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Mini review

Diabetes and the plasticity of sensory neurons Douglas W. Zochodne ∗ Division of Neurology, Department of Medicine, 2E3.26 Walter C Mackenzie, Health Sciences Centre, Edmonton, Alberta T6G 2B7, Canada

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Article history: Received 15 September 2014 Received in revised form 11 November 2014 Accepted 13 November 2014 Available online xxx Keywords: Diabetes mellitus Diabetic polyneuropathy Sensory neurons Insulin signaling Regeneration PTEN

a b s t r a c t Diabetes mellitus targets sensory neurons during the development of peripheral neuropathy. While polyneuropathy is often routinely considered as another ‘microvascular’ complication of diabetes mellitus, this concept may no longer address the complexities and unique qualities of direct neuronal involvement. The list of altered molecules and pathways in diabetic neurons continues to grow and includes those related to structure, neuronal ‘stress’, and protection. A role for abnormal direct neuronal insulin signaling has emerged as an important contributing factor in neurodegeneration. Finally, important molecular players that influence neuronal and axon growth, such as PTEN (phosphatase and tensin homolog deleted on chromosome 10) are considered. A better mechanistic understanding of the pathogenesis of diabetic polyneuropathy may foster targeted therapies that reverse a long history of therapeutic failures. © 2014 Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5.

Ischemia, microangiopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alterations in the molecular phenotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Insulin signals neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Regeneration and plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

In this review, I address selective aspects of sensory neurodegeneration in diabetes beginning with assumptions about a microvascular etiology, the molecular footprint of diabetic sensory neurons, the role for direct neuronal insulin signaling, and new ideas governing peripheral sensory neuron plasticity. 1. Ischemia, microangiopathy Polyneuropathy continues to be widely classified as a ‘microvascular’ complication of diabetes mellitus, alongside nephropathy, and retinopathy. This entrenched viewpoint, difficult to dispel, is challenged by new evidence. The complex differences among differentiated endorgans of peripheral nerve, kidney, and retina support unique mechanisms of diabetic targeting. Nerve, kidney,

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and retina are tissues that are variably vulnerable to ischemia and hypoxia. Others with comparable or greater vulnerability are only involved later in the disease, and to a lesser extent. Evidence from human or animal studies in diabetes to support an exclusive microvascular cause of polyneuropathy is not uniform. Polyneuropathy can develop in children and after relatively short durations of diabetes, clinical features that argue against a chronic form of generalized ischemia. Although studies are limited, reductions in indicator mean transit times and hypoxia in exposed human diabetic peripheral nerves are described. However,these studies were carried out in patients with longstanding disease [1,2]. Theriault et al. [3] did not identify declines in blood flow of the human sural nerve of diabetic subjects, whereas patients with more severe axon loss tended to have higher rates of flow; not ‘shunt’, since the approach specifically emphasized endoneurial measures. In animal models, only some laboratories have linked declines in nerve blood flow with experimental neuropathy. Several technical factors including the type of measurement, near nerve temperature control, duration of diabetes may have contributed to these discrepant

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findings, summarized previously [4]. In our own laboratory, work over two decades failed to confirm any relationship between nerve blood flow and experimental polyneuropathy in experiments carried out using a variety of models, experimentalists, and blood flow measurement approaches. A number of investigations linking improvement in experimental neuropathy with interventions that increase nerve blood flow are also reported but most have been associations only and have had limited endpoints. Since a wide range of approaches all reporting this form of success has been described, the linkage has raised skepticism. Along these lines, as far back has 1992, PK Thomas entitled a review “Diabetic neuropathy: models, mechanisms, and mayhem” [5]. Microangiopathy, or alterations in the structure and function of the microvascular supply of the peripheral nerve and ganglia (vasa nervorum), likely emerge in parallel with direct neuronal changes but are likely not causative. Microangiopathy renders vasa nervorum, the vascular supply of the peripheral nerve, more sensitive to vasoconstrictors, such as endothelin or norepinephrine [6]. Moreover, diabetes dampens rises in nerve blood flow (hyperemia) following nerve trunk injury [7]. However, microvascular disease fails to explain the cascade of associated molecular changes associated with diabetic polyneuropathy [8]. For example, axotomy is associated with rises in growth molecules such as Beta III tubulin and GAP43, whereas both decline in chronic diabetes [9,10]. The changes of neuronal gene output in diabetes indicate a degenerative rather than axonal injury response, discussed next.

2. Alterations in the molecular phenotype The spectrum of molecular alterations in diabetic neurons has widened and depends on the model chosen and its duration. For example, rats with a type 1 model of diabetes induced by streptozotocin (STZ) amd maintained for 12 months had declines in their mRNA content of all three subunits of the neurofilament polymer, ˇIII tubulin, Trk receptors for neurotrophins and GAP43 [9,10]. The decline in neurofilament subunit mRNA levels, also seen in 10 month type 1 BB/Wor rats [11], correlated with loss of ultrastructurally imaged neurofilaments in axons and rises in Ckd5, p-GSK-3ˇ, SAPK/JNK, and p42/44, kinases that phosphorylate NfH and NfM. Increased phosphorylation may influence their spacing and longevity [12,13]. The gradual and eventual loss of key structural proteins also correlates with axon atrophy, a feature of longstanding experimental diabetes. Surprisingly; however, mice that completely lack neurofilament proteins in their axons, an interesting phenotype identified by Eyer and colleagues, nonetheless develop polyneuropathy, and it may be accelerated [14]. Thus, it is unlikely that subtle changes in neurofilament account for diabetic polyneuropathy. Neuropeptides may be altered in diabetic sensory neurons and their terminals including ˛ and ˇCGRP, SP or PACAP [9] [15–17]. After axotomy injury in diabetic rats, VIP, galanin, and CCK failed to rise. Specific changes in ion channel and function include changes in sodium channels or their subunits, P2X2 and P2X3 receptors, TrpV channels, HCN channels, and others. Their expression and activity may relate to the development of pain, particularly in early neuropathy before there is loss of afferents. Unlike the declines in many mRNAs of chronic diabetes, there are rises in HSP27, a pro-survival molecular chaperone protein [9]. Overexpression of human HSP27 enhanced peripheral nerve regeneration in nondiabetic mice and in diabetic mice prevented loss of footpad thermal sensation, mechanical allodynia, epidermal axon loss, and sensory conduction changes [18,19]. Diabetic neurons upregulate apotosis and ‘stress’ related molecules. Actual neuronal loss, reported in some controversial early and short term models, is likely not a feature [20]. For

example, one year old diabetic rats have normal sensory neuron numbers as assessed by unbiased three dimensional counts [21]. Neurons did not develop TUNEL labeling, an index of apoptosis although they did express activated caspase-3. Its expression was prominent in proximal axon segments, perikaryal cytoplasm, and occasionally in nuclei. Bcl-2 expression, an anti-apoptotic molecule, and cytochrome c were not altered in neurons. Type 1 diabetic BB/Wor rats had upregulation of cleaved capsase-3, Bcl-xl, and Bax without neuron loss [22]. Overall these findings support the idea that diabetic sensory neurons respond to ‘stress’ by upregulating apoptosis related machinery, but do not necessarily succumb. While cleaved caspase-3 was increased in the cytoplasm and nuclei of diabetic DRG neurons, we now recognize that its expression does not obligate cellular ‘execution’ [23–25]. NF␬B is a complex transcription factor considered to be a ‘stress’ detecting system [26–28]. NF␬B is associated with both damaging and protective signals in neurons [29]. In diabetes, it may promote neurodegeneration through inappropriate upregulation [28,29] perhaps related to its impaired ability to transcribe [30]. PARP (poly(ADP-ribose) polymerase), a DNA repair molecule, was altered in rat 12 month DRG sensory neurons [21]. PARP expression spilled over from its normal nuclear localization to the cytoplasm and proximal axon segments. Proximal axon segments undergo dystrophic changes in human and experimental DPN [31,32] and colocalize with sites of mitochondrial accumulation, oxidative stress, and activated caspase-3 [33]. Treatment of diabetic mice with pharmacological PARP inhibitors and mice lacking PARP are protected from the changes of DPN but the site of protection is uncertain [34,35]. AGEs (advanced glycosylation endproducts) result from nonenzymatic reactions (glycation) of glucose [36,37] and are permanently deposited in tissues and bind to receptors, most notably among them RAGE (receptor for AGEs) [Fig. 1A]. Whereas, type 1 diabetic mice lacking RAGE appear protected from polyneuropathy [38,39] (de la Hoz et al., unpublished data), the ZDF model of type 2 diabetes in rats had rises in DRG mRNA levels of RAGE but normal protein levels [40]. RAGE-AGE signaling may also offer neuroprotection [41]. ‘Nitrergic stress’ from excessive NO production may contribute toward neuron damage and death in diabetes, particularly as it combines with the superoxide radical (02 −) to form peroxynitrite (ONOO−). Peroxynitrite nitrates protein tyrosines [42] and activates PARP. Although, nNOS (neuronal) levels rise in DRG sensory neurons after axotomy [43], NOS subtype expression was not altered in long term DRG neurons [44] but there was a low grade rise in overall NOS activity and excessive nitrotyrosine, a footprint of NO presence in neuron perikarya and proximal axonal segments. Mice lacking iNOS (inducible), but not nNOS were protected from experimental DPN [45,45]. A peroxynitrite decomposition catalyst also conferred protection [46] [Fig. 2]. In summary, the repertoire of molecular changes in sensory neurons exposed to diabetes is unique and several features indicate a response to cellular ‘stress’.

3. Insulin signals neurons That insulin might possess actions beyond glucose regulation has been recognized for some time. For example, in 1972 Frazier, and colleagues [47] proposed that insulin had trophic properties resembling nerve growth factor (NGF) based on structural similarities. Insulin receptors (IRs) and insulin receptor substrate (IRS1,2), scaffolds for intracellular insulin signaling are widely expressed by peripheral neurons [Fig. 1B and C]. In the PNS, insulin facilitates nerve regeneration; whether, applied as a systemic injection or administered intrathecally where it has the capacity to access

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Fig. 1. Selected expression of some key molecular players that impact diabetic sensory neurons. Expression is illustrated in dorsal root ganglia (DRG) of RAGE (A), the receptor for advanced glycation endproducts (AGEs), products of chronic hyperglycemia. Insulin receptors are expressed in the cytoplasm of DRG sensory neurons (B) and, adult sensory neurons in vitro and in their nuclei (C). Receptors for the gastric peptide GLP-1 (glucagon like peptide-1) are also expressed in adult DRG sensory neurons, shown colocalized with neurofilament (D). Bar = 50 ␮m (A–D). Images in Fig. 1c are reproduced, with permission from [74].

neurons in the DRG [48,49]. Exploiting insulin trophic pathways can also influence the development of neuropathic changes in diabetes. Low doses of insulin, insufficient to lower glucose levels, applied near the sciatic nerve unilaterally corrected electrophysiological abnormalities in diabetic rats, despite evidence for progressive neuropathy in the contralateral nerve treated with carrier alone [50]. Similarly low dose intrathecal insulin, also insufficient to alter diabetic hyperglycemia, reversed electrophysiological, and structural changes of diabetic neuropathy; improvements in motor and sensory conduction slowing, axon atrophy, and epidermal innervation were observed [51–53]. In a parallel experiment, sequestering endogenous spinal fluid insulin by administering an anti-insulin antibody intrathecally induced electrophysiological and structural changes in axons resembling those in diabetes [52]. There were rises in insulin receptor expression during both regeneration and in a type 1 model of diabetes [48]. In experimental type 2 diabetes using ZDF diabetic rats, mRNA levels of IRˇ and IRS-2 were elevated in DRG sensory neurons, also suggesting possible sensitization or compensation for abnormal insulin signalling. More recently, insulin has been administered intranasally, a strategy that allows it to access CSF and sensory neurons. Intranasal insulin has attenuated features of experimental diabetic neuropathy [54,55]. In

preliminary work, intranasal insulin improved CNS abnormalities in long term diabetic mice [56]. Insulin may also signal neuron terminals directly. In the skin of the mouse footpad, IRs were expressed in dermal afferent axons and in a subset of epidermal axons [57]. In separate type 1 and type 2 diabetic models respectively, small doses of insulin injected into the plantar skin of the hindpaw induced a local unilateral rise in the density of epidermal axons, limited to the footpad exposed to insulin. Chen et al. applied topical insulin to the cornea of diabetic mice and demonstrated that the approach prevented axon loss in the sub-basal plexus, as detected using corneal confocal microscopy (CCM) [58], a technique sensitive to axon loss in human diabetes [59]. Kamiya et al. noted that 8 month diabetic type 1 insulinopenic BB/Wor had more severe molecular, functional, and morphometric abnormalities of nociceptive C-fibers than type 2 hyperinsulinemic diabetic BBZDR/Wor-rats of identical duration and exposure to hyperglycemia [60]. These authors have argued that the loss of insulin signaling accounts for a more severe polyneuropathy [61]. After they are ligated with insulin, IRs undergo autophosphorylation, exhibit tyrosine kinase activity and then signal through the IRS-1 and 2 docking protein pathways [62,63]. Downstream

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Fig. 2. A simplified schema identifying some of the changes in pathways and molecules important in the development of diabetic polyneuropathy.

the signals converge on the same transduction cascades utilized by growth factors [52,64–66]. These include PI3K’s p85 subunit, directly associated with IRS-1 and activation of pAkt, a survival and growth molecule [63,67–69] and MAPK [70]. Insulin also stimulates the synthesis of axonal structural proteins such as neurofilament, [71,10]. C-peptide, arising from proinsulin cleavage, may possess ‘insulinomimetic’ actions and in type 1 diabetes, it may reverse structural and functional abnormalities [72]. Our lab first described ‘neuronal insulin resistance’ involving DRG sensory neurons, initially in abstract form [73] later in detail [74], and confirmed by others [75]. The issue is important because many patients treated with insulin nonetheless develop polyneuropathy. Systemic insulin may not access neuronal perikarya in DRGs or nerve terminals in adequate doses to adequately signal neurons. Direct administration to neurons through intrathecal or intraplantar dosing overcomes this limitation. In addition, exposure of neurons to intermittent systemic doses given to a type 1 diabetic or high circulating levels in a type 2 diabetic, might be sufficient to cause neuronal insulin resistance. Since, polyneuropathy is now recognized in ‘prediabetic’ patients with metabolic syndrome alone, it is possible that high circulating insulin exposure might generate resistance, downregulation of neuronal growth transduction pathways and neuropathy. Adult sensory neurons treated with insulin in the nanomolar range have enhanced neurite outgrowth [76]. However, we noted that adult sensory neurons exposed to higher, micromolar doses of insulin continuosly or briefly or chronically exposed to picomolar doses lost their trophic response [74]. Mechanisms may include down-regulation of the insulin receptor or down-regulation of pAkt and pGSK-3ˇ. Both are associated with attenuated neuronal plasticity. Glucagon-like peptide (GLP-1) is an incretin hormone, a peptide secreted by intestinal L-cells in response to meal ingestion and its receptors expressed on sensory neurons mediate growth [77] [Fig. 1D]. Exendin-4, a GLP-1 agonist increased process outgrowth and attenuated features of experimental diabetic neuropathy independent of glycemia [78–80].

4. Regeneration and plasticity From the above discussion, we argue that diabetic polyneuropathy arises from the combination of a number of mechanisms. Their relative importance remains debatable. Not discussed here are the impacts of elevated polyol flux in neuronal function, or abnormalities of mitochondrial function. All may impact plasticity, the capacity of neurons to withstand varied insults and to respond to injury. Diabetes mellitus thus imposes a ‘double hit’ adding neurodegeneration to attenuated regeneration, with mechanisms that include microangiopathy of the local injury milieu, Schwann cell dysfunction and alterations in key growth molecules [7,81]. PTEN (phosphatase and tensin homolog deleted on chromosome ten) is a tumour suppressor phosphatase that dephosphorylates phosphatidylinositol 3,4, and 5 triphosphate (PIP3), an intermediary in the growth factor receptor-PI3K p85-pAkt growth pathway. By suppressing pAkt signaling, PTEN suppresses growth. PTEN, widely expressed in sensory neurons, is prominent in IB-4 nonpeptidergic neurons that exhibit restrained growth properties [82,83]. PTEN inhibition or knockdown enhances the outgrowth of adult sensory neurons in vitro and in vivo. PTEN mRNA and protein expression were increased in DRG sensory neurons of mice with experimental diabetes [84]. The findings indicated that diabetes had upregulated a known regenerative ‘brake’, an unexpected finding, and one that might complement other explanations of diabetic regenerative failure. To test whether PTEN knockdown might support in vivo nerve regrowth, we administered PTEN siRNA to regenerating diabetic axons at a nerve crush site. Through retrograde transport, the siRNA had the remarkable capability to knockdown PTEN in both the injured sciatic nerve and the ipsilateral DRG. Peripheral siRNA application improved recovery of compound muscle action potential amplitudes (CMAPs), motor and sensory conduction velocity of maturing regenerating axons, mechanical sensitivity, numbers and calibers of regenerating myelinated axons, and epidermal axon reinnervation. Several additional regenerative ‘brakes’ that are intrinsically expressed in sensory neurons have not been studied in diabetic models such as RhoA-ROK, [85–87]. Inhibition of ROK using

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HA-1077 increased neurite outgrowth in vitro and elongation of axons from a transection in vivo. Rb1, the protein product of the retinoblastoma gene is a recent addition to the list of regenerative roadblocks expressed in peripheral neurons. Its knockdown enhances the outgrowth of adult primary sensory neurons in vitro and in vivo [88]. Mice had an improvement in their recovery of mechanical sensitivity, hindpaw grip strength, and regenerating sensory axon conduction velocity.

[17]

[18]

[19]

5. Conclusions

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Polyneuropathy is more complex than a ‘microvascular complication’ of diabetes and involves a repertoire of molecular alterations and abnormalities of insulin signaling that accompany neurodegeneration. Proteins and pathways involved in neuronal plasticity have a role in axon regrowth following diabetic damage.

[21] [22]

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Acknowledgements The author acknowledges the dedicated work of members of his laboratory in generating experimental data quoted in this review including Drs. Bhagat Singh, Anand Krishnan, Kim Christie, Lawrence Korngut, Chu Cheng, and Ms. Michelle Kan. The laboratory has been supported by the Canadian Institutes of Health Research (184584), Canadian Diabetes Association (OG-3-123669), Juvenile Diabetes Foundation, Alberta Heritage Foundation for Medical Research, Alberta Innovates-Health Solutions, and NIH (Diabetes Complications Consortium 12GHSU172).

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