content. Control rats are shown by dark bars, rats with diabetes are shown by open bars. Inset shows a typical RT-PCR. Values are means ± SEM of relative densitometric values.

 
MNCV measurements
To determine if the reduction in LPL in the sciatic nerve coincided with a reduction in nerve function, MNCV was measured 2 d after the induction of diabetes. Consistent with the observations by others (18), a significant decrease in MNCV was observed in the rats with diabetes (65.0 ± 1.3 m/s compared with 81.0 ± 1.8 m/s; P < 0.001, n = 8 and 6, respectively) (Fig. 4Go).



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  		Figure 4. MNCV in common peroneal branch of sciatic nerve 2 d after induction of diabetes. Control (n = 4) rats are shown by dark bars, STZ (n = 5) rats are shown by open bars. *, P < 0.001 t test.

 
Insulin treatment
One group of rats with diabetes was treated with insulin for 3 d to maintain euglycemia, whereas a second group of rats with diabetes received vehicle. At d 4, the insulin-treated rats had a mean plasma glucose of 13.6 ± 2.4 mM compared with 10.2 ± 0.5 mM in the control group (P = 0.285, Fig. 5Go). The rats with STZ-induced diabetes, which were not treated with insulin, had a mean plasma glucose of 25.5 ± 0.4 mM at d 4 (P = 0.002 vs. insulin treated, n = 4 per group). Rats treated with insulin for 3 d had normal levels of sciatic nerve LPL activity (7.6 ± 0.6 nmol FFA/min·g compared with 5.7 ± 1.3 nmol FFA/min·g in vehicle-treated rats, ns) (Fig. 6Go). Rats not treated with insulin had a lower LPL activity than the other two groups (2.2 ± 0.3 nmol FFA/min·g; P = 0.002 vs. insulin treated).



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  		Figure 5. Time course of blood glucose for experiment where rats were treated with insulin. Control (n = 4) rats are shown by the closed circles. STZ ( n = 4) rats are shown by open circles, and insulin-treated STZ rats (n = 4) are open triangles. *, P < 0.001 vs. control, two-way ANOVA followed by a Tukey a posteriori test.

 


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  		Figure 6. Sciatic nerve LPL activity after 4 d of insulin treatment. Nondiabetic rats (controls), untreated rats with diabetes (STZ), insulin-treated rats with diabetes (STZ + Ins). *, P < 0.05 compared with STZ group; one-factor ANOVA followed by a Tukey a posteriori test (n = 4 rats/group).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Diabetic neuropathy is among the most common disorders of peripheral nerves (22). While LPL has been shown to be expressed in parts of the CNS, such as the spinal cord and brain (4, 5, 6, 7), its role in the nervous system has yet to be elucidated. Diabetes has been associated with a decrease in LPL activity in nonneural tissue (for review see Ref. 10). LPL in the nervous system behaves similarly, as work conducted on the brain by Gavin et al. (13) demonstrated that diabetes was associated with reductions in LPL activity by approximately 50% 10 d after induction of the disease . In the study reported here, a 50% decrease was observed in peripheral nerve LPL activity within 2 d of the induction of diabetes with STZ and remained low for the duration of the experiment (35 d; Fig. 1Go). This decrease in LPL activity is among the earliest biochemical changes observed following the onset of diabetes.

MNCV in the sciatic nerve also decreased significantly 2 d after the induction of diabetes (Fig. 4Go). The decrease in MNCV is consistent with the literature (18, 23) and is one of the early signs of diabetic peripheral neuropathy. While a clear decrease is seen in the MNCV, morphological changes to the nerve normally occur only after 20 wk of hyperglycemia (23).

Statistical examination of our results using a forward stepwise regression analysis demonstrated a strong relationship between the LPL activity and the plasma glucose values (Fig. 2Go). Despite the fact that no such relationship was observed when the two groups were looked at individually, we believe that the decrease in LPL could be either due to the hyperglycemia or hypoinsulinemia. This is especially true because recent clinical trials indicate that the severity of diabetic neuropathy is correlated with the level of patient glycemic control (24, 25). The effects rendered by hyperglycemia tend to be seen in chronic diabetes (23) rather than acutely.

Brain LPL activity in rats with diabetes was restored to normal after 4 d of insulin therapy (13). Sciatic nerve LPL activity also returned to normal with insulin therapy (Fig. 6Go), suggesting that insulin might regulate LPL activity in the peripheral nerve. The possibility that levels of blood glucose affect LPL activity is not excludable at this time. The possibility that the decrease in LPL activity in the sciatic nerve is due to a neurotoxic effect of STZ is doubtful because the treatment of the STZ-induced diabetic rats with insulin returned sciatic nerve LPL activity to normal.

LPL has been shown both in vitro and in vivo to be regulated post translationally (26, 27, 28). The RT-PCR data suggest that LPL in the sciatic nerve is no different, with LPL mRNA levels not changing over the 35 d of the study (Fig. 3Go). Although no sciatic nerve LPL mRNA levels were measured after treatment with insulin, previous work conducted on adipose tissue in human patients with diabetes has shown that treatment with insulin does not change the level of LPL mRNA levels despite an increase in LPL activity (27).

Work conducted in vitro has shown that LPL in hypothalamic cell cultures is responsible for the incorporation of [14C] triolein into cellular triglycerides and phospholipids, particularly sphingomyelin (5). Additionally, work conducted in this laboratory showed in vitro that 1.17 Schwann cells express cell surface LPL activity that can be inhibited by tetrahydrolipstatin (THL), a general mammalian lipase inhibitor, and by antiserum raised against rat adipose tissue LPL (8). Inhibition of LPL activity in these cells led to a decreased incorporation of emulsified [14C] triolein-derived radioactivity into phospholipids (8). It is possible that the role of LPL in the sciatic nerve is the same as that proposed for brain LPL (29) and nonneuronal tissue LPL (1), that is, to supply the tissue with triglyceride fatty acids from circulating lipoproteins.

Peripheral nerve myelin is formed by the differentiation of the Schwann cell plasma membranes. Although, the exact composition of myelin differs between species, phospholipids make up the greatest portion of the myelin (30). If inhibition of LPL activity in vitro leads to a decrease in phospholipid synthesis, it is possible that the observed decrease in sciatic nerve LPL activity in the rats with diabetes could manifest itself in thinner myelin at a later time point. Support for this hypothesis is evident in several animal models. In the fatty liver dystrophy (fld) mouse model, deficiencies are seen in LPL activity during the suckling period, which are resolved during the weaning period (31, 32). A peripheral neuropathy is evident at 4 d of age that lasts for the life of the mouse (32). Abnormalities are evident at 4 d of age, as myelin sheaths are markedly thinner than in their age-matched control littermates (32). In rodents, peripheral nerve myelination begins shortly after birth and involves three phases: 1) an initial slow increase in myelin during the first few postnatal days; 2) a period of rapid myelination during the next 2–3 wk; and 3) a leveling off to steady-state levels as animals reach adulthood (33). It is possible that because the LPL deficiency is not seen throughout the life of the fld mouse but only during the initial phase of myelination, that the first phase would be the most important to ensure healthy myelin throughout the life span of the animal. Nerve lesions and loss of myelinated fibers in the PNS of cats with LPL deficiency (34) is further evidence of the possible role of LPL in the nervous system.

LPL is not only involved in the hydrolysis of triglyceride-rich lipoproteins (1) but also contributes to the nonhydrolytic uptake of lipoproteins by cells (2, 3). Whether or not the nonhydrolytic function of LPL in the nervous system is important has yet to be elucidated, but the fact that only a mild neuropathy is seen in LPL deficient patients indicates that this noncatalytic action of LPL might have a role to play in myelin formation.

Further support for the role of LPL in peripheral nerves is found in human patients with abetalipoproteinemia, who have reduced LPL activity (35, 36). Marked diminution in amplitude of sensory potentials has been found in tibial and sural nerves with slowing of conduction velocity (37). Biopsies of the sural nerves showed a loss of large myelinated fibers. Paranodal demyelination appears to correlate with the severity and duration of the disease (37). The neuropathy associated with abetalipoproteinemia has been linked to a vitamin E deficiency as treatment has been shown to ameliorate the neuropathy (38, 39). Vitamin E has been concluded to be a universal participant of antioxidant defense reactions in biological membranes because it acts at all stages of membrane oxidative damage (40). It is interesting to note that, in rats rendered diabetic with STZ, treatment with high doses of vitamin E partially prevents nerve dysfunction (41). On the other hand, vitamin E has been shown to be slightly increased, although not significantly, in rats with STZ-induced diabetes (42), suggesting that pharmacological doses are required to see an effect in the diabetic rat.

THL is known to inhibit vitamin E absorption (43) and, as stated before, in vitro work conducted in our laboratory has shown that THL inhibits LPL activity in 1.17 Schwann cells (8). Additionally, inhibition of LPL in the same cell line caused a decrease in the amount of cell associated [14C] tocopherol (our unpublished results). This finding supports other work conducted on erythrocytes and fibroblasts where the addition of LPL results in an increase of cellular tocopherol (44). This suggests that LPL might be playing an important role in the metabolism of vitamin E and the prevention of neuropathy in the PNS. This could possibly explain the temporal relationship between the MNCV and decrease in LPL activity as free radicals have been shown to decrease MNCV in patients with diabetes (45, 46, 47).

In conclusion, these results show that STZ-induced diabetes causes a decrease in LPL activity in the sciatic nerve that, as is observed in other tissues, is reversible with insulin treatment similar to that observed in other tissues. These data may suggest a role for LPL in the pathophysiology of diabetic neuropathy.


   Acknowledgments
 
We would like to thank Dr. L. Raymond Whalen for his expert technical assistance. The [14C] tocopherol was provided by Herbert J. Kayden of New York University.


   Footnotes
 
This research was supported by NIH Grant D-K42266 (to R.H.E.) and NIH Grant DK-53922 (to D.N.I.). L.D.M.C.-B.F. is supported by an American Diabetes Association mentor-based postdoctoral fellowship.

Abbreviations: LPL, Lipoprotein lipase; MNCV, motor nerve conduction velocity; PNS, peripheral nervous system; STZ, streptozotocin; THL, tetrahydrolipstatin.

Received September 24, 2001.

Accepted for publication December 4, 2001.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Eckel RH 1989 Lipoprotein lipase. A multifunctional enzyme relevant to common metabolic diseases. N Engl J Med 320:1060–1068[Abstract]
  2. Beisiegel U, Weber W, Bengtsson-Olivecrona G 1991 Lipoprotein lipase enhances the binding of chylomicrons to low density lipoprotein receptor-related protein. Proc Natl Acad Sci USA 88:8342–8346[Abstract/Free Full Text]
  3. Merkel M, Kako Y, Radner H, Cho IS, Ramasamy R, Brunzell JD, Goldberg IJ, Breslow JL 1998 Catalytically inactive lipoprotein lipase expression in muscle of transgenic mice increases very low density lipoprotein uptake: direct evidence that lipoprotein lipase bridging occurs in vivo. Proc Natl Acad Sci USA 95:13841–13846[Abstract/Free Full Text]
  4. Brecher P, Kuan HT 1979 Lipoprotein lipase and acid lipase activity in rabbit brain microvessels. J Lipid Res 20:464–471[Abstract]
  5. Eckel RH, Robbins RJ 1984 Lipoprotein lipase is produced, regulated, and functional in rat brain. Proc Natl Acad Sci USA 81:7604–7607[Abstract/Free Full Text]
  6. Vilaro S, Camps L, Reina M, Perez-Clausell J, Llobera M, Olivecrona T 1990 Localization of lipoprotein lipase to discrete areas of the guinea pig brain. Brain Res 506:249–253[CrossRef][Medline]
  7. Bessesen DH, Richards CL, Etienne J, Goers JW, Eckel RH 1993 Spinal cord of the rat contains more lipoprotein lipase than other brain regions. J Lipid Res 34:229–238[Abstract]
  8. Huey PU, Marcell T, Owens GC, Etienne J, Eckel RH 1998 Lipoprotein lipase is expressed in cultured Schwann cells and functions in lipid synthesis and utilization. J Lipid Res 39:2135–2142[Abstract/Free Full Text]
  9. Yost TJ, Sadur CN, Eckel RH 1995 Glycohemoglobin levels relate to the response of adipose tissue lipoprotein lipase to insulin/glucose in obese non-insulin-dependent diabetes mellitus. Metabolism 44:1475–1480[CrossRef][Medline]
  10. Eckel RH 1993 Lipoprotein lipases and diabetes mellitus. In: Draznin B, Eckel RH, eds. Diabetes and atherosclerosis. New York: Elsevier-Science; 77–102
  11. Taskinen MR 1987 Lipoprotein lipase in diabetes. Diabetes-Metab Rev 3:551–570[Medline]
  12. Yost TJ, Froyd KK, Jensen DR, Eckel RH 1995 Change in skeletal muscle lipoprotein lipase activity in response to insulin/glucose in non-insulin-dependent diabetes mellitus. Metabolism 44:786–790[CrossRef][Medline]
  13. Gavin LA, Cavalieri RR, Moeller M, McMahon FA, Castle JN, Gulli R 1987 Brain lipoprotein lipase is responsive to nutritional and hormonal modulation. Metabolism 36:919–924[CrossRef][Medline]
  14. Brown MR, Dyck PJ, McClearn GE, Sima AA, Powell HC, Porte DJ 1998 Central and peripheral nervous system complications. Diabetes 31:65–70
  15. McCall A 1992 The impact of diabetes on the CNS. Diabetes 41:557–570[Abstract]
  16. Sima AA 1996 Metabolic alterations of peripheral nerve in diabetes. Semin Neurol 16:129–137[Medline]
  17. Clark CMJ, Lee DA 1995 Prevention and treatment of the complications of diabetes mellitus. N Engl J Med 332:1210–1217[Free Full Text]
  18. Carsten RE, Whalen LR, Ishii DN 1989 Impairment of spinal cord conduction velocity in diabetic rats. Diabetes 38:730–736[Abstract]
  19. Eckel RH, Kern PA, Sadur CN, Yost TJ 1986 Methods for studying lipoprotein lipase in human adipose tissue. In: Pohl SL, Clarke WL, Larner J, eds. Methods in diabetes research. New York: Wiley; 259–273
  20. Belfrage P, Vaughn M 1969 Simple liquid-liquid partition system for isolation of labeled oleic acid from mixtures with glycerides. J Lipid Res 10:341–344[Abstract]
  21. Schlaepfer IR, Eckel RH 1999 Plasma triglyceride reduction in mice after direct injections of muscle-specific lipoprotein lipase DNA. Diabetes 48:223–227[Abstract]
  22. Zochodne DW 1999 Diabetic neuropathies: features and mechanisms. Brain Pathol 9:369–391[Medline]
  23. Malone JI, Lowitt S, Korthals JK, Salem A, Miranda C 1996 The effect of hyperglycemia on nerve conduction and structure is age dependent. Diabetes 45:209–215[Abstract]
  24. DCCT Research Group 1993 The effect of intensive treatment of diabetes on the development and progression of long term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986[Abstract/Free Full Text]
  25. DCCT Research Group 1995 The effect of intensive treatment of diabetes therapy on the development and progression of neuropathy. Ann Intern Med 122:561–568[Abstract/Free Full Text]
  26. Semenkovich CF, Wims M, Noe L, Etienne J, Chan L 1989 Insulin regulation of lipoprotein lipase activity in 3T3-L1 adipocytes is mediated at posttranscriptional and posttranslational levels. J Biol Chem 264:9030–9038[Abstract/Free Full Text]
  27. Simsolo RB, Ong JM, Saffari B, Kern PA 1992 Effect of improved diabetes control on the expression of lipoprotein lipase in human adipose tissue. J Lipid Res 33:89–95[Abstract]
  28. Raynolds MV, Awald PD, Gordon DF, Gutierrez-Hartmann A, Rule DC, Wood WM, Eckel RH 1990 Lipoprotein lipase gene expression in rat adipocytes is regulated by isoproterenol and insulin through different mechanisms. Mol Endocrinol 4:1416–1422[Abstract]
  29. Ben-Zeev O, Doolittle MH, Singh N, Chang CH, Schotz MC 1990 Synthesis and regulation of lipoprotein lipase in the hippocampus. J Lipid Res 31:1307–1313[Abstract]
  30. Garbay B, Heape AM, Sargueil F, Cassagne C 2000 Myelin synthesis in the peripheral nervous system. Prog Neurobiol 61:267–304[CrossRef][Medline]
  31. Langner CA, Birkenmeier EH, Ben-Zeev O, Schotz MC, Sweet HO, Davisson MT, Gordon JI 1989 The fatty liver dystrophy (fld) mutation. A new mutant mouse with a developmental abnormality in triglyceride metabolism and associated tissue-specific defects in lipoprotein lipase and hepatic lipase activities. J Biol Chem 264:7994–8003[Abstract/Free Full Text]
  32. Langner CA, Birkenmeier EH, Roth KA, Bronson RT, Gordon JI 1991 Characterization of the peripheral neuropathy in neonatal and adult mice that are homozygous for the fatty liver dystrophy (fld) mutation. J Biol Chem 266:11955–11964[Abstract/Free Full Text]
  33. Heape A, Juguelin H, Fabre M, Boiron F, Garbay B, Fournier M, Bonnet J, Cassagne C 1986 Correlation between the morphology and the lipid and protein compositions in the peripheral nervous system of individual 8-d-old normal and trembler mice. Dev Brain Res 25:173–180[CrossRef]
  34. Jones BR, Johnstone AC, Cahill JI, Hancock WS 1986 Peripheral neuropathy in cats with inherited primary hyperchylomicronaemia. Vet Rec 119:268–272[Abstract]
  35. Kuo PT, Bassett DR, Di George AM, Carpenter GG 1965 Lipolytic activity of post-heparin plasma in hyperlipemia and hypolipemia. Circ Res 16:221[Abstract/Free Full Text]
  36. Barnard G, Fosbrooke AS, Lloyd JK 1970 Neutral lipids of plasma and adipose tissue in abetalipoproteinemia. Clin Chim Acta 28:417–422[CrossRef][Medline]
  37. Wichman A, Buchthal F, Pezeshkpour GH, Gregg RE 1985 Peripheral neuropathy in abetalipoproteinemia. Neurology 35:1279–1289[Abstract/Free Full Text]
  38. Muller DP, Lloyd JK, Wolff OH 1983 Vitamin E and neurological function: abetalipoproteinaemia and other disorders of fat absorption. Ciba Found Symp 101:106–121[Medline]
  39. Hegele RA, Angel A 1985 Arrest of neuropathy and myopathy in abetalipoproteinemia with high-dose vitamin E therapy. Can Med Assoc J 132:41–44[Abstract]
  40. Evstigneeva RP, Volkov IM, Chudinova VV 1998 Vitamin E as a universal antioxidant and stabilizer of biological membranes. Memb Cell Biol 12:151–172
  41. van Dam PS, Bravenboer B, van Asbeck BS, Marx JJ, Gispen WH 1999 High rat food vitamin E content improves nerve function in streptozotocin-diabetic rats. Eur J Pharmacol 376:217–222[CrossRef][Medline]
  42. Al Moutaery K, Arshaduddin M, Tariq M, Al Deeb S 1998 Functional recovery and vitamin E level following sciatic nerve crush injury in normal and diabetic rats. Intern J Neurosci 96:245–254[Medline]
  43. Melia AT, Koss-Twardy SG, Zhi J 1996 The effect of orlistat, an inhibitor of dietary fat absorption, on the absorption of vitamins A and E in healthy volunteers. J Clin Pharmacol 36:647–653[Abstract]
  44. Traber MG, Olivecrona T, Kayden HJ 1985 Bovine milk lipoprotein lipase transfers tocopherol to human fibroblasts during triglyceride hydrolysis in vitro. J Clin Invest 75:1729–1734
  45. Chistyakov DA, Savost’anov KV, Zotova EV, Nosikov VV 2001 Polymorphisms in the Mn-SOD and EC-SOD genes and their relationship to diabetic neuropathy in type 1 diabetes mellitus. BioMed Central Med Genet 2:4
  46. Cameron NE, Cotter MA, Hohman TC 1996 Interactions between essential fatty acid, prostanoid, polyol pathway and nitric oxide mechanisms in the neurovascular deficit of diabetic rats. Diabetologia 39:172–182[CrossRef][Medline]
  47. Greene DA, Stevens MJ, Obrosova I, Feldman EL 1999 Glucose-induced oxidative stress and programmed cell death in diabetic neuropathy. Eur J Pharmacol 375:217–223[CrossRef][Medline]



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M. H.G. Verheijen, R. Chrast, P. Burrola, and G. Lemke
Local regulation of fat metabolism in peripheral nerves
Genes & Dev., October 1, 2003; 17(19): 2450 - 2464.
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