Essay: Diabetes mellitus

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  • Diabetes mellitus
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Diabetes mellitus is a group of metabolic diseases characterized by chronic hyperglycemia that result from defects in the body\’s ability to produce and/or use insulin. Insulin is produced by the pancreatic β-cells and helps glucose from the bloodstream entering into the cells in order to be converted into energy. In uncontrolled diabetes, there is an inadequate supply of glucose to the cells and a build-up of glucose in the bloodstream. Diabetes incidence is increasing drastically and it is estimated that 552 million people will have diabetes in 2030 (Whiting et al., 2011).
Axonal transport is an essential process in neurons allowing efficient communication between the cell body and synapse. Axonal transport keeps axons and nerve terminals supplied with proteins, lipids and mitochondria, and clears recycled or misfolded proteins. Moreover, axonal transport is crucial for intracellular neural transmission and allows neurons responding effectively to trophic signals or stress insults (Perlson et al., 2010).
Impairment of axonal transport has been emerging as a common factor in several neurodegenerative disorders (Millecamps and Julien, 2013) and is also known to be affected in experimental models of diabetes (McLean, 1997). Here, we review the current state of knowledge about axonal transport impairment in diabetes, focusing on the various components and mechanisms that control such transport both at peripheral (PNS) and central nervous systems (CNS).
Diabetes mellitus and axonal transport
Role of axonal cytoskeleton
Recent studies have revealed that defects of the cytoskeleton and axonal transport are associated with several types of peripheral neuropathy and central neurological diseases (Cheng et al., 2011). Axonal transport occurs along the cellular cytoskeleton which provides not only structural support to the neuron, but also allows cells growing and changing in size and shape over time. There are three major components of the neuronal cytoskeleton, namely microtubules, intermediate filaments and microfilaments, which can be affected by diabetes.
Microtubules are the main elements responsible for the polarity of the axon. The α-tubulin side of the microtubule defines the minus end, which is located closer to the cell body, whereas the β-tubulin side defines the plus end, which is located closer to the synapse. This orientation not only gives polarity to the microtubule but also to the axon (Conde and Caceres, 2009). The polarity of the microtubule directs motors of axonal transport to undergo anterograde (toward the plus end) or retrograde (toward the minus end) transport (Figure 1). Conversely, in dendrites, microtubules are found in mixed polarity. Microtubules are essential for axonal transport and any changes in their components may lead to impaired axonal transport under diabetes.
Figure 1. Fast axonal transport. In axons, microtubules are oriented with the plus ends pointing toward the synapse and the minus ends facing the cell body. Most molecular motors of the kinesin family unidirectionally move toward the microtubule plus end, mediating transport toward the synapse (anterograde). In the opposite direction, the molecular motor cytoplasmic dynein moves toward the microtubule minus end and mediates transport of most cargoes toward the cell body (retrograde) Anterograde transport provides newly synthesized components essential for neuronal function and maintenance, including many small vesicles as well as mitochondria and dense-core vesicles. Retrograde transport carries mainly mitochondria and vesicular cargoes such as signaling endosomes.
Diabetic neuropathy involves an impairment of axonal transport, a reduction in axon calibre and a reduced capacity for nerve regeneration, which are dependent on the integrity of the axonal cytoskeleton for proper nerve function. Reduced synthesis of tubulin mRNA and an elevated non-enzymatic glycation of peripheral nerve tubulin was described. Particularly, it was demonstrated that after eight weeks of diabetes T alpha 1 alpha-tubulin mRNA is reduced in streptozotocin (STZ)-induced diabetic rats (Mohiuddin et al., 1995), and an increase in tubulin glycation was detected in the sciatic nerve of STZ-induced diabetic rats after two weeks of diabetes duration, which may contribute to axonal transport abnormalities by impairment of microtubule function (Cullum et al., 1991, McLean et al., 1992). Brain tubulin is also glycated in early experimental diabetes, consequently affecting its ability to form microtubules (Williams et al., 1982). Nevertheless, this finding was not replicated in subsequent studies, where it was demonstrated that glycation was not associated with inhibition of microtubule assembly (Cullum et al., 1991, Eaker et al., 1991). In the sural nerves of diabetic patients it was detected an increase in advanced glycation end products accumulation in cytoskeletal proteins (Ryle and Donaghy, 1995), suggesting that axonal cytoskeletal proteins glycation may play a role in axonal degeneration polyneuropathy in diabetes.
Tau is a microtubule associated protein, whose main function is to modulate the stability of axonal microtubules. Excessive tau phosphorylation is known to disrupt its binding to microtubules altering molecular trafficking, which ultimately may lead to synaptic dysfunction (Ebneth et al., 1998, Obulesu et al., 2011). Diabetes induces hyperphosphorylation of tau in the brain, as for example in the hippocampus (Qu et al., 2011), and proteolytic tau cleavage (Kim et al., 2009), both of which are associated with Alzheimer\’s disease (Iqbal et al., 2009). Tau modification can be induced by hyperglycemia and insulin dysfunction, which may contribute to the increased incidence of Alzheimer\’s disease in diabetic patients (Kim et al., 2009). Tau modification impairs axonal transport through microtubule network disruption and axonal highways blocking, ultimately giving rise to compromised synapse function and consequent neurodegeneration (Falzone et al., 2009, Falzone et al., 2010). In Alzheimer\’s disease, glycation of tau may play a role in stabilizing paired helical filaments aggregation leading to tangle formation (Ko et al., 1999). It is likely that similar processes may be occuring under diabetes.
Neurofilaments (NF) are the intermediate filaments (10 nm) found specifically in neurons that assemble from three subunits based upon the apparent molecular weight: NF-L (70 kDa), NF-M (150 kDa), and NF-H (200 kDa) (Sharp et al., 1982). Once assembled, these filaments lack overall polarity, and do not undergo the remodeling characteristic of actin and microtubules. Neurofilaments serve primarily to provide structural stabilization to the cell, and to regulate the radial growth of axons. Aggregation of neurofilaments is a common marker of neurodegenerative diseases (Liu et al., 2011). Abnormal NF expression, processing, and structure may contribute to diabetic neuropathy, since reduced synthesis of NF proteins or formation of incorrectly associated NFs could severely disrupt the axonal cytoskeleton (Fernyhough and Schmidt, 2002).
Neurofilament mRNAs are selectively reduced in diabetic rats and alterations on post-translational modification of NF proteins have been detected. Reduced myelinated fiber size is correlated with loss of axonal NFs in peripheral nerves of STZ-induced diabetic rats (Medori et al., 1985, Yagihashi et al., 1990), and the levels of mRNAs encoding for NF-L and NF-H are reduced in the same animal model of diabetes (Mohiuddin et al., 1995). Altered expression of several isoforms of NF-associated protein kinases may also contribute to diabetes-induced changes (McLean, 1997). Specific phosphorylation of C-terminal domains of the large NF subunits has been implicated in axonal transport. Several kinases are involved in regulating NF phosphorylation status, being NFs hyperphosphorylation a hallmark of several neurodegenerative diseases. Aberrant NF phosphorylation in sensory neurons of animal models of type 1 diabetes has been described (Fernyhough et al., 1999). Moreover, in the spinal cord of diabetic rats there is hyperphosphorylation of NF-H, accompanied by a reduced activity of the main NF-associated protein kinases that predominantly phosphorylate the C-terminal domain of NF-H (Pekiner and McLean, 1991). Additionally, upregulation of kinases like Cdk5, GSK-3β and p42/43 leads to increased phosphorylation of NFs in an animal model of type 1 diabetes. Specifically, increasing activity of GSK-3β correlates with increased phosphorylation of NF-H, while decreasing activity of Cdk5 is associated with reduced phosphorylation of NF-M, which may result in progressive deficits of axonal function, maturation and size (Kamiya et al., 2009).
Microfilaments (or actin filaments) are the thinnest filaments of the cytoskeleton, having 6 nm in diameter. Actin cytoskeleton provides both dynamics and stability. Actin monomers assemble into a flexible helical polymer with two distinct ends, one fast growing and one slower growing. In the cell, actin filaments are often bundled into networks and can be stabilized by interacting proteins. Actin plays a role in the formation of new spines as well as in stabilizing spine volume increase (Dillon and Goda, 2005), and the dynamics of actin leads to the formation of new synapses as well as increased cell communication. The actin cytoskeleton controls several cellular processes. In animal models of diabetes there is an impairment of slow axonal transport of cytoskeletal elements in both slow component a: containing tubulin and NF proteins; and slow component b: containing polypeptides such as actin (Vitadello et al., 1985, Medori et al., 1988, Macioce et al., 1989). Actin undergoes glycation in the brain of STZ-induced diabetic rats and the appearance of glycated actin is prevented by administration of insulin (Pekiner et al., 1993). Other study showed altered mobility of a component of brain actin that was apparently related to its glycation in an insulin-dependent manner (McLean et al., 1992).
More recently, it was investigated if the receptor for advanced glycation end-product (RAGE) plays a role in axonal transport impairment via interaction with its cytoplasmic domain binding partner mDia1, which is involved in actin structure modifications. Slow axonal transport in the peripheral nerves is indeed affected by diabetes, but in a RAGE-independent manner (Juranek et al., 2013). Moreover, mDia1 axonal transport is impaired, suggesting that diabetes-induced changes affecting actin binding proteins occur early in the course of the disease (Juranek et al., 2013), and forward the hypothesis that mDia1 axonal transport impairment might be tightly correlated with the level of diabetes-evoked actin glycation (Pekiner et al., 1993).
Taken together, these observations in experimental diabetes indicate that post-translational modifications, as well as altered expression of cytoskeletal proteins (tubulin, neurofilament and actin), may interfere with cytoskeletal assembly, contributing to altered axonal transport and subsequent nerve dysfunction.
Motor proteins and diabetes
Intracellular transport is powered by three sets of molecular motors: myosins, kinesins and dyneins. Myosins move on microfilaments and are thought to be responsible for short range transport, whereas kinesin and dynein proteins use microtubules as tracks for long distance transport and are capable of recognizing the microtubule polarity (Langford, 1995). A number of studies have shown that most kinesin-family motors move towards the plus-end of the microtubules that are usually used to deliver cargos towards the cell periphery. In contrast, dynein moves in the opposite direction for transport toward the cell center (Hirokawa and Takemura, 2005). Kinesins, dyneins and myosins have the so-called “motor domains” that move along the microtubules or actin filaments in a specific direction by using the energy derived from ATP hydrolysis.
Kinesins are microtubule based anterograde intracellular transport motors (Figure 1). Anterograde transport provides newly synthesized components essential for neuronal function and maintenance. Ultrastructural studies have demonstrated that the material moving in fast anterograde transport includes many small vesicles and tubulo-vesicular structures as well as mitochondria and dense-core vesicles (Tsukita and Ishikawa, 1980). Material in fast anterograde transport is needed for the supply and turnover of intracellular membrane compartments (i.e. mitochondria and endoplasmic reticulum) and for the supply of proteins required for the maintenance of axonal metabolism. Conventional kinesins usually form a protein dimer of two identical heavy chains and each of them binds to a kinesin light chain. The heavy chain contains a highly conserved globular head called motor domain, which includes a microtubule-binding site and an ATP-binding/hydrolysis site, a short, flexible neck linker, a stalk domain, which has a long, central coiled-coil region for dimerization and a tail domain for light chain and cargo binding (Verhey et al., 2011). The two heads of kinesin move in a hand-over-hand mechanism along the microtubule. This movement is highly processive, once bound to the microtubule the motor will move over long distances prior to detaching, allowing a very efficient transport of cargo over the long distances of the axon (Vale et al., 1996).
In contrast to anterograde axonal transport, which takes advantage of several different kinesin motor proteins, cytoplasmic dynein is the major motor protein driving retrograde transport (Figure 1). Cytoplasmic dynein is a multi-subunit complex that contains two heavy chains that are associated with intermediate chains, light intermediate chains, and light chains. The heavy chains harbor ATPase activity and bind microtubules, whereas the other chains are involved in cargo binding and binding to dynactin. The overall bias is toward minus end-directed motility, but the ability of dynein to change directions may allow the motor to avoid obstacles encountered during active transport along the axon. Studies on dynein have shown that the dynein motor wanders across the surface of the microtubule, and takes frequent backward steps (Wang et al., 1995). Also, individual fluorescently labeled dynein-dynactin complexes exhibit bidirectional motility towards both the plus and minus ends of microtubules, reflecting the flexibility of the dynein structure that leads to an enhanced ability to navigate around obstacles in the cell. (Ross et al., 2006).
Changes in motor protein content and distribution have been reported under experimental diabetes. In STZ-induced diabetic rats, KIF5B content is increased in the sciatic nerve, as well as KIF5B and SYD (scaffold protein which interacts with kinesin) mRNA levels in spinal cord sensory and motor neurons (Rahmati et al., 2015). At CNS level, diabetes decreases the content of the kinesin KIF1A in the retina. Analyzing its immunoreactivity in all retinal layers it was demonstrated that with the exception of the photoreceptor layer, its immunoreactivity is decreased in STZ-induced diabetic rats after 8 weeks of diabetes. Changes in kinesin KIF5B immunoreactivity were also detected by immunohistochemistry in the retina at 8 weeks of diabetes, being increased at the photoreceptor layer and outer nuclear layer, and decreased in the inner plexiform layer and ganglion cell layer, whereas no significant changes were detected in dynein immunoreactivity in the retina (Baptista et al., 2014).
In cones lacking KIF3A (kinesin present in photoreceptors), changes in photoreceptor properties occur, resulting in progressive cone degeneration and absence of a photopic electroretinogram (Avasthi et al., 2009). Additionally, rod photoreceptors lacking KIF3A degenerate rapidly between 2 and 4 weeks (Avasthi et al., 2009). In a model retinal neurotoxicity induced by N-methyl-D-aspartate occurs an early upregulation of KIF5B levels in the retina, whereas a significant downregulation occurs in the optic nerve, suggesting that a depletion of KIF5B precedes axonal degeneration of the optic nerve (Kuribayashi et al., 2010). These studies highlight the importance of proper kinesin function in the visual pathway. Therefore, it is expected that any imbalance in their content due to diabetes might have an impact in axonal transport in the retina.
In the hippocampus of STZ-induced diabetic rats, increased expression and immunoreactivity of KIF1A and KIF5B was detected, but no alterations in dynein were found (Baptista et al., 2013). In hippocampal cultures incubated with high glucose, mimicking hyperglycemic conditions, and specifically in the axons of hippocampal neurons, there is an increased number of fluorescent accumulations of KIF1A and synaptotagmin-1, and decreased KIF5B, SNAP-25 and synaptophysin immunoreactivity (Baptista et al., 2013).
Together, the observations of alterations in kinesin motor proteins in the retina and hippocampus triggered by diabetes, suggest that anterograde axonal transport mediated by these kinesins may be impaired in retinal and hippocampal neurons, and may therefore underlie changes already detected in synaptic protein levels in nerve terminals induced by diabetes (Gaspar et al., 2010a, Baptista et al., 2011, Baptista et al., 2013).
Axonal transport impairments under diabetes in the PNS
Neurons are highly polarized cells, making them particularly dependent on active intracellular transport. Inhibition of axonal transport rapidly leads to loss of function in the distal axon and to “dying back” axonal degeneration. Any impairment of axonal transport is considered an early and possibly causative event in many neurodegenerative diseases.
In experimental diabetes, several studies have demonstrated that axonal transport in PNS is affected by this disease. One of the earliest structural changes detected was a decrease in the calibre of myelinated axons in the rat, suggesting that an abnormality in the axonal transport of proteins is possibly the very first change to appear, leading to the development of peripheral nerve abnormalities (Jakobsen et al., 1980). As previously mentioned, several components of the cytoskeleton are affected in diabetes, and the transport of slow components a and components b is impaired (Macioce et al., 1989, Tomlinson et al., 1990). Reduced rate of slow axonal transport of proteins occurs in motor fibres of the sciatic nerve of STZ-induced diabetic rats (Mayer et al., 1984, Vitadello et al., 1985, Medori et al., 1988, Larsen and Sidenius, 1989). These alterations were correlated with reductions in axonal transport of NF proteins, tubulins and actin. NF protein transport has been shown to be affected at an early stage (Larsen and Sidenius, 1989), which could lead to changes in the speed of nerve conduction, since NFs preserve axonal calibre (Cleveland et al., 1991). Also, a reduction in the slow axonal transport of cytoskeletal proteins may therefore lead to proximal swelling and distal deterioration of axons in diabetic nerve (Jakobsen, 1976, Medori et al., 1985, Bomers et al., 1996) (Figure 2).
Figure 2. Morphologic changes occurring in diabetic axons. Diabetic axons present an increased number of microtubules and neurofilaments proximally, as well as increased cross-sectional area near the cell body. On the other hand, axonal cross-sectional area near the synapse is decreased, and the total number of microtubules and neurofilaments also decrease distally. As a consequence of cytoskeleton and nerve terminals derangements, motor proteins fail to bind microtubule end, contributing for the impairment of axonal transport.
Abnormal synthesis or post-translational modifications of the axonal cytoskeleton can not only influence axonal growth and caliber, but also impair nerve regeneration (Longo et al., 1986, Ekstrom and Tomlinson, 1989, Pekiner et al., 1996). Changes on retrograde signaling from the site of injury to the cell body were described in experimental diabetes (Fink et al., 1987, Logan and McLean, 1988), and the delivery of growth factors are also known to be affected (Jakobsen et al., 1981, Fernyhough et al., 1995).
It has been reported that experimental diabetes causes a reduction in the axonal transport of isotopically labelled unidentified proteins and glycoproteins in several types of peripheral nerves (Jakobsen and Sidenius, 1979, Sidenius and Jakobsen, 1979, Jakobsen and Sidenius, 1980, Sidenius and Jakobsen, 1980, Meiri and McLean, 1982). Studies regarding axonal transport rates in sciatic nerve of STZ-induced diabetic rats suggest that the primary event in the development of neurological abnormalities in diabetes is an impairment of the retrograde axonal transport (Jakobsen and Sidenius, 1979, Sidenius and Jakobsen, 1981), secondarily leading to the impairment of the anterograde transport of structural proteins (Jakobsen and Sidenius, 1980). Fast axonal transport is impaired at sciatic nerve and the changes found in protein and glycoconjugates synthesis and transport can be related to the early reduction in axon calibre and conduction velocity in peripheral nerve of STZ-induced diabetic rat (Sidenius and Jakobsen, 1979). Regarding retrograde axonal transport, diabetes also induces a decrease in peripheral axon organelle speed in sciatic nerve and dorsal and ventral nerve roots at 1 month of diabetes (Abbate et al., 1991). Moreover, axonal transport of receptors in the sciatic nerves of STZ-induced diabetic rats is affected, suggesting that impaired axonal transport of receptors may explain part of the neurological disturbances observed in diabetic patients (Laduron and Janssen, 1986). The reduction in fast transport rate in the sciatic nerve of diabetic rats was eliminated by maintenance of normal blood glucose levels with insulin administration (Meiri and McLean, 1982). Insulin treatment is able to prevent the slowing in transport occurring in diabetic rats and reverse an already slowed transport velocity (Sidenius and Jakobsen, 1982). In short-term experimental diabetes, defects in both anterograde and retrograde axonal transport of 6-phosphofructokinase activity were also detected, which were prevented by intensive insulin treatment (Willars et al., 1987). Moreover, decreased tubulin and actin transport rates are counteracted by ganglioside treatment suggesting a pharmacological effect that could be correlated with molecular interactions between integral membrane glycolipids and cytoskeletal elements (Figliomeni et al., 1992).
More recently, it was demonstrated that hyperglycemia impairs axonal transport in olfactory receptor neurons in mice. Increased oxidative stress in STZ-induced wild type diabetic mice activates the p38 MAPK pathway in association with phosphorylation of tau, attenuating axonal transport rates in the olfactory system. In STZ-induced superoxide dismutase-overexpressing mice, in which superoxide levels are reduced, these deficits are reversed (Sharma et al., 2010).
Diabetes also induces changes in the axonal transport of distal trophic factors to the soma. Increasing evidence shows that retrograde transport impairments of nerve growth factor (NGF) accounts for some functional deficits occurring in experimental diabetic neuropathy. Expression deficits in both NGF and its high-affinity receptor, trkA, were described in animal models of diabetes, leading to decreased retrograde axonal transport of NGF and decreased support of NGF-dependent sensory neurons, concomitant with decreased expression of neuropeptides expressed by these neurons, such as substance P and calcitonin gene-related peptide (Tomlinson et al., 1997). NGF and neurotrophin-3 (NT-3) retrograde transport was also found to be significantly reduced in the cervical vagus nerve in diabetic animals (Lee et al., 2001). In the sciatic nerve of STZ-induced diabetic rats, a clear reduction in the retrograde transport of NGF is detected (Hellweg et al., 1994). In STZ-induced diabetic rats the relative levels of phosphorylated (activated) c-Jun N-terminal kinase (JNK) and p38 retrogradly transported in sciatic nerve are increased compared with age-matched controls. Treatment of diabetic animals with NT-3 prevents the activation of JNK and p38, suggesting that JNK and p38 axonally transported mediate the transfer of diabetes-related stress signals, possibly triggered by loss of neurotrophic support, from the periphery to the sensory neuron soma (Middlemas et al., 2003). Moreover, it was also proposed that impaired PI3 kinase/Akt signal pathway may partly account for the reduced retrograde axonal transport of neurotrophins in the vagus nerve of STZ-induced diabetic rats (Cai and Helke, 2003).
Axonal transport impairments under diabetes in the CNS
Although most studies regarding changes in axonal transport triggered by diabetes have been focused in changes occurring at peripheral nervous system, evidences from studies in the optic nerve, spinal cord and brain also indicate that axonal transport is impaired at the central nervous system.
Analysis of slow axonal transport in the optic nerve of STZ-induced diabetic rats (4-6 weeks diabetes duration) and BioBreeding rats with spontaneous diabetes (2.5-3.5 months duration), showed impaired transport of NF subunits, tubulin and actin (Medori et al., 1985, Medori et al., 1988), further evidencing that cytoskeleton proteins transport is altered under diabetes. Moreover, a delay in the transport of 60, 52 and 30 kDa polypeptides, likely to be the glycolytic enzymes aldolase, neuron-specific enolase and pyruvate kinase, respectively, was also detected in both animal models of diabetes (Medori et al., 1988).
In the brain of STZ-induced diabetic rats, altered electrophoretic mobility of actin from a cytoskeletal protein preparation was detected, suggesting the presence of a product of nonenzymatic glycation. Furthermore, diabetes also leads to an increase in the phosphorylation of spinal cord neurofilament proteins. These post-translational modifications of neuronal cytoskeletal proteins in the spinal cords and brains of diabetic rats may contribute, as already referred, to the impairment of axonal transport and subsequent nerve dysfunction in experimental diabetes (McLean et al., 1992).
In the retina of diabetic rabbits, a reduction in slow axonal transport was observed, with a concomitant reduction in fast axonal transport and protein synthesis, whereas protein degradation remains unchanged (Chihara, 1981, Chihara et al., 1982). These evidences suggest that changes in axonal transport in the optic nerve may be a reflection of reduced protein synthesis in retinal ganglion cells (RGCs) (Tsukada and Chihara, 1986). Studies using fluoro-gold, a neuronal retrograde tracer, demonstrated a decreased accumulation of this tracer in RGCs of STZ-induced diabetic rats, thus suggesting that retrograde axonal transport from the dorsal lateral geniculate nucleus in the brain to the RGCs in the retina is impaired (Zhang et al., 1998, Zhang et al., 2000). Nevertheless, the accumulation of fluoro-gold in RGCs of OLETF rats, an animal model of type II diabetes with obesity, is not significantly decreased compared with control rats, suggesting that, the impairment of retrograde axonal transport in RGCs is higher in type 1 than in type 2 diabetic rats (Zhang et al., 1998). Changes in polyol pathway may play a role in the progressive impairment of retrograde axonal transport in the optic nerve of STZ-induced diabetic rats, suggesting that it may be a consequence of metabolic changes associated with diabetes (Ino-Ue et al., 2000). Besides changes in retrograde transport, more recently, it was found a deficit in the anterograde transport from the retina to the superior colliculus after induction of diabetes with STZ (Fernandez et al., 2012a, b).
In summary, potential changes in motor protein content and distribution previously described in the retina (Baptista et al., 2014), might underlie some changes already detected in axonal transport in the retina and visual pathway under diabetic conditions (Zhang et al., 2000, Fernandez et al., 2012a).
Mitochondria axonal transport deficits under diabetes
Since neurons are highly polarized cells, with long axons constituting a major challenge to the movement of proteins, vesicles, and organelles between cell bodies and presynaptic sites, axonal transport motor proteins require ATP demands, therefore implying the localization of functional mitochondria along the axons. The supply of appropriate levels of ATP is mainly produced by mitochondria via oxidative phosphorylation. The majority of mitochondria are produced in the cell body and transported along axonal microtubules by protein motors to reach areas with high ATP and calcium buffering requirements (Lin and Sheng, 2015). Distal cellular compartments such as synapses depend upon the efficient delivery of mitochondria through active transport to provide local sources with ATP. Generally, kinesin motors drive anterograde mitochondrial transport, while dyneins are responsible for retrograde transport. Nevertheless, single mitochondrion rarely move in only one direction (Lin and Sheng, 2015). Their transport along microtubules typically involves pauses of short and long duration and abrupt changes in direction, which suggests that individual mitochondrion are simultaneously coupled to kinesins, dyneins, and anchoring machinery whose actions compete or oppose one another (Figure 3).
Figure 3. Axonal mitochondrial transport. In neurons, mitochondria can be observed to undergo dynamic, bidirectional transport along neuronal axons, changing direction frequently, pausing or switching to persistent docking. These complex mitochondrial mobility patterns are a result of mitochondrial coupling to anterograde and retrograde motor proteins.
Averaging the bidirectional and saltatory components yields a net mitochondrial velocity that falls between fast moving vesicles and slow-moving cytoskeletal proteins: 0.3-2.0 μm/s (Cai et al., 2011). Mobile mitochondria can become stationary or pause in regions that have a high metabolic demand and can move again rapidly in response to physiological changes. Defects in mitochondrial transport are implicated in the pathogenesis of several major neurological disorders (Sheng and Cai, 2012).
KIF5 motors are responsible for axonal transport of mitochondria. In KIF5A-/- neurons, the velocity of mitochondrial transport is reduced both in anterograde and retrograde direction (Karle et al., 2012). Decreased number of mitochondria in axons will likely decrease ATP supply to molecular motors leading to decreased anterograde and retrograde movement of both mitochondria and vesicles (De Vos et al., 2008). Growing evidence suggests that mitochondrial dysfunction play a significant role in neurodegenerative diseases like Huntington\’s disease, Alzheimer\’s disease and amyotrophic lateral sclerosis (Brownlees et al., 2002, Stamer et al., 2002, Zhao et al., 2010, Reddy, 2011).
It was already described that diabetes-induced nerve degeneration is mediated by alterations in mitochondrial ultrastructure and physiology (Fernyhough et al., 2010). Moreover, alterations in mitochondrial trafficking has also been proposed as a mediator of neurodegeneration in diabetic nerves (Fernyhough et al., 2010), but as far as we are concerned, there are no studies addressing the effect of diabetes on mitochondria axonal transport rates in the CNS. In the axons of hippocampal neurons exposed to elevated glucose, we did not detect any significant change in the intensity of fluorescence, distribution or number of accumulations related with mitochondria, when compared to control (Baptista et al., 2013). Nevertheless, we cannot exclude the possibility that mitochondria in the axons of hippocampal neurons are being affected by diabetes since other factors, besides hyperglycemia, may also have an impact in mitochondria transport. Neuroinflammation also plays a role in diabetes complications and may lead to changes in axonal transport of mitochondria. It was reported that tumor necrosis factor (TNF) induces perinuclear clustering of mitochondria by impairing kinesin-mediated transport in L929 cells (De Vos et al., 1998).
Neuroinflammation and axonal transport impairments
Neuroinflammation may contribute to changes in axonal transport (Figure 4). Pro-inflammatory cytokines, such as TNF and interleukin-1β, are upregulated in the hippocampus of diabetic BB/Wor rats (Sima et al., 2009) and STZ-induced diabetic animals (Kuhad et al., 2009). TNF receptor-1 activation induces the activation of kinase pathways, resulting in hyperphosphorylation of kinesin light chain and inhibition of kinesin activity, evidencing direct regulation of kinesin-mediated organelle transport by extracellular stimuli via cytokine receptor signaling pathways (De Vos et al., 2000). Exposure of hippocampal neuronal cultures to TNF enhances the phosphorylation of JNK in neurites. TNF treatment induces the dissociation of KIF5B from tubulin in axons and inhibits axonal transport of mitochondria and synaptophysin by reducing the mobile fraction via JNK (Stagi et al., 2006). Nitric oxide released from activated microglia, inhibits axonal movement of synaptic vesicle precursors containing synaptophysin and synaptotagmin in hippocampal neurons, suggesting that disturbance of axonal transport by microglia-derived nitric oxide may therefore be responsible for axonal injury and synaptic dysfunction in brain diseases characterized by neuroinflammation (Stagi et al., 2005). Moreover, hydrogen peroxide, a common reactive oxygen species elevated during inflammation, also inhibits axonal transport in hippocampal cultures (Fang et al., 2012) (Figure 4). Further studies will be needed to determine if similar pathways may be active under diabetic conditions, therefore contributing for previously detected changes in axonal transport.
Figure 4. Microglia-driven inflammation and axonal transport impairment. In hippocampal cultures, nitric oxide (NO) released from activated microglia inhibits axonal movement of synaptic vesicles. Tumor necrosis factor (TNF) produced by activated glial cells in inflammatory or degenerative neurological diseases affects neurites by acting on the kinesin-tubulin complex and inhibiting axonal mitochondria and synaptophysin transport in hippocampal cultures. Moreover, hydrogen peroxide (H2O2), a common reactive oxygen species elevated during inflammation, also inhibits axonal transport.
Defects in axonal transport are early pathogenic events that may contribute for the development and progression of diabetic complications such as diabetic neuropathy, retinopathy and encephalopathy. Disruption of axonal transport can occur through several ways, including alterations in the cytoskeleton, molecular motors, cargoes (via inhibition of their attachment to motors), mitochondrial damage, and through microglia-mediated release of inflammatory mediators (via inhibition of motor attachment to microtubules). Nevertheless, little is known regarding the cellular and molecular mechanisms associated with axonal transport impairments under diabetes. Advances in the understanding of such mechanisms, may be crucial to develop novel neuroprotective strategies for diabetic complications.
Diabetes mellitus is the most common metabolic disorder in humans and it has been associated with several complications affecting peripheral and central nervous system. Proper axonal transport is crucial for neuronal maintenance and function. Alterations in axonal transport have been correlated with the progression of several neurodegenerative diseases. Inhibition of axonal transport leads to a rapid loss of function in the distal axon and to axonal degeneration. This might occur due to alterations in neuronal cytoskeleton and motor proteins, impaired ATP supply or neuroinflammatory processes which disable molecular motors to undertake transport along the axon.
Axonal transport is known to be affected in experimental models of diabetes. Most studies regarding nerve dysfunction in diabetes have been focused in changes detected at peripheral nervous system. Nevertheless, studies at central nervous system, namely in the retina and the hippocampus, suggest that axonal transport is impaired in diabetes and may play a role in diabetic retinopathy and diabetic encephalopathy. Alterations in various components of the transport machinery, changes in neuronal cytoskeleton and changes in intracellular transport of distal trophic signals to the soma have been described under diabetes. This article reviews currently state of knowledge about axonal transport defects in diabetes which might contribute to the progression of several diabetic complications.

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