Progress in clinical and biological research, 1985
These findings suggest that the Y79 retinoblastoma cell may be a useful experimental system in wh... more These findings suggest that the Y79 retinoblastoma cell may be a useful experimental system in which to study certain aspects of taurine metabolism. The cells contain high concentrations of taurine when they are grown under normal conditions. This can occur in two ways. One is through synthesis of taurine from serine; the other is by taurine uptake facilitated by a high-affinity transport system. These results regarding synthesis and uptake are consistent with what has been reported for retinal preparations from other species (Lombardini 1980; Sabceda 1980; Schmidt 1980; Pourcho 1981; Adler 1983). The retinoblastoma cells did not release taurine, however, when they were depolarized. Cultured chick embryo retinal neurons also do not release taurine following depolarization (Adler 1983). Therefore, neither of these culture systems provides any evidence for a direct role of taurine release in retinal neurotransmission. The retinoblastoma cells take up relatively low concentrations of t...
Progress in clinical and biological research, 1985
These findings suggest that the Y79 retinoblastoma cell may be a useful experimental system in wh... more These findings suggest that the Y79 retinoblastoma cell may be a useful experimental system in which to study certain aspects of taurine metabolism. The cells contain high concentrations of taurine when they are grown under normal conditions. This can occur in two ways. One is through synthesis of taurine from serine; the other is by taurine uptake facilitated by a high-affinity transport system. These results regarding synthesis and uptake are consistent with what has been reported for retinal preparations from other species (Lombardini 1980; Sabceda 1980; Schmidt 1980; Pourcho 1981; Adler 1983). The retinoblastoma cells did not release taurine, however, when they were depolarized. Cultured chick embryo retinal neurons also do not release taurine following depolarization (Adler 1983). Therefore, neither of these culture systems provides any evidence for a direct role of taurine release in retinal neurotransmission. The retinoblastoma cells take up relatively low concentrations of t...
Purpose of review-This review will summarize recent findings of the effect of supplemental fatty ... more Purpose of review-This review will summarize recent findings of the effect of supplemental fatty acids, with an emphasis on omega-3 polyunsaturated fatty acids, as a treatment for diabetic peripheral neuropathy. Recent findings-Pre-clinical studies have provided evidence that treating diabetic rodents with δ linolenic acid (omega-6 18:3) and to a greater extent with eicosapentaenoic and docosahexaenoic acids (omega-3 20:5 and 22:6, respectively) improve and even reverse vascular and neural deficits. Additional studies have shown resolvins, metabolites of eicosapentaenoic and docosahexaenoic acids, can induce neurite outgrowth in neuron cultures and that treating type 1 or type 2 diabetic mice with resolvin D1 or E1 provides benefit for peripheral neuropathy similar to fish oil. Summary-Omega-3 polyunsaturated fatty acids derived from fish oil and their derivatives have anti-inflammatory properties and could provide benefit for diabetic peripheral neuropathy. However, clinical trials are needed to determine whether this statement is true.
American Journal of Physiology-regulatory Integrative and Comparative Physiology, Mar 1, 2008
Increasing afferent renal nerve activity decreases efferent renal nerve activity and increases ur... more Increasing afferent renal nerve activity decreases efferent renal nerve activity and increases urinary sodium excretion. Activation of renal pelvic mechanosensory nerves is impaired in streptozotocin (STZ)-treated rats (model of type 1 diabetes). Decreased activation of renal sensory nerves would lead to increased efferent renal nerve activity, sodium retention, and hypertension. We examined whether the reduced activation of renal sensory nerves in STZ rats was due to increased renal angiotensin activity and whether activation of the renal sensory nerves was impaired in obese Zucker diabetic fatty (ZDF) rats (model of type 2 diabetes). In an isolated renal pelvic wall preparation from rats treated with STZ for 2 wk, PGE 2 failed to increase the release of substance P, from 5 Ϯ 1 to 6 Ϯ 1 pg/min. In pelvises from sham STZ rats, PGE 2 increased substance P release from 6 Ϯ 1 to 13 Ϯ 2 pg/min. Adding losartan to the incubation bath increased PGE2-mediated release of substance P in STZ rats, from 5 Ϯ 1 to 10 Ϯ 2 pg/min, but had no effect in sham STZ rats. In pelvises from obese ZDF rats (22-46 wk old), PGE2 increased substance P release from 12.0 Ϯ 1.2 to 18.3 Ϯ 1.2 pg/min, which was less than that from lean ZDF rats (10.3 Ϯ 1.6 to 22.5 Ϯ 2.4 pg/min). Losartan had no effect on the PGE2-mediated substance P release in obese or lean ZDF rats. We conclude that the mechanisms involved in the decreased responsiveness of the renal sensory nerves in STZ rats involve activation of the renin angiotensin system in STZ but not in obese ZDF rats. kidney; prostaglandin; neuropathy; substance P RENAL MECHANOSENSORY NERVES are activated by increases in renal pelvic pressure of a magnitude commonly seen during moderate volume expansion (20). The functional responses to activation of these sensory nerves include decreases in efferent renal sympathetic nerve activity (ERSNA) leading to increases in urinary sodium excretion, a renorenal reflex response (26). Among the various mechanisms activated by increased renal pelvic pressure is induction of cyclooxygenase-2 (COX-2) leading to increased renal pelvic synthesis of PGE 2 . PGE 2 activates the cAMP-protein kinase A transduction pathway resulting in a Ca 2ϩ -dependent release of the neuropeptide substance P (16, 22) and activation of the afferent renal nerves. Activation of the renorenal reflex mechanism by increases in renal pelvic pressure associated with increased urine flow would facilitate the excretion of an increased sodium load by decreasing ERSNA. The importance of the renorenal reflexes in the long-term control of body fluid and sodium homeostasis
The study of diabetic neuropathy has relied primarily on the use of streptozotocin-treated rat an... more The study of diabetic neuropathy has relied primarily on the use of streptozotocin-treated rat and mouse models of type 1 diabetes. This chapter will review the creation and use of other rodent models that have been developed in order to investigate the contribution of factors besides insulin deficiency to the development and progression of diabetic neuropathy as it occurs in obesity, type 1 or type 2 diabetes. Diabetic peripheral neuropathy is a complex disorder with multiple mechanisms contributing to its development and progression. Even though many animal models have been developed and investigated, no single model can mimic diabetic peripheral neuropathy as it occurs in humans. Nonetheless, animal models can play an important role in improving our understanding of the etiology of diabetic peripheral neuropathy and in performing preclinical screening of potential new treatments. To date treatments found to be effective for diabetic peripheral neuropathy in rodent models have failed in clinical trials. However, with the identification of new endpoints for the early detection of diabetic peripheral neuropathy and the understanding that a successful treatment may require a combination therapeutic approach there is hope that an effective treatment will be found.
License, which permits unrestricted use, distribution, and reproduction in any medium, provided t... more License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We have demonstrated that treating diet-induced obese (DIO) mice with the vasopeptidase inhibitor ilepatril improved neural function. Vasopeptidase inhibitors block angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) activity. We propose that increased activity of ACE and NEP contributes to pathophysiology of DIO. To address this issue C57Bl/6J mice or mice deficient in NEP were fed a high-fat diet and treated with ilepatril, enalapril, ACE inhibitor, or candoxatril, NEP inhibitor, using both prevention and intervention protocols. Endpoints included glucose utilization and neural function determination. In the prevention study glucose tolerance was impaired in DIO C57Bl/6J mice and improved with ilepatril or enalapril. Sensory nerve conduction velocity, thermal nociception, and intraepidermal nerve fiber density were impaired in DIO C57...
Effect of inhibition of angiotensin converting enzyme and/or neutral endopeptidase on vascular an... more Effect of inhibition of angiotensin converting enzyme and/or neutral endopeptidase on vascular and neural complications in
The effect of physiological concentrations of ethanolamine on choline uptake and incorporation in... more The effect of physiological concentrations of ethanolamine on choline uptake and incorporation into phosphatidylcholine was investigated in human Y79 retinoblastoma cells, a multipotential, undifferentiated retinal cell line that has retained many neural characteristics. These cells have a high-affinity uptake system for choline, and the majority of the choline taken up was incorporated into phosphatidylcholine via the CDP-choline pathway. The presence of extracellular ethanolamine significantly decreased high-affinity choline uptake and, subsequently, the amount of choline incorporated into phosphatidylcholine. When 100 mumol/L ethanolamine was added, there was a decrease of about 8% in the phosphatidylcholine content. Ethanolamine had no effect on choline incorporation into phosphatidylcholine, however, once choline was taken up by the cell. The K'M and V'max for high-affinity choline uptake was increased from 0.93 to 9.74 microM and 19.60 to 79.25 pmol/min per mg protein, respectively, by the presence of 25 mumol/L ethanolamine. In contrast, 25 mumol/L choline had no effect on the kinetic parameters of high-affinity ethanolamine uptake. Therefore, the reduction in high-affinity choline transport by ethanolamine apparently is not simply due to competitive inhibition. 2,2-Dimethylethanolamine and 2-methylethanolamine both reduced choline uptake to a greater extent than ethanolamine. However, because these compounds exist at much lower concentrations than ethanolamine, they probably have little physiological influence. These results suggest that changes in ethanolamine concentration within the physiologic range can regulate the synthesis and content of phosphatidylcholine in a neural cell by influencing the uptake of choline.
Journal of Diabetes Research is delighted to announce the installation of Dr. Mark Yorek as the n... more Journal of Diabetes Research is delighted to announce the installation of Dr. Mark Yorek as the new Chief Editor for the journal. In this Editorial, Dr. Yorek discusses his research background, his ideas for the journal’s development, and his views on the direction of the field of diabetes.
Introduction. Current clinical guidelines for management of diabetic peripheral neuropathy (DPN) ... more Introduction. Current clinical guidelines for management of diabetic peripheral neuropathy (DPN) emphasize good glycemic control. However, this has limited effect on prevention of DPN in type 2 diabetic (T2D) patients. This study investigates the effect of insulin treatment on development of DPN in a rat model of T2D to assess the underlying causes leading to DPN. Methods. Twelve-week-old male Sprague-Dawley rats were allocated to a normal chow diet or a 45% kcal high-fat diet. After eight weeks, the high-fat fed animals received a mild dose of streptozotocin to induce hyperglycemia. Four weeks after diabetes induction, the diabetic animals were allocated into three treatment groups receiving either no insulin or insulin-releasing implants in a high or low dose. During the 12-week treatment period, blood glucose and body weight were monitored weekly, whereas Hargreaves’ test was performed four, eight, and 12 weeks after treatment initiation. At study termination, several blood param...
Tumour necrosis factor α (TNF-α) regulates the transport of myo-inositol in 3T3-L1 adipocytes. Tr... more Tumour necrosis factor α (TNF-α) regulates the transport of myo-inositol in 3T3-L1 adipocytes. Treating 3T3-L1 adipocytes with TNF-α decreases Na+/myo-inositol co-transporter (SMIT) mRNA levels and myo-inositol accumulation in a concentration-and time-dependent manner. TNF-α decreases the V′max for high-affinity myo-inositol transport with little change in the K′m. Studies with actinomycin D suggest that RNA synthesis is required for the TNF-α-induced effect on SMIT mRNA levels. In contrast with the effect of TNF-α, hyperosmolarity increases SMIT mRNA levels and myo-inositol accumulation in 3T3-L1 adipocytes. Hyperosmolarity increases SMIT gene expression as evidenced by the inhibition of hyperosmotic induction of SMIT mRNA levels by actinomycin D, and of myo-inositol accumulation by actinomycin D and cycloheximide. TNF-α and osmotic stress have previously been shown to activate similar signal transduction pathways in mammalian cells. In 3T3-L1 adipocytes, both TNF-α and hyperosmola...
Progress in clinical and biological research, 1985
These findings suggest that the Y79 retinoblastoma cell may be a useful experimental system in wh... more These findings suggest that the Y79 retinoblastoma cell may be a useful experimental system in which to study certain aspects of taurine metabolism. The cells contain high concentrations of taurine when they are grown under normal conditions. This can occur in two ways. One is through synthesis of taurine from serine; the other is by taurine uptake facilitated by a high-affinity transport system. These results regarding synthesis and uptake are consistent with what has been reported for retinal preparations from other species (Lombardini 1980; Sabceda 1980; Schmidt 1980; Pourcho 1981; Adler 1983). The retinoblastoma cells did not release taurine, however, when they were depolarized. Cultured chick embryo retinal neurons also do not release taurine following depolarization (Adler 1983). Therefore, neither of these culture systems provides any evidence for a direct role of taurine release in retinal neurotransmission. The retinoblastoma cells take up relatively low concentrations of t...
Progress in clinical and biological research, 1985
These findings suggest that the Y79 retinoblastoma cell may be a useful experimental system in wh... more These findings suggest that the Y79 retinoblastoma cell may be a useful experimental system in which to study certain aspects of taurine metabolism. The cells contain high concentrations of taurine when they are grown under normal conditions. This can occur in two ways. One is through synthesis of taurine from serine; the other is by taurine uptake facilitated by a high-affinity transport system. These results regarding synthesis and uptake are consistent with what has been reported for retinal preparations from other species (Lombardini 1980; Sabceda 1980; Schmidt 1980; Pourcho 1981; Adler 1983). The retinoblastoma cells did not release taurine, however, when they were depolarized. Cultured chick embryo retinal neurons also do not release taurine following depolarization (Adler 1983). Therefore, neither of these culture systems provides any evidence for a direct role of taurine release in retinal neurotransmission. The retinoblastoma cells take up relatively low concentrations of t...
Purpose of review-This review will summarize recent findings of the effect of supplemental fatty ... more Purpose of review-This review will summarize recent findings of the effect of supplemental fatty acids, with an emphasis on omega-3 polyunsaturated fatty acids, as a treatment for diabetic peripheral neuropathy. Recent findings-Pre-clinical studies have provided evidence that treating diabetic rodents with δ linolenic acid (omega-6 18:3) and to a greater extent with eicosapentaenoic and docosahexaenoic acids (omega-3 20:5 and 22:6, respectively) improve and even reverse vascular and neural deficits. Additional studies have shown resolvins, metabolites of eicosapentaenoic and docosahexaenoic acids, can induce neurite outgrowth in neuron cultures and that treating type 1 or type 2 diabetic mice with resolvin D1 or E1 provides benefit for peripheral neuropathy similar to fish oil. Summary-Omega-3 polyunsaturated fatty acids derived from fish oil and their derivatives have anti-inflammatory properties and could provide benefit for diabetic peripheral neuropathy. However, clinical trials are needed to determine whether this statement is true.
American Journal of Physiology-regulatory Integrative and Comparative Physiology, Mar 1, 2008
Increasing afferent renal nerve activity decreases efferent renal nerve activity and increases ur... more Increasing afferent renal nerve activity decreases efferent renal nerve activity and increases urinary sodium excretion. Activation of renal pelvic mechanosensory nerves is impaired in streptozotocin (STZ)-treated rats (model of type 1 diabetes). Decreased activation of renal sensory nerves would lead to increased efferent renal nerve activity, sodium retention, and hypertension. We examined whether the reduced activation of renal sensory nerves in STZ rats was due to increased renal angiotensin activity and whether activation of the renal sensory nerves was impaired in obese Zucker diabetic fatty (ZDF) rats (model of type 2 diabetes). In an isolated renal pelvic wall preparation from rats treated with STZ for 2 wk, PGE 2 failed to increase the release of substance P, from 5 Ϯ 1 to 6 Ϯ 1 pg/min. In pelvises from sham STZ rats, PGE 2 increased substance P release from 6 Ϯ 1 to 13 Ϯ 2 pg/min. Adding losartan to the incubation bath increased PGE2-mediated release of substance P in STZ rats, from 5 Ϯ 1 to 10 Ϯ 2 pg/min, but had no effect in sham STZ rats. In pelvises from obese ZDF rats (22-46 wk old), PGE2 increased substance P release from 12.0 Ϯ 1.2 to 18.3 Ϯ 1.2 pg/min, which was less than that from lean ZDF rats (10.3 Ϯ 1.6 to 22.5 Ϯ 2.4 pg/min). Losartan had no effect on the PGE2-mediated substance P release in obese or lean ZDF rats. We conclude that the mechanisms involved in the decreased responsiveness of the renal sensory nerves in STZ rats involve activation of the renin angiotensin system in STZ but not in obese ZDF rats. kidney; prostaglandin; neuropathy; substance P RENAL MECHANOSENSORY NERVES are activated by increases in renal pelvic pressure of a magnitude commonly seen during moderate volume expansion (20). The functional responses to activation of these sensory nerves include decreases in efferent renal sympathetic nerve activity (ERSNA) leading to increases in urinary sodium excretion, a renorenal reflex response (26). Among the various mechanisms activated by increased renal pelvic pressure is induction of cyclooxygenase-2 (COX-2) leading to increased renal pelvic synthesis of PGE 2 . PGE 2 activates the cAMP-protein kinase A transduction pathway resulting in a Ca 2ϩ -dependent release of the neuropeptide substance P (16, 22) and activation of the afferent renal nerves. Activation of the renorenal reflex mechanism by increases in renal pelvic pressure associated with increased urine flow would facilitate the excretion of an increased sodium load by decreasing ERSNA. The importance of the renorenal reflexes in the long-term control of body fluid and sodium homeostasis
The study of diabetic neuropathy has relied primarily on the use of streptozotocin-treated rat an... more The study of diabetic neuropathy has relied primarily on the use of streptozotocin-treated rat and mouse models of type 1 diabetes. This chapter will review the creation and use of other rodent models that have been developed in order to investigate the contribution of factors besides insulin deficiency to the development and progression of diabetic neuropathy as it occurs in obesity, type 1 or type 2 diabetes. Diabetic peripheral neuropathy is a complex disorder with multiple mechanisms contributing to its development and progression. Even though many animal models have been developed and investigated, no single model can mimic diabetic peripheral neuropathy as it occurs in humans. Nonetheless, animal models can play an important role in improving our understanding of the etiology of diabetic peripheral neuropathy and in performing preclinical screening of potential new treatments. To date treatments found to be effective for diabetic peripheral neuropathy in rodent models have failed in clinical trials. However, with the identification of new endpoints for the early detection of diabetic peripheral neuropathy and the understanding that a successful treatment may require a combination therapeutic approach there is hope that an effective treatment will be found.
License, which permits unrestricted use, distribution, and reproduction in any medium, provided t... more License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We have demonstrated that treating diet-induced obese (DIO) mice with the vasopeptidase inhibitor ilepatril improved neural function. Vasopeptidase inhibitors block angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) activity. We propose that increased activity of ACE and NEP contributes to pathophysiology of DIO. To address this issue C57Bl/6J mice or mice deficient in NEP were fed a high-fat diet and treated with ilepatril, enalapril, ACE inhibitor, or candoxatril, NEP inhibitor, using both prevention and intervention protocols. Endpoints included glucose utilization and neural function determination. In the prevention study glucose tolerance was impaired in DIO C57Bl/6J mice and improved with ilepatril or enalapril. Sensory nerve conduction velocity, thermal nociception, and intraepidermal nerve fiber density were impaired in DIO C57...
Effect of inhibition of angiotensin converting enzyme and/or neutral endopeptidase on vascular an... more Effect of inhibition of angiotensin converting enzyme and/or neutral endopeptidase on vascular and neural complications in
The effect of physiological concentrations of ethanolamine on choline uptake and incorporation in... more The effect of physiological concentrations of ethanolamine on choline uptake and incorporation into phosphatidylcholine was investigated in human Y79 retinoblastoma cells, a multipotential, undifferentiated retinal cell line that has retained many neural characteristics. These cells have a high-affinity uptake system for choline, and the majority of the choline taken up was incorporated into phosphatidylcholine via the CDP-choline pathway. The presence of extracellular ethanolamine significantly decreased high-affinity choline uptake and, subsequently, the amount of choline incorporated into phosphatidylcholine. When 100 mumol/L ethanolamine was added, there was a decrease of about 8% in the phosphatidylcholine content. Ethanolamine had no effect on choline incorporation into phosphatidylcholine, however, once choline was taken up by the cell. The K'M and V'max for high-affinity choline uptake was increased from 0.93 to 9.74 microM and 19.60 to 79.25 pmol/min per mg protein, respectively, by the presence of 25 mumol/L ethanolamine. In contrast, 25 mumol/L choline had no effect on the kinetic parameters of high-affinity ethanolamine uptake. Therefore, the reduction in high-affinity choline transport by ethanolamine apparently is not simply due to competitive inhibition. 2,2-Dimethylethanolamine and 2-methylethanolamine both reduced choline uptake to a greater extent than ethanolamine. However, because these compounds exist at much lower concentrations than ethanolamine, they probably have little physiological influence. These results suggest that changes in ethanolamine concentration within the physiologic range can regulate the synthesis and content of phosphatidylcholine in a neural cell by influencing the uptake of choline.
Journal of Diabetes Research is delighted to announce the installation of Dr. Mark Yorek as the n... more Journal of Diabetes Research is delighted to announce the installation of Dr. Mark Yorek as the new Chief Editor for the journal. In this Editorial, Dr. Yorek discusses his research background, his ideas for the journal’s development, and his views on the direction of the field of diabetes.
Introduction. Current clinical guidelines for management of diabetic peripheral neuropathy (DPN) ... more Introduction. Current clinical guidelines for management of diabetic peripheral neuropathy (DPN) emphasize good glycemic control. However, this has limited effect on prevention of DPN in type 2 diabetic (T2D) patients. This study investigates the effect of insulin treatment on development of DPN in a rat model of T2D to assess the underlying causes leading to DPN. Methods. Twelve-week-old male Sprague-Dawley rats were allocated to a normal chow diet or a 45% kcal high-fat diet. After eight weeks, the high-fat fed animals received a mild dose of streptozotocin to induce hyperglycemia. Four weeks after diabetes induction, the diabetic animals were allocated into three treatment groups receiving either no insulin or insulin-releasing implants in a high or low dose. During the 12-week treatment period, blood glucose and body weight were monitored weekly, whereas Hargreaves’ test was performed four, eight, and 12 weeks after treatment initiation. At study termination, several blood param...
Tumour necrosis factor α (TNF-α) regulates the transport of myo-inositol in 3T3-L1 adipocytes. Tr... more Tumour necrosis factor α (TNF-α) regulates the transport of myo-inositol in 3T3-L1 adipocytes. Treating 3T3-L1 adipocytes with TNF-α decreases Na+/myo-inositol co-transporter (SMIT) mRNA levels and myo-inositol accumulation in a concentration-and time-dependent manner. TNF-α decreases the V′max for high-affinity myo-inositol transport with little change in the K′m. Studies with actinomycin D suggest that RNA synthesis is required for the TNF-α-induced effect on SMIT mRNA levels. In contrast with the effect of TNF-α, hyperosmolarity increases SMIT mRNA levels and myo-inositol accumulation in 3T3-L1 adipocytes. Hyperosmolarity increases SMIT gene expression as evidenced by the inhibition of hyperosmotic induction of SMIT mRNA levels by actinomycin D, and of myo-inositol accumulation by actinomycin D and cycloheximide. TNF-α and osmotic stress have previously been shown to activate similar signal transduction pathways in mammalian cells. In 3T3-L1 adipocytes, both TNF-α and hyperosmola...
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