- Email: [email protected]
New Directions in Diabetic Neuropathy
ARTICLE IN PRESS
New Directions in Diabetic Neuropathy: Evolution or Extinction? P. Fernyhough*,†,1, N.A. Calcutt{ *University of Manitoba, Winnipeg, MB, Canada † St. Boniface Hospital Research Centre, Winnipeg, MB, Canada { University of California, San Diego, La Jolla, CA, United States 1 Corresponding author: e-mail address: [email protected]
Contents 1. NCV as an Endpoint in Animal Models 2. Treatment Paradigms 3. Insanity: Doing the Same Thing Over and Over Again and Expecting a Different Result References
229 230 231 232
The earlier chapters “Neuropathy in the DCCT/EDIC” by Pop-Busui and “The Perfect Clinical Trial” by Bril explained the value of long clinical trials (5 or more years) to enable any therapeutic effect against progressive diabetic neuropathy to be detected. These calculations were based primarily on findings from the Diabetes Control and Complications Trial (DCCT), where intensive insulin therapy significantly protected nerve conduction velocity (NCV) in type 1 diabetic patients (DCCT, 1993, 2002). Because of the slow degradation of NCV at a rate that has historically been of approximately 0.5–1.0 m/s per annum, a trial of this duration was required to see separation between untreated and treated groups given the study group sizes and data variability. NCV clearly provides an objective measure that gives information about the current status of large myelinated nerve fiber dysfunction and is predictive of its progression. Thus, it is a strongly validated measure of large fiber neuropathy that can detect effective therapeutic intervention.
International Review of Neurobiology ISSN 0074-7742 http://dx.doi.org/10.1016/bs.irn.2016.03.009
#
2016 Elsevier Inc. All rights reserved.
229
ARTICLE IN PRESS 230
P. Fernyhough and N.A. Calcutt
1. NCV AS AN ENDPOINT IN ANIMAL MODELS Drugs entered into clinical trial against diabetic neuropathy have, to date, been selected primarily based upon their ability to prevent NCV slowing in rodent models of diabetes. A potential problem with this approach is the applicability of such preclinical efficacy studies to the human setting. The NCV deficit in animal models usually develops within the first month of onset of type 1 diabetes (Eliasson, 1964; Greene, De Jesus, & Winegrad, 1975). The acute disruption of metabolism causes rapid changes in endoneurial blood flow and other parameters that negatively impact nerve conduction such as Schwann cell function, nodal function, and axonal function (Hounsom & Tomlinson, 1997; Sima, 2004; Yagihashi, Yamagishi, & Wada, 2007). These acute alterations in cell biology and function are preventable and rapidly reversible by many interventions and occur months before any structural deterioration of large myelinated nerve fibers is detectable. It remains to be unequivocally proven that these early deficits in nerve function are causal factors in subsequent structural deterioration of large myelinated nerve fibers. The other proboscidean in this particular parlour is that structural deterioration of large nerve fibers is a very subtle affair in diabetic rodents. In STZ-diabetic rats, where the majority of preclinical drug studies have been performed, there is minimal overt degeneration of large myelinated nerve fibers, no demyelination, and little axonal pathology (Kalichman, Dines, Bobik, & Mizisin, 1998; Zochodne, Verge, Cheng, Sun, & Johnston, 2001). The only established and widely reproduced sign of a degenerative process is impaired maturation of axonal diameter and later axonal dwindling (Jakobsen, 1976a, 1976b). As discussed earlier in this volume, alternative models that develop a large-fiber neuropathology that reflects the human disease, such as cats, are available but have not yet been widely used (Mizisin et al., 2007; Mizisin, Shelton, Burgers, Powell, & Cuddon, 2002). At present, there is little evidence to suggest that positive effects on NCV deficits in animal models of diabetic neuropathy provide any true mechanistic insight into the degenerative process occurring in human diabetic neuropathy or have predictive value for efficacy when translated to clinical use. It may well be that the preclinical pipeline that has fed clinical trials has always been broken, or at least is not correctly aligned.
2. TREATMENT PARADIGMS The majority of preclinical studies have used a prevention paradigm. Drugs are applied at the beginning of the study and forestall development
ARTICLE IN PRESS New Directions in Diabetic Neuropathy
231
of deficits in NCV. In some longer-term studies this approach has also prevented onset of reduced axonal caliber of large myelinated fibers (Calcutt et al., 2003, 1999; Kato, Mizuno, Makino, Suzuki, & Yagihashi, 2000). However, the ability of an intervention to correct established structural deterioration of large myelinated fibers has rarely, if ever, been evaluated. It is therefore not surprising that drugs have shown minimal effects in phase 2 and phase 3 clinical trials with patients exhibiting established neuropathy that is likely accompanied by large-fiber degeneration and loss. Indeed it is plausible that the statistically significant, but sadly unimpressive, 1.0–1.5 m/s improvements in NCV reported in recent well-designed and executed clinical trials (Bril, Hirose, Tomioka, & Buchanan, 2009; Wahren, Foyt, Daniels, & Arezzo, 2016) represent the maximal effect that can be achieved against large-fiber dysfunction when the bulk of the NCV deficit in humans may reflect established structural pathology that is unresponsive to the intervention. To date, the drugs under investigation have not demonstrated efficacy against pertinent indices of neuropathy in appropriate animal models.
3. INSANITY: DOING THE SAME THING OVER AND OVER AGAIN AND EXPECTING A DIFFERENT RESULT After 30+ years of failed clinical trials, we owe it to those with diabetic neuropathy, and those likely to face it in the future, to review current approaches to developing therapies for diabetic neuropathy. Fortunately, we may not have to completely reinvent the wheel, just adjust our approaches, biases, and inertia. The measurement of NCV is a valid and useful endpoint in clinical trials for diabetic neuropathy. However, it need not be the central component upon which any decision on success or failure is made. Indeed, the perceived failure of a recent clinical trial of C-peptide that could not separate improvement of NCV in treated subjects vs those treated with placebo but did report statistically significant improvement of vibration perception (Wahren et al., 2016) highlights the absurdity of focusing on NCV as the dominant biomarker for neuropathy while ignoring the patient. As the authors of the above study noted, measuring large-fiber NCV may not even reflect other more relevant aspects of large-fiber sensory function. The chapters “Alternative Quantitative Tools in the Assessment of Diabetic Peripheral and Autonomic Neuropathy” by Vinik and “Wherefore Art Thou O Treatment for Diabetic Neuropathy?” by Malik describe interesting and, for us, compelling arguments for using measures of small-fiber neuropathy, both sensory and autonomic, that allow us to reassess our model
ARTICLE IN PRESS 232
P. Fernyhough and N.A. Calcutt
of the preclinical drug screen as a precursor to clinical trials. Perhaps the most pertinent development in recent years is that studies in rodent models of diabetes are now using an array of small-fiber endpoints that replicate the clinical condition to test ideas on etiology and screen new therapies (Beiswenger, Calcutt, & Mizisin, 2008; Christianson, Riekhof, & Wright, 2003; Christianson, Ryals, Johnson, Dobrowsky, & Wright, 2007; Davidson, Coppey, Holmes, & Yorek, 2012a, 2012b). Loss of epidermal fibers, loss of sweat gland innervation, loss of thermal (hot and cold) sensation, and loss of corneal nerve fiber density all occur in both diabetic animals and humans (Arezzo, Schaumburg, & Laudadio, 1986; Breiner, Lovblom, Perkins, & Bril, 2014; Hossain, Sachdev, & Malik, 2005; Kennedy, Wendelschafer-Crabb, & Johnson, 1996; Liu et al., 2015; Malik et al., 2003; Zinman, Bril, & Perkins, 2004). Other advantages of working with small-fiber endpoints arise from reports that onset of structural change can be detected early in the course of disease in both diabetic animals and humans (Azmi et al., 2015; Christianson et al., 2003, 2007; Mehra et al., 2007; Petropoulos et al., 2015; Quattrini et al., 2007; Smith, Ramachandran, Tripp, & Singleton, 2001). Corneal nerve fiber loss, which can be detected by confocal microscopy, can be viewed noninvasively so as to allow frequent iterative assessment before and after therapeutic interventions in diabetic rodents and humans (Chen et al., 2013; Tavakoli et al., 2013). It should also be remembered that the aspects of diabetic neuropathy that most trouble patients reflect sensory and autonomic dysfunction. Once fully validated, the introduction of measures of small-fiber nerve pathology and dysfunction as primary goals and endpoints in clinical trials of treatments for diabetic neuropathy may allow shorter, less costly, trials that have better chances of gaining regulatory approval and improving the lives of patients.
REFERENCES Arezzo, J. C., Schaumburg, H. H., & Laudadio, C. (1986). Thermal sensitivity tester. Device for quantitative assessment of thermal sense in diabetic neuropathy. Diabetes, 35, 590–592. Azmi, S., Ferdousi, M., Petropoulos, I. N., Ponirakis, G., Alam, U., Fadavi, H., et al. (2015). Corneal confocal microscopy identifies small-fiber neuropathy in subjects with impaired glucose tolerance who develop type 2 diabetes. Diabetes Care, 38, 1502–1508. Beiswenger, K. K., Calcutt, N. A., & Mizisin, A. P. (2008). Dissociation of thermal hypoalgesia and epidermal denervation in streptozotocin-diabetic mice. Neuroscience Letters, 442, 267–272. Breiner, A., Lovblom, L. E., Perkins, B. A., & Bril, V. (2014). Does the prevailing hypothesis that small-fiber dysfunction precedes large-fiber dysfunction apply to type 1 diabetic patients? Diabetes Care, 37, 1418–1424.
ARTICLE IN PRESS New Directions in Diabetic Neuropathy
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Bril, V., Hirose, T., Tomioka, S., & Buchanan, R. (2009). Ranirestat for the management of diabetic sensorimotor polyneuropathy. Diabetes Care, 32, 1256–1260. Calcutt, N. A., Allendoerfer, K. L., Mizisin, A. P., Middlemas, A., Freshwater, J. D., Burgers, M., et al. (2003). Therapeutic efficacy of sonic hedgehog protein in experimental diabetic neuropathy. The Journal of Clinical Investigation, 111, 507–514. Calcutt, N. A., Campana, W. M., Eskeland, N. L., Mohiuddin, L., Dines, K. C., Mizisin, A. P., et al. (1999). Prosaposin gene expression and the efficacy of a prosaposinderived peptide in preventing structural and functional disorders of peripheral nerve in diabetic rats. Journal of Neuropathology and Experimental Neurology, 58, 628–636. Chen, D. K., Frizzi, K. E., Guernsey, L. S., Ladt, K., Mizisin, A. P., & Calcutt, N. A. (2013). Repeated monitoring of corneal nerves by confocal microscopy as an index of peripheral neuropathy in type-1 diabetic rodents and the effects of topical insulin. Journal of the Peripheral Nervous System, 18, 306–315. Christianson, J. A., Riekhof, J. T., & Wright, D. E. (2003). Restorative effects of neurotrophin treatment on diabetes-induced cutaneous axon loss in mice. Experimental Neurology, 179, 188–199. Christianson, J. A., Ryals, J. M., Johnson, M. S., Dobrowsky, R. T., & Wright, D. E. (2007). Neurotrophic modulation of myelinated cutaneous innervation and mechanical sensory loss in diabetic mice. Neuroscience, 145, 303–313. Davidson, E. P., Coppey, L. J., Holmes, A., & Yorek, M. A. (2012a). Changes in corneal innervation and sensitivity and acetylcholine-mediated vascular relaxation of the posterior ciliary artery in a type 2 diabetic rat. Investigative Ophthalmology & Visual Science, 53, 1182–1187. Davidson, E. P., Coppey, L. J., & Yorek, M. A. (2012b). Early loss of innervation of cornea epithelium in streptozotocin-induced type 1 diabetic rats: Improvement with ilepatril treatment. Investigative Ophthalmology & Visual Science, 53, 8067–8074. DCCT. (1993). The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. The New England Journal of Medicine, 329, 977–986. DCCT. (2002). Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA, 287, 2563–2569. Eliasson, S. G. (1964). Nerve conduction changes in experimental diabetes. The Journal of Clinical Investigation, 43, 2353–2358. Greene, D. A., De Jesus, P. V., Jr., & Winegrad, A. I. (1975). Effects of insulin and dietary myoinositol on impaired peripheral motor nerve conduction velocity in acute streptozotocin diabetes. The Journal of Clinical Investigation, 55, 1326–1336. Hossain, P., Sachdev, A., & Malik, R. A. (2005). Early detection of diabetic peripheral neuropathy with corneal confocal microscopy. Lancet, 366, 1340–1343. Hounsom, L., & Tomlinson, D. R. (1997). Does neuropathy develop in animal models? Clinical Neuroscience, 4, 380–389. Jakobsen, J. (1976a). Axonal dwindling in early experimental diabetes. I. A study of cross sectioned nerves. Diabetologia, 12, 539–546. Jakobsen, J. (1976b). Axonal dwindling in early experimental diabetes. II. A study of isolated nerve fibres. Diabetologia, 12, 547–553. Kalichman, M. W., Dines, K. C., Bobik, M., & Mizisin, A. P. (1998). Nerve conduction velocity, laser Doppler flow, and axonal caliber in galactose and streptozotocin diabetes. Brain Research, 810, 130–137. Kato, N., Mizuno, K., Makino, M., Suzuki, T., & Yagihashi, S. (2000). Effects of 15-month aldose reductase inhibition with fidarestat on the experimental diabetic neuropathy in rats. Diabetes Research and Clinical Practice, 50, 77–85. Kennedy, W. R., Wendelschafer-Crabb, G., & Johnson, T. (1996). Quantitation of epidermal nerves in diabetic neuropathy. Neurology, 47, 1042–1048.
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Liu, Y., Billiet, J., Ebenezer, G. J., Pan, B., Hauer, P., Wei, J., et al. (2015). Factors influencing sweat gland innervation in diabetes. Neurology, 84, 1652–1659. Malik, R. A., Kallinikos, P., Abbott, C. A., van Schie, C. H., Morgan, P., Efron, N., et al. (2003). Corneal confocal microscopy: A non-invasive surrogate of nerve fibre damage and repair in diabetic patients. Diabetologia, 46, 683–688. Mehra, S., Tavakoli, M., Kallinikos, P. A., Efron, N., Boulton, A. J., Augustine, T., et al. (2007). Corneal confocal microscopy detects early nerve regeneration after pancreas transplantation in patients with type 1 diabetes. Diabetes Care, 30, 2608–2612. Mizisin, A. P., Nelson, R. W., Sturges, B. K., Vernau, K. M., Lecouteur, R. A., Williams, D. C., et al. (2007). Comparable myelinated nerve pathology in feline and human diabetes mellitus. Acta Neuropathologica, 113, 431–442. Mizisin, A. P., Shelton, G. D., Burgers, M. L., Powell, H. C., & Cuddon, P. A. (2002). Neurological complications associated with spontaneously occurring feline diabetes mellitus. Journal of Neuropathology and Experimental Neurology, 61, 872–884. Petropoulos, I. N., Green, P., Chan, A. W., Alam, U., Fadavi, H., Marshall, A., et al. (2015). Corneal confocal microscopy detects neuropathy in patients with type 1 diabetes without retinopathy or microalbuminuria. PLoS One, 10, e0123517. Quattrini, C., Tavakoli, M., Jeziorska, M., Kallinikos, P., Tesfaye, S., Finnigan, J., et al. (2007). Surrogate markers of small fiber damage in human diabetic neuropathy. Diabetes, 56, 2148–2154. Sima, A. A. (2004). Diabetic neuropathy in type 1 and type 2 diabetes and the effects of C-peptide. Journal of the Neurological Sciences, 220, 133–136. Smith, A. G., Ramachandran, P., Tripp, S., & Singleton, J. R. (2001). Epidermal nerve innervation in impaired glucose tolerance and diabetes-associated neuropathy. Neurology, 57, 1701–1704. Tavakoli, M., Mitu-Pretorian, M., Petropoulos, I. N., Fadavi, H., Asghar, O., Alam, U., et al. (2013). Corneal confocal microscopy detects early nerve regeneration in diabetic neuropathy after simultaneous pancreas and kidney transplantation. Diabetes, 62, 254–260. Wahren, J., Foyt, H., Daniels, M., & Arezzo, J. C. (2016). Long-acting C-peptide and neuropathy in type 1 diabetes: A 12-month clinical trial. Diabetes Care, 39, 596–602. Yagihashi, S., Yamagishi, S., & Wada, R. (2007). Pathology and pathogenetic mechanisms of diabetic neuropathy: Correlation with clinical signs and symptoms. Diabetes Research and Clinical Practice, 77(Suppl. 1), S184–S189. Zinman, L. H., Bril, V., & Perkins, B. A. (2004). Cooling detection thresholds in the assessment of diabetic sensory polyneuropathy: Comparison of CASE IV and Medoc instruments. Diabetes Care, 27, 1674–1679. Zochodne, D. W., Verge, V. M., Cheng, C., Sun, H., & Johnston, J. (2001). Does diabetes target ganglion neurones? Progressive sensory neurone involvement in long-term experimental diabetes. Brain, 124, 2319–2334.
New Directions in Diabetic Neuropathy: Evolution or Extinction? P. Fernyhough*,†,1, N.A. Calcutt{ *University of Manitoba, Winnipeg, MB, Canada † St. Boniface Hospital Research Centre, Winnipeg, MB, Canada { University of California, San Diego, La Jolla, CA, United States 1 Corresponding author: e-mail address: [email protected]
Contents 1. NCV as an Endpoint in Animal Models 2. Treatment Paradigms 3. Insanity: Doing the Same Thing Over and Over Again and Expecting a Different Result References
229 230 231 232
The earlier chapters “Neuropathy in the DCCT/EDIC” by Pop-Busui and “The Perfect Clinical Trial” by Bril explained the value of long clinical trials (5 or more years) to enable any therapeutic effect against progressive diabetic neuropathy to be detected. These calculations were based primarily on findings from the Diabetes Control and Complications Trial (DCCT), where intensive insulin therapy significantly protected nerve conduction velocity (NCV) in type 1 diabetic patients (DCCT, 1993, 2002). Because of the slow degradation of NCV at a rate that has historically been of approximately 0.5–1.0 m/s per annum, a trial of this duration was required to see separation between untreated and treated groups given the study group sizes and data variability. NCV clearly provides an objective measure that gives information about the current status of large myelinated nerve fiber dysfunction and is predictive of its progression. Thus, it is a strongly validated measure of large fiber neuropathy that can detect effective therapeutic intervention.
International Review of Neurobiology ISSN 0074-7742 http://dx.doi.org/10.1016/bs.irn.2016.03.009
#
2016 Elsevier Inc. All rights reserved.
229
ARTICLE IN PRESS 230
P. Fernyhough and N.A. Calcutt
1. NCV AS AN ENDPOINT IN ANIMAL MODELS Drugs entered into clinical trial against diabetic neuropathy have, to date, been selected primarily based upon their ability to prevent NCV slowing in rodent models of diabetes. A potential problem with this approach is the applicability of such preclinical efficacy studies to the human setting. The NCV deficit in animal models usually develops within the first month of onset of type 1 diabetes (Eliasson, 1964; Greene, De Jesus, & Winegrad, 1975). The acute disruption of metabolism causes rapid changes in endoneurial blood flow and other parameters that negatively impact nerve conduction such as Schwann cell function, nodal function, and axonal function (Hounsom & Tomlinson, 1997; Sima, 2004; Yagihashi, Yamagishi, & Wada, 2007). These acute alterations in cell biology and function are preventable and rapidly reversible by many interventions and occur months before any structural deterioration of large myelinated nerve fibers is detectable. It remains to be unequivocally proven that these early deficits in nerve function are causal factors in subsequent structural deterioration of large myelinated nerve fibers. The other proboscidean in this particular parlour is that structural deterioration of large nerve fibers is a very subtle affair in diabetic rodents. In STZ-diabetic rats, where the majority of preclinical drug studies have been performed, there is minimal overt degeneration of large myelinated nerve fibers, no demyelination, and little axonal pathology (Kalichman, Dines, Bobik, & Mizisin, 1998; Zochodne, Verge, Cheng, Sun, & Johnston, 2001). The only established and widely reproduced sign of a degenerative process is impaired maturation of axonal diameter and later axonal dwindling (Jakobsen, 1976a, 1976b). As discussed earlier in this volume, alternative models that develop a large-fiber neuropathology that reflects the human disease, such as cats, are available but have not yet been widely used (Mizisin et al., 2007; Mizisin, Shelton, Burgers, Powell, & Cuddon, 2002). At present, there is little evidence to suggest that positive effects on NCV deficits in animal models of diabetic neuropathy provide any true mechanistic insight into the degenerative process occurring in human diabetic neuropathy or have predictive value for efficacy when translated to clinical use. It may well be that the preclinical pipeline that has fed clinical trials has always been broken, or at least is not correctly aligned.
2. TREATMENT PARADIGMS The majority of preclinical studies have used a prevention paradigm. Drugs are applied at the beginning of the study and forestall development
ARTICLE IN PRESS New Directions in Diabetic Neuropathy
231
of deficits in NCV. In some longer-term studies this approach has also prevented onset of reduced axonal caliber of large myelinated fibers (Calcutt et al., 2003, 1999; Kato, Mizuno, Makino, Suzuki, & Yagihashi, 2000). However, the ability of an intervention to correct established structural deterioration of large myelinated fibers has rarely, if ever, been evaluated. It is therefore not surprising that drugs have shown minimal effects in phase 2 and phase 3 clinical trials with patients exhibiting established neuropathy that is likely accompanied by large-fiber degeneration and loss. Indeed it is plausible that the statistically significant, but sadly unimpressive, 1.0–1.5 m/s improvements in NCV reported in recent well-designed and executed clinical trials (Bril, Hirose, Tomioka, & Buchanan, 2009; Wahren, Foyt, Daniels, & Arezzo, 2016) represent the maximal effect that can be achieved against large-fiber dysfunction when the bulk of the NCV deficit in humans may reflect established structural pathology that is unresponsive to the intervention. To date, the drugs under investigation have not demonstrated efficacy against pertinent indices of neuropathy in appropriate animal models.
3. INSANITY: DOING THE SAME THING OVER AND OVER AGAIN AND EXPECTING A DIFFERENT RESULT After 30+ years of failed clinical trials, we owe it to those with diabetic neuropathy, and those likely to face it in the future, to review current approaches to developing therapies for diabetic neuropathy. Fortunately, we may not have to completely reinvent the wheel, just adjust our approaches, biases, and inertia. The measurement of NCV is a valid and useful endpoint in clinical trials for diabetic neuropathy. However, it need not be the central component upon which any decision on success or failure is made. Indeed, the perceived failure of a recent clinical trial of C-peptide that could not separate improvement of NCV in treated subjects vs those treated with placebo but did report statistically significant improvement of vibration perception (Wahren et al., 2016) highlights the absurdity of focusing on NCV as the dominant biomarker for neuropathy while ignoring the patient. As the authors of the above study noted, measuring large-fiber NCV may not even reflect other more relevant aspects of large-fiber sensory function. The chapters “Alternative Quantitative Tools in the Assessment of Diabetic Peripheral and Autonomic Neuropathy” by Vinik and “Wherefore Art Thou O Treatment for Diabetic Neuropathy?” by Malik describe interesting and, for us, compelling arguments for using measures of small-fiber neuropathy, both sensory and autonomic, that allow us to reassess our model
ARTICLE IN PRESS 232
P. Fernyhough and N.A. Calcutt
of the preclinical drug screen as a precursor to clinical trials. Perhaps the most pertinent development in recent years is that studies in rodent models of diabetes are now using an array of small-fiber endpoints that replicate the clinical condition to test ideas on etiology and screen new therapies (Beiswenger, Calcutt, & Mizisin, 2008; Christianson, Riekhof, & Wright, 2003; Christianson, Ryals, Johnson, Dobrowsky, & Wright, 2007; Davidson, Coppey, Holmes, & Yorek, 2012a, 2012b). Loss of epidermal fibers, loss of sweat gland innervation, loss of thermal (hot and cold) sensation, and loss of corneal nerve fiber density all occur in both diabetic animals and humans (Arezzo, Schaumburg, & Laudadio, 1986; Breiner, Lovblom, Perkins, & Bril, 2014; Hossain, Sachdev, & Malik, 2005; Kennedy, Wendelschafer-Crabb, & Johnson, 1996; Liu et al., 2015; Malik et al., 2003; Zinman, Bril, & Perkins, 2004). Other advantages of working with small-fiber endpoints arise from reports that onset of structural change can be detected early in the course of disease in both diabetic animals and humans (Azmi et al., 2015; Christianson et al., 2003, 2007; Mehra et al., 2007; Petropoulos et al., 2015; Quattrini et al., 2007; Smith, Ramachandran, Tripp, & Singleton, 2001). Corneal nerve fiber loss, which can be detected by confocal microscopy, can be viewed noninvasively so as to allow frequent iterative assessment before and after therapeutic interventions in diabetic rodents and humans (Chen et al., 2013; Tavakoli et al., 2013). It should also be remembered that the aspects of diabetic neuropathy that most trouble patients reflect sensory and autonomic dysfunction. Once fully validated, the introduction of measures of small-fiber nerve pathology and dysfunction as primary goals and endpoints in clinical trials of treatments for diabetic neuropathy may allow shorter, less costly, trials that have better chances of gaining regulatory approval and improving the lives of patients.
REFERENCES Arezzo, J. C., Schaumburg, H. H., & Laudadio, C. (1986). Thermal sensitivity tester. Device for quantitative assessment of thermal sense in diabetic neuropathy. Diabetes, 35, 590–592. Azmi, S., Ferdousi, M., Petropoulos, I. N., Ponirakis, G., Alam, U., Fadavi, H., et al. (2015). Corneal confocal microscopy identifies small-fiber neuropathy in subjects with impaired glucose tolerance who develop type 2 diabetes. Diabetes Care, 38, 1502–1508. Beiswenger, K. K., Calcutt, N. A., & Mizisin, A. P. (2008). Dissociation of thermal hypoalgesia and epidermal denervation in streptozotocin-diabetic mice. Neuroscience Letters, 442, 267–272. Breiner, A., Lovblom, L. E., Perkins, B. A., & Bril, V. (2014). Does the prevailing hypothesis that small-fiber dysfunction precedes large-fiber dysfunction apply to type 1 diabetic patients? Diabetes Care, 37, 1418–1424.
ARTICLE IN PRESS New Directions in Diabetic Neuropathy
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Bril, V., Hirose, T., Tomioka, S., & Buchanan, R. (2009). Ranirestat for the management of diabetic sensorimotor polyneuropathy. Diabetes Care, 32, 1256–1260. Calcutt, N. A., Allendoerfer, K. L., Mizisin, A. P., Middlemas, A., Freshwater, J. D., Burgers, M., et al. (2003). Therapeutic efficacy of sonic hedgehog protein in experimental diabetic neuropathy. The Journal of Clinical Investigation, 111, 507–514. Calcutt, N. A., Campana, W. M., Eskeland, N. L., Mohiuddin, L., Dines, K. C., Mizisin, A. P., et al. (1999). Prosaposin gene expression and the efficacy of a prosaposinderived peptide in preventing structural and functional disorders of peripheral nerve in diabetic rats. Journal of Neuropathology and Experimental Neurology, 58, 628–636. Chen, D. K., Frizzi, K. E., Guernsey, L. S., Ladt, K., Mizisin, A. P., & Calcutt, N. A. (2013). Repeated monitoring of corneal nerves by confocal microscopy as an index of peripheral neuropathy in type-1 diabetic rodents and the effects of topical insulin. Journal of the Peripheral Nervous System, 18, 306–315. Christianson, J. A., Riekhof, J. T., & Wright, D. E. (2003). Restorative effects of neurotrophin treatment on diabetes-induced cutaneous axon loss in mice. Experimental Neurology, 179, 188–199. Christianson, J. A., Ryals, J. M., Johnson, M. S., Dobrowsky, R. T., & Wright, D. E. (2007). Neurotrophic modulation of myelinated cutaneous innervation and mechanical sensory loss in diabetic mice. Neuroscience, 145, 303–313. Davidson, E. P., Coppey, L. J., Holmes, A., & Yorek, M. A. (2012a). Changes in corneal innervation and sensitivity and acetylcholine-mediated vascular relaxation of the posterior ciliary artery in a type 2 diabetic rat. Investigative Ophthalmology & Visual Science, 53, 1182–1187. Davidson, E. P., Coppey, L. J., & Yorek, M. A. (2012b). Early loss of innervation of cornea epithelium in streptozotocin-induced type 1 diabetic rats: Improvement with ilepatril treatment. Investigative Ophthalmology & Visual Science, 53, 8067–8074. DCCT. (1993). The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. The New England Journal of Medicine, 329, 977–986. DCCT. (2002). Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA, 287, 2563–2569. Eliasson, S. G. (1964). Nerve conduction changes in experimental diabetes. The Journal of Clinical Investigation, 43, 2353–2358. Greene, D. A., De Jesus, P. V., Jr., & Winegrad, A. I. (1975). Effects of insulin and dietary myoinositol on impaired peripheral motor nerve conduction velocity in acute streptozotocin diabetes. The Journal of Clinical Investigation, 55, 1326–1336. Hossain, P., Sachdev, A., & Malik, R. A. (2005). Early detection of diabetic peripheral neuropathy with corneal confocal microscopy. Lancet, 366, 1340–1343. Hounsom, L., & Tomlinson, D. R. (1997). Does neuropathy develop in animal models? Clinical Neuroscience, 4, 380–389. Jakobsen, J. (1976a). Axonal dwindling in early experimental diabetes. I. A study of cross sectioned nerves. Diabetologia, 12, 539–546. Jakobsen, J. (1976b). Axonal dwindling in early experimental diabetes. II. A study of isolated nerve fibres. Diabetologia, 12, 547–553. Kalichman, M. W., Dines, K. C., Bobik, M., & Mizisin, A. P. (1998). Nerve conduction velocity, laser Doppler flow, and axonal caliber in galactose and streptozotocin diabetes. Brain Research, 810, 130–137. Kato, N., Mizuno, K., Makino, M., Suzuki, T., & Yagihashi, S. (2000). Effects of 15-month aldose reductase inhibition with fidarestat on the experimental diabetic neuropathy in rats. Diabetes Research and Clinical Practice, 50, 77–85. Kennedy, W. R., Wendelschafer-Crabb, G., & Johnson, T. (1996). Quantitation of epidermal nerves in diabetic neuropathy. Neurology, 47, 1042–1048.
ARTICLE IN PRESS 234
P. Fernyhough and N.A. Calcutt
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